Progress in Lipid Research 56 (2014) 67–91

Contents lists available at ScienceDirect

Progress in Lipid Research journal homepage: www.elsevier.com/locate/plipres

Review

Epoxy acetylenic lipids: Their analogues and derivatives Dmitry V. Kuklev, Valery M. Dembitsky ⇑ Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109, USA

a r t i c l e

i n f o

Article history: Received 21 May 2014 Accepted 22 August 2014 Available online 1 September 2014 Keywords: Acetylenic Polyynes Epoxides Lipids Fatty acids Alcohols

a b s t r a c t Currently, approximately 250 natural acetylenic epoxy structures are known. The present review describes research concerning biologically active epoxy acetylenic lipids and related compounds isolated from different sources. Intensive searches for new classes of pharmacologically potent agents produced by living organisms have resulted in the discovery of dozens of such compounds that possess high anticancer, cytotoxic, antibacterial, antiviral, and other activities. Acetylenic epoxides primarily belong to a class of molecules containing triple bond(s) and epoxy group(s) belonging to different lipid classes and/or other groups. This review emphasises natural and synthetic acetylenic epoxides and other related compounds as important sources of leads for drug discovery. The present review is the first article devoted to natural acetylenic epoxides. Ó 2014 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Fatty acids and glycerides . . . . . . . . . . . . . . . . . . . . . . . . Hydrocarbons, fatty alcohols, ketones, and derivatives . Furanoid acetylenic epoxides . . . . . . . . . . . . . . . . . . . . . Thiophene and dithiine epoxides . . . . . . . . . . . . . . . . . . Pyrane and macrocyclic epoxides . . . . . . . . . . . . . . . . . . Cyclohexanoid epoxides. . . . . . . . . . . . . . . . . . . . . . . . . . Spiroketal enol ether acetylenic epoxides. . . . . . . . . . . . Marine acetylenic halogenated epoxides . . . . . . . . . . . . Acetylenic Epoxy Sterols . . . . . . . . . . . . . . . . . . . . . . . . Vitamin D3 derivatives . . . . . . . . . . . . . . . . . . . . . . . . . Epoxy acetylenic carotenoids . . . . . . . . . . . . . . . . . . . . Enediyne antibiotics and derivatives . . . . . . . . . . . . . . Miscellaneous compounds. . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

⇑ Corresponding author. Present address: Institute of Drug Discovery, 8 Ha-Marpe Str., Har-Hotsvim, P.O. Box 45289, Jerusalem 91451, Israel. Tel./fax: +972 526 877 444. E-mail address: [email protected] (V.M. Dembitsky). http://dx.doi.org/10.1016/j.plipres.2014.08.001 0163-7827/Ó 2014 Elsevier Ltd. All rights reserved.

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . .

68 68 70 74 75 76 76 78 78 79 80 80 82 83 85 85 85

68

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

1. Introduction Natural acetylenic epoxides and related compounds display important biological activities, including antitumour, antibacterial, antimicrobial, antifungal, phototoxic, and other chemical and medicinal properties [1–7]. Compounds with acetylene, vinyl– acetyl, and acetylene–allene type bond systems were first discovered in the late 19th century in some mushrooms. Because molecules containing these fragments are most often unstable, their presence in natural objects appeared unusual. However, as experimental findings have been accumulated, it has become evident that compounds of this type that are characteristic of natural life are widely represented and perform important functions; in particular, these compounds act as antibiotic, anticancer, antibacterial and other agents. Acetylenic epoxides and related lipophilic metabolites that contain a [AC„CA] bond(s) and an ethylene oxide group (also called oxirane) are interesting metabolites and are found in both terrestrial and marine organisms [7,8]. Graphic chemical structures are shown in Fig. 1. In many cases, intensive chemical and pharmacological studies during the last five decades have led to the validation of traditional claims and have facilitated the identification of traditional medicinal plants and of their active principles [4,7]. More than 1300 acetylenic metabolites have been isolated and identified from plant and animal species [1–3,7–14]. Thousands of terrestrial and marine epoxy and acetylenic compounds are being screened worldwide to validate their use as anticancer drugs; however, terrestrial acetylenic compounds compose a particularly interesting group of anticancer agents and other biologically active compounds [1–4,7]. The present review is the first article devoted to natural epoxy acetylenic lipids. This review focuses on the origin, structures, and biological activities of natural epoxy acetylenic lipids and selected semi- and/or synthetic-related compounds. Their modes of action and future prospects are also discussed.

2. Fatty acids and glycerides The aerial parts of Erigeron philadelphicus were found to produce the isomeric methyl esters of 7-(3-methyl-oxiranyl)-2-heptene4,6-diynoic acid (1 and 2) [15]. The same compounds were detected along with polyacetylenes in Chrysoma pauciflosculosa [16]. Two derivatives of matricaria esters, 2(Z)-10-hydroxy- and 2(Z)-10-acetoxy-8,9-epoxydecen-4,6-diynoate (3 and 4, respectively), were detected in extracts of the rabbitbrush Chrysothamnus nauseosus (family Asteraceae) [17,18], and these derivatives were found to inhibit the feeding of 3rd instar Colorado potato beetle larvae. Compound 4 was isolated from Chrysothamnus parryi [19]. A fatty acid that was identified as 8-(3-oct-2-ynyl-oxiranyl)octanoic acid (5) composes 60% of the seed oil of Crepis foetida (family Compositae) [20]. Acetylenic acid and methyl ester (6 and 7, respectively), which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, were found in the root bark of

O R

O

R1 n

n = 1, 2, 3, 4, 5

R

Paramacrolobium caeruleum [21]. Acetylenic acid (8) was prepared as an inhibitor of human neutrophil LTA4 hydrolase [22]. An unusual acetylenic amide (9) was isolated from the extract of Spilanthes alba [23]. Acetylenic N-alkylamide (10a), with evidence of immune stimulating properties, was isolated from the extract of Spilanthes acmella [24], in S. acmella flowers [25], in roots of Acmella ciliata [26], and in the aerial parts of Salmea scandens [27]; an identical metabolite (10b) was isolated from the leaves and flower heads of Acmella radicans var. radicans (family Asteraceae) [28]. An unusual methyl ester of fatty acid (11) was isolated from N-fixing lichens Leptogium saturninum and Peltigera canina [29]. L. saturninum (order Peltigerales) displayed strong multi-copper oxidase (e.g., tyrosinase) and heme-containing peroxidase activities [30,31]. Peltigera sp., which is a cyanolichen that contains Nostoc sp. as a cyanobiont, produced arginase and arginine [32,33], which are also produced from phycobiliprotein pigments [34], and displayed laccase activity [35]. Both lichen species were found to contain unusual lipids and fatty acids [36–38]. A panaxydol derivative (12a) was obtained from Panax ginseng [39]. Both compounds 12a and 12b showed IC50 values of 0.06 and 12.7 lg/mL for inhibiting the proliferation of L2110 leukaemia and HeLa cells, respectively. Panaxydol linoleate (13) and ginsenoyne A linoleate (14) were found in the extract of the root of P. ginseng; these compounds showed cytotoxic activities against murine and human malignant cells (DT, NIH/3T3, L-1210, HeLa, T24 and MCF7 cells) in vitro [40]. Several bioactive fatty acids (as Na salts) and their methyl and ethyl esters (15a, b, c-17a, b, and c) were prepared [41]. These acids are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective pharmaceuticals. The myxomycetes (plasmodial slime moulds) are a group of fungus-like organisms usually present and sometimes abundant in terrestrial ecosystems. The myxomycete lifecycle involves two extremely different trophic (feeding) stages, one consisting of uninucleate amoebae, with or without flagella, and the other consisting of a distinctive multinucleate structure, the plasmodium [42]. Their chemical constituents include more than 100 natural compounds; lipids, fatty acids, alkaloids, amino acids, peptides, terpenes, naphthoquinone pigments, and aromatic and carbohydrate compounds from 26 species of four orders from myxomycetes were reported in several review articles [43–45]. These constituents are fatty acids, amino acids, alkaloids, naphthoquinones, aromatic metabolites, terpenoids, esters, and their derivatives. Thus, slime moulds not only have become one of the important research objects for natural products but also are expected to be new bioactive resources for natural products. The slime mould Lycogala epidendrum, commonly known as wolf’s milk, is a cosmopolitan species. Recently, some interesting lipids were isolated from this myxomycete. Specifically, rare fatty acids (18–21) and three triacylglycerides (TAG), named lycogarides A (22), B (23), and C (24), were isolated from the myxomycete L. epidendrum [46,47]. More recently, two unusual TAG, lycogarides D (25) and E (26 and 27), and two diacylglycerols (DAG), lycogarides F (28) and G (29), were reported [48].

O

O R1

R1 n

O R

n = 1 or 2

Fig. 1. Graphical display of chemical structures of natural acetylenic epoxides R, R1@H, alkyl, phenolic, cyclic and/or heterocyclic moiety.

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

O

69

O COOH

O

5

COOMe 1

O RO

O COOR 6R=H 7 R = Me

COOMe

O

2

COOH COOMe

8

3R=H 4 R = Ac O

H N O

O 11

9

O

COOMe H

12a R = H 12b R = Me

H O

O

H

O

10a O

H N

Br

H

O

H N

OH

H H

10b

COOR O

H

O 13

O

O

O 14 O O

O

O

RO 15a R = H 15b R = Me 15c R = Et

O

O

OR

O

16a R = H 16b R = Me 16c R = Et

O

RO

O

17a R = H 17b R = Me 17c R = Et

RO O

H

O

HO

H

18 R = H 19 R = Me

O HO

O

20 H

O

21

Discoveries of di- (28 and 29) and TAG (22–27) containing acetylenic epoxy fatty acids are uncommon in nature. Some other examples have been described in the scientific literature. Gunstone and Sealy [49] reported that the fatty acids of the seed oil of the Ongokea gore tree, which is also known as isano or boleko oil, contain several acetylenic acids. The TAG of boleko oil contain the following fatty acids: 6%, saturated (C14, C16, and C18); 19%, oleic and linoleic; 51%, five fatty acids (17-octadecene-9,11-diynoic; 13-octadecene-9,11-diynoic; 11-octadecen-9-ynoic; 9,12-octadecadiynoic; and 13,17-octadecadiene-9,11-diynoic acids); 22%, four hydroxy derivatives of fatty acids (8-hydroxy-17-octadecene-9,11-diynoic; 8-hydroxy-13,17-octadecadiene-9,11-diynoic; 8-hydroxy-13-octadecene-9,11-diynoic; and 8-hydroxy-9,12-octadecadiynoic acids); and 2%, dihydroxystearic acid. Two fatty acids (20-heneicosen-6-ynoic and 18-nonadecen-4ynoic acids) and a new triglyceride containing these acetylenic acids were isolated from the leaves of Hymenodictyon excelsum (family Rubiaceae) [50]. The extract of H. excelsum showed anticoagulant, anti-inflammatory, and sunscreen effects [51]. Acetylenic fatty acids in TAG varied from 6.6% in the moss Calliergon cordifolium to 80.2% in the liverwort Riccia antipyretica. Three acetylenic acids were identified among the monoenoics (6a-18:1; 9a-18:1; and 12a-18:1) and dienoics (6a,9c-18:2; 9a,12c-18:2; and 9c,12a-18:2). Four acetylenic acids were identified among the polyenoics (6a,9c,12c-18:3; 8a,11c,14c-20:3; 6a,9c,2c,15c-18:4; and 5a,8c,11c,14c-20:4) [52].

70

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

Some usual conjugated ene-yne acetylenic FAs, including trans-10-heptadecen-8-ynoic (pyrulic, 7.4%), trans-11-octadecen9-ynoic (ximenynic, 3.5%) acids, cis-7,trans-11-octadecadiene-9ynoic (heisteric, 22.6%), and 9,10-epoxystearic acids, can be identified in the seed oil of Heisteria silvanii (family Olacaceae). Two further conjugated acetylenic FAs, 9,11-octadecadiynoic (0.1%) and 13-octadecene-9,11-diynoic (0.4%) acids, were tentatively identified by their mass spectra. Twenty-six species of the separated TAG were identified by their abundant quasimolecular ions, [MH], and by their corresponding carboxylate anions, [RCOO], of the fatty acids. The major molecular species of the TAG were found to be 16:0/18:1/18:1, 16:0/18:1/18:3 (heisteric acid), 17:2 (pyrulic acid)/18:1/18:1, and 18:1/18:1/ 18:3 (heisteric acid). A TAG containing acetylenic FA was also found [53].

O O O Et

O

25 Lycogaride D

O

O O

Et O O

Et O O O

R O

O

26 Lycogaride E, R = saturated FA 27 R = unsaturated FA

O

Et

O

O

Et O O

O O

Et

O

28 Lycogaride F

O

5

O

O

O

O

O

Et O

O

O

O

3

O

4

O

Et

22 Lycogaride A

O

OH

O

O

O

O OH

Et 29 Lycogaride G

O

5

O

Many mosses and liverworts contain acetylenic fatty acids exclusively occurring in TAG or in small amounts in the more polar lipid fraction, i.e., phospho- and/or glycolipids [38,56–67].

O

O

O

O

12

4

23 Lycogaride B

O

O

3. Hydrocarbons, fatty alcohols, ketones, and derivatives O

O

5

O

O

O O

O

4

O

H

24 Lycogaride C

The TAG of types AAA, ABA, ABA, AAB and AAB (containing positional isomers of acetylenic FAs) were prepared [54,55]. Using the lipases from Candida cylindracea and from Candida rugosa, Jie et al. [54] were able to catalyse the release of 10-undecynoic acid and of 9-octadecynoic acid from their corresponding TAG; however, 13-docosynoic acid was less readily released in the case of glycerol tri-(13-docosynoate).

Notably, the P. ginseng root has long been used as a medicinal herb in East Asian countries. Many different acetylenic compounds, including fatty alcohols, ketones, hydrocarbons, and derivatives, were isolated from the genus Panax. Extracts from ginseng roots exhibited significant antitumour activities. An ethyl acetate fraction extracted from Korean ginseng root inhibited the growth of murine leukaemia L5178Y cells and murine Sarcoma 180 cells in vitro [68]. Petroleum ether extracts of P. ginseng roots showed inhibitory activity against three human renal cell carcinoma (RCC) cell lines: A498, Caki-1, and CURC II [69]. A petroleum ether extract from Korean ginseng roots inhibited the growth of murine leukaemia L5178Y cells and murine Sarcoma 180 cells in vitro and inhibited DNA, RNA, and protein synthesis in the latter cells [70]. An extract of the roots of Panax notoginseng exhibited significant anti-tumour-promoting activity on stage two carcinogenesis of mouse skin tumours [71]. Water extracts of Pfaffia paniculata (Brazilian ginseng) roots showed cytotoxic effects on the Ehrlich tumour in its ascitic form in mice [72]. Additionally, an American ginseng root extract demonstrated an effect on the proliferation of the breast cancer cell lines MCF-7, T-47D, and BT-20 [73]. Other cytotoxic activities of ginseng root extracts have also been observed and reported [74–76].

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

Panaxydol (30) is present in red ginseng powder at concentrations of 297 lg/g. The antitumour alcohols panaxydol and panaxynol, which were isolated from a powder of the P. ginseng root, inhibited the growth of various types of cultured tumour cell lines [77–81]. These alcohols inhibited the growth of various types of cultured cell lines in a concentration-dependent fashion. Their inhibitory activity was much stronger against malignant cells than against normal cells. ATPase activities of cells from Sarcoma 180 and rat liver were slightly inhibited by panaxydol. Panaxydol, falcarinol and panaxytriol inhibited the synthesis of DNA, RNA, and proteins in lymphoid leukaemia L-1210 cells incubated with these drugs for 4–16 h [82–84]. Tetradeca-13-ene-1,3-diyne-6,7-epoxide (panaxyne epoxide, 31) revealed cytotoxic activity against L1210 cells [85]. The contents of some polyacetylenes in P. ginseng are quite high. A series of other polyacetylene compounds of ginseng origin, including chlorine-containing chloropanaxydiol (32) and panaxydol, were tested for cytotoxic activities in different cell and tissue cultures [86–88]. Chloropanaxydiol showed inhibitory activity against leukaemia cells (L-1210) in tissue cultures and exhibited fungicidal properties. Heptadeca-1-ene-4,6-diyne-3,9-diol 10-acetate (10acetyl panaxytriol from Korean ginseng roots) showed strong cytotoxic activity against L-1210 cells (ED50 = 1.2 lg/mL) [89]. Epoxy acetylenes (33, 34, 38–40) from the root of P. ginseng were tested for their cytotoxic activities on murine and human malignant cells (DT, NIH/3T3, L-1210, HeLa, T24 and MCF7 cells) in vitro [90]. Most of these epoxy acetylenes showed more potent cytotoxicity than 5-fluorouracil (5-FU) and cisplatin (CDDP). Of the active compounds, panaxydol (30) was found to be most efficient (IC50 DT cells: 0.65 lM; 3T3 cells: 1.3 lM; L-1210 cells: 0.19 lM). Panaxydol (30) and 9,10-epoxy-16-hydroxy-octadeca-17-ene-12, 14-diyne-1-al (49) (from Foeniculi fructus, bitter fennel), as well as anaxydol and panaxynol (from P. ginseng), dose-dependently inhibited the growth of a human gastric adenocarcinoma cell line, MK-1 cells [91–93]. O

30 Panaxydol OH

H

37 PQ-4 O

O

OH

Cl 32 1-Chloropanaxydiol

HO OH

OH

O

O 40 Ginsenoyne E

33 Ginsenoyne I O

34 Ginsenoyne H OAc

O 39 Ginsenoyne D

OH

O

O 38 Ginsenoyne A

31 Panaxyne epoxide O

O

O

O 41 PQ-5

H

OAc

OH

O

O 35 PQ-2 OH

42 PQ-6 OH O

O 36 PQ-3

H

43 PQ-8

O

Cytotoxic polyacetylenes PQ-2 (35) and PQ-3 (36) from Panax quinquefolium exhibited strong cytotoxic activities against leukaemia cells (L-1210) in tissue cultures [94]. Anticancer agents panaquinquecol 4 (PQ-4) (37), panaquinquecol 5 PQ-5 (41), and

71

panaquinquecol 6 (PQ-6) (42) were isolated from roots extracts of P. quinquefolium as active ingredients, and these anticancer agents had IC50 values of 0.5, 10, and 0.5 lg/mL, respectively, against murine leukaemia L1210 [95,96]. C17-polyacetylenes PQ-4 (35) and PQ-6 (42) and a C14-polyacetylene, PQ-5 (41), were isolated from dried roots of P. quinquefolium [97]. The cytotoxic activities of acetylenes 37 and 42 against leukaemia cells (L-1210) were approximately 20 times higher than that of the metabolite (41). Panaxydol, heptadeca-1,8-diene-4,6-diyne-3,10-diol, and 8-methoxy-panaxydol (44) from Acanthopanax senticosus roots seem to induce various pro-apoptosis mechanisms in animal cells [98–104]. Compound 44 was preferably used in treating leukaemia. Anticancer agent 45, which inhibited L-1210, Ehrlich, and HeLa cell lines with IC50 values of 0.2, 1.3, and 2.1 lg/mL, respectively, has been isolated from Japanese ginseng [105]. C17- and C14-polyacetylenes (46) and (43, PQ-8), from the dried roots of P. quinquefolium, showed strong cytotoxic activities (IC50 = 0.1 and 0.5 lg/mL, respectively) against leukaemia cells (L-1210) in tissue cultures [95,96]. Polyacetylenic compounds isolated from the roots of Gymnaster koraiensis (family Compositae), including the gymnasterkoreaynes A to F, were separated by bioassay-guided fractionation using the L1210 tumour cell line as a model for cytotoxicity [106]. Of the compounds isolated, gymnasterkoreayne B (47) exhibited significant cytotoxicity against L-1210 tumour cells, with ED50 values of 0.12–3.3 lg/mL. In addition, gymnasterkoreaynes A–F showed considerable anti-proliferative activities against various cancer cells via the inhibition of NO production and the inhibition of ACAT [107]. The aerial parts of Coreopsis longula were found to produce heptadeca-1,9E,15E-trien-11,13-diyn-7,8-epoxide (48) [108]. Aqueous ethanol extracts of stems, leaves, flowers, and roots from E. philadelphicus showed antimicrobial activities against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans [109]. The polyacetylenic diepoxide compound gummiferol (50) was isolated from the leaves of Adenia gummifera (family Passifloraceae) using KB cytotoxicity-guided fractionation. This compound exhibited cytotoxic actions on KB cell lines and a broad cytotoxic spectrum against another ten human cancer cell lines (Table 1) [110]. This medicinal plant, A. gummifera, is used to improve animal health in Tanzania. Diastereomer 51 was recently synthesised [111]. Both compounds showed a growth-inhibitory activity against human cancer cells [112]. Repandiol (52), which is the cytotoxic diepoxide (2R,3R,8R,9R)4,6-decadiyne-2,3:8,9-diepoxy-1,10-diol, was isolated from the Hydnum repandum and H. repandum var. album mushrooms [113,114]. Repandiol displayed pronounced cytotoxic effects against various tumour cells. Repandiol was found to form interstrand cross-links of DNA, linking deoxyguanosines on opposite strands primarily within the 50 -GNC and 50 -GNNC sequences preferred by diepoxyoctane. However, repandiol was a significantly less efficient cross-linker than diepoxyalkanes (diepoxyoctane and diepoxybutane) [115]. 7,10-Dihydroxy-8,9-epoxyheptadec-1-ene-11,13,15-triyne (53) was isolated from the roots of Cacosmia rugosa [116]. Acetylenic epoxides 54 and 56 were found in some Clibadium species: Clibadium asperum, Clibadium glomeratum, Clibadium erosum, Clibadium grandifolium, Clibadium leiocarpum, and Clibadium pilonicum [117]. The C9-diacetylenic epoxide 7,8-epoxy-3,5-nonadiyn-1-ol (55) is from the fungus Clitocybe rhizophora [118]. Both metabolites 54 and 56 were found in the roots of Bidens graveolens [119]. Metabolite 57 was detected in the essential oil of St. John’s wort [121], and 1,9-undecadiene-3,5,7-triynyl-oxirane (58) was synthesised by chloroplasts from the cotyledons in safflower seedlings and in subcellular fractions [122]. Cell suspension cultures derived

72

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

from the safflower variety US-10 respond to treatment with cell-wall elicitors from either Phytophthora megasperma f. glycinea or Alternaria carthami by producing polyacetylenic phytoalexins (59 or 66) [123].

OH

O

OH

CHO 60

O

O

53

O

H

O

OH

H

OH

61 54

O

O

O

O O OH

45

50 Gummiferol

55

62

64

AcO

58 O

HO

66

OH

Epoxy acetylenes 60 and 61 were detected in extracts of the roots of Brazilian species of the genera Lobelia (Lobelia camporum, Lobelia exaltata, Lobelia fistulosa, Lobelia langeana, Lobelia nummularioides, Lobelia thapsoidea) and Siphocampylus (Siphocampylus macropodus, Siphocampylus sulfureus, Siphocampylus verticillatus, Siphocampylus westinianus) [124]. Volatile compound 62 was detected in essential oils from traditional Chinese medicine Po Chai pills [125]. More than 80 compounds were identified from the fruit oil and the fruit-shell oil of Alpinia oxyphylla, including metabolite 63 [126]. The acetylenic alcohol cis-8,9-epoxyheptadeca-1-en11,13-diyn-10-ol (64) was identified in the polar component of Cirsium japonicum root oil [127] and, more recently, in the same plant [128]. Roots of Solidago multiradiata were found to contain compound 65 [120]. Polyacetylenic phytoalexin (67) was obtained from the roots of Arctium lappa [129] and was isolated from Ptilostemon diacanthum, Ptilostemon afer [130], and the roots, green parts, and flower heads of Centaurea scabiosa [131]. The strong lipoxygenase inhibitor caulerpenyne is produced in lower amounts by green algae from the Caulerpaceae family. Additionally, this inhibitor was isolated from several Caulerpa species from the Mediterranean Sea, Pacific Ocean (Caulerpa taxifolia and Caulerpa prolifera), and the Caribbean Sea (C. prolifera, Caulerpa racemosa, and Caulerpa lanuginosa) [132–134]. Although caulerpenyne (does not contain an epoxy group) represents a major toxic metabolite of Caulerpa, its epoxy derivatives, 68 and 69, could also contribute to the cytotoxicity of the species. Minor caulerpenyne metabolites (68 and 69) were shown to inhibit the growth of marine bacteria and marine ciliates (Protozoa) in vitro [135]. The toxicities of pure compounds 68 and 69 were also evaluated in three models: mice (lethality), mammalian cells in culture (cytotoxicity), and sea urchin eggs (disturbance of cell proliferation). These caulerpenyne analogues were found to be more or less toxic, with varied efficiency depending on the assay [136,137]. Two potentially toxic sesquiterpenes, 70 and 71, were detected in the tropical green seaweed C. taxifolia (Cap Martin, Monaco) [138].

59

O H

O

52 Repandiol

O

H O

47 Gymnasterkoreayne B

48

65

57

51 8,9-epi-Gummiferol

O

O

H O

O

OH

OH

56

O

46 OH

63

OH

O O

O

OH

O

AcO

O

OH

O

OH

O

H

OH

OH

O

OHC

49

44 8-Methoxypanaxydol OH

OH

H

OMe

67

Artemisia annua (sweet wormwood, qinghao) has traditionally been used in Chinese medicine. Extracts of A. annua showed activities against HeLa cancer cells (IC50 54.1 lg/mL) and antiproliferative effects on four cancer cell lines (AGS, HeLa, HT-29 and MCF-7). A. annua contains the anticancer metabolite artemisinin (strong activity against human hepatocellular carcinoma cell lines HepG2 and SMMC-7721) [139–141], a highly unstable polyacetylene named annuadiepoxide (72) [142] and an insecticidal polyacetylene, pontica epoxide (75). Two antibiotics, biformin (or polyacetylenic 9-carbon glycol, 73) and biforminic acid (74), were obtained from the fungus Polyporus biformis (syn: Trichaptum biforme, Basidiomycetes) grown on a modified Czapek-Dox liquid medium [143,144]. Both compounds showed antibacterial activities against Bacillus subtilis, S. aureus, Photobacterium fischeri and P. aeruginosa [145]. The same compound, 74, has been isolated from the culture filtrate of the fungus Trametes pubescens [146]. This compound showed antifungal activity against Aspergillus niger and Aspergillus ochraceus. Three ponticaepoxides (75–77) were isolated from the roots of Achillea ptarmica [147] and from the Anthemideae family: genus Artemisia (31 species), Chrysanthemum tchihatchewii, Chrysanthemum serotinum, Chrysanthemum uliginosum, and Chrysanthemum myconis [8,10,148–150]. Water and ethanol extracts of crushed leaves of Oplopanax elatus (Oplopanax horridus or Oplopanax japonicus) showed antitumour effects against human lung, pancreas, and stomach neoplasms [151]. The polyacetylenes oploxynes A (78) and falcarindiol were isolated from the stems of O. elatus. Oploxyne A (78) inhibited the formation of nitric oxide (NO, IC50 = 1.98 lM) and prostaglandin E2 (PGE2, IC50 = 3.08 lM) in lipopolysaccharide (LPS)-induced murine macrophage RAW 267.7 cells [152]. Synthetic compounds displayed potent cytotoxicity against neuroblastoma and prostate cancer cell lines [153]. Fifteen acetylenic compounds, including metabolite 79, were isolated and characterised from the flower heads of Chrysanthemum leucanthemum [154]. The water extract of Chrysanthemum

73

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

indicum was shown to possess anti-inflammatory and anticancer activities, and the methylene chloride fraction of C. indicum exhibited strong cytotoxic activity compared with the other fractions and clearly suppressed constitutive STAT3 activation against both DU145 and U266 cells but not MDA-MB-231 cells [155]. Chrysanthemum tea can be obtained from dried flowers. Chrysanthemum tea has many purported medicinal uses, including aiding in the recovery from influenza and acne and as a ‘‘cooling’’ herb. In traditional Chinese medicine, chrysanthemum tea is also said to clear the liver and the eyes. In Western herbal medicine, chrysanthemum tea is consumed or used as a compress to treat circulatory disorders, such as atherosclerosis and varicose veins. Chrysanthemum tea was first consumed during the Song Dynasty (960–1279) [156]. AcO

O

O

virgin female, were synthesised, including an epoxy analogue (88) [164]. OH O

O

OH

78 Oploxyne A OH

82

O

O 79 O

O

80 H

O

68

OAc

OAc O

OAc

69 O

OAc

OH 85

OAc H

O

71 OAc

O

O

OAc OAc

H H

O

Z

70

AcO O

84

OAc OAc 81

OAc

83

OAc

HO

86

O

O

OH

O

87

O OAc 88

75 Pontica epoxide

72 Annuadiepoxide

O

O OH

76 73 Biformin O

O OH

77 74 Biforminic acid

A polyacetylenic metabolite, 1-acetoxy-4,5-epoxytetradeca6,12-diene-8,10-diyne (80), was isolated from Dahlia scapigera var scapigera f. merckii [157]. Hydrocarbon 81 was present in species of the Anthemideae and Heliantheae [148] tribes, and compound 82 was obtained from coffee powder containing lotus root and rice [158]. Roots of Centaurea deusta contain four epoxy polyacetylenes (67, 80, 83 and 84) [159]. The higher fungi of Poria sinuosa were found to produce many polyacetylenic metabolites, including alcohol (85) [160]. Metabolite 86, which has strong antimicrobial activity against S. aureus, was isolated from the seedlings of the Helianthus annuus cv Russian [161] sunflower. The same epoxide (86), as a plant growth inhibitor, was isolated from the insect galls on flower buds of Hedera rhombea Bean (family Araliaceae) formed by the ivy flower bud gall midge Asphondylia sp. (family Cecidomyiidae) [162]. Plant growth inhibitor 87 was obtained from falcarindiol that was isolated from galls of H. rhombea (Araliaceae) induced by Asphondylia sp. (family Cecidomyiidae) [163]. Several analogues of the major component, a sex pheromone of the Thaumetopoea pityocampa

The roots of Solidago spathulata produced the C17 acetylenic compound (8E)-17-acetoxy-15n,16n-epoxy-1,8-heptadecadien11,13-diyn-7n-ol (89) [165]. An acetylenic alcohol (90) was isolated from Saussurea katochaete (family Asteraceae) collected in China [166]. Fool’s parsley, Aethusa cynapium (also known as fool’s cicely or poison parsley), contained a small amount of the diacetylenic epoxide 91 [167]. Two unusual acetylenic compounds, 6,7-epoxide (92) and 6,7-12,13-diepoxide (93), which are biogenetically derived from the pentayne Me(C„C)5CH@CH2, were found in the Helenieae tribe [168]. Compounds 94a, b–97 were prepared by the reaction of polyenynes with ozone and with peracids from natural acetylenes isolated from plant species [169]. Compound 96 was also synthesised by transformations of acetylenic c-glycols [170]. Synthetic c-amino a-acetylenic epoxide 98 selectively inhibited the growth of transformed cells and demonstrated the inhibition of aldehyde reductase [171]. Bioactive acetylenic epoxy amino compounds 99 and 100 were prepared by the reaction of propargyl amines with epichlorohydrin [172]. Two naturally occurring anti-feedants (101 and 102) were prepared [173]. The acetylenic epoxide (3R,9R,10R)-9,10-epoxy-1heptadecene-4,6-diyn-3-ol (103) was synthesised and used for the treatment of cancer [174]. Three semisynthetic analogues of panaxydol (104–106) showed antiproliferative activities against L1210 cells [175]. Epoxydiacetylene alcohols (107–110), which are analogues of natural compounds, were synthesised [176]. Several bioactive monoacetylenic oxiranes (111–118) were prepared by epoxidation of the respective hydrocarbons with AcOOH [177,178]. The enantiomeric epoxy alcohols (119 and 120), e.g., 2,3-epoxypropan-1-ol, were prepared and separated by GC–MS [179]. 2,3-Di-prop-1-ynyl-oxirane (121) was synthesised [180]. Synthetic acetylenic diepoxide (122) showed carcinogenic activity against sarcoma cell lines [181].

74

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

O AcO

89

Me

O

OH

S O

O

OH

92 O

O

90

O

Me S O

E or Z O

O

91

93

AcO

O O

O MeO

OAc

95

94a (E) 94b (Z)

O

O

O

O

97

OMe

96 H 2N

H

O

O

N

H 98

H

99

O N

O

100

RO O

103

OH OH

101 R = H MeOOC 102 R = Ac

O

OH

OH

105 O

O 104 O R1

50 lg/mL) and against the majority of Gram-negative organisms (MIC values 6.3 approximately greater than 50 lg/mL). Cepacin B (124) has excellent activity against staphylococci (MIC less than 0.05 lg/mL) and against some Gram-negative organisms (MIC values 0.1 approximately greater than 50 lg/mL). Two antifungal acetylenic epoxides, wyerone epoxide (125) and wyerol epoxide (126), were identified in Vicia faba, and these compounds, 125 and 126, were produced by a necrotrophic fungi Botrytis cinerea and Botrytis fabae [183]. Aporpinone B (127) and 10 -acetylaporpinone B (128), with an unusual skeleton containing an acetylene unit, were isolated from the culture of the Aporpium caryae (Basidiomycete) wood-inhabiting fungus. Both metabolites showed weak to moderate antibacterial activities against B. subtilis, S. aureus, and E. coli [184].

O

O

106

O

R OH

107 R = R2 = Me, R1 = H 108 R = R2 = Et, R1 = H 109 R = Et, R1 = H, R2 = Me 110 R = R1 = Me, R2 = Et O HO 119 O

H

111

R2

O

O 114

O

112 R = H 113 R = Me

H

CHO

118 121

120

OH 117

O

HO

116

O

O

115

R

O

O 122

4. Furanoid acetylenic epoxides Two acetylenic antibiotics, cepacin A (123) and B (124), were isolated from the fermentation broth of Pseudomonas cepacia SC 11,783 [182]. Cepacin A has good activity against Staphylococci (MIC 0.2 lg/mL) but weak activity against Streptococci (MIC

Table 1 Cytotoxicity of gummiferol (50) isolated from Adenia ummifera. Cell line

ED50 (lg/mL)

Cell line

ED50 (lg/mL)

BCA-1 HT-1080 LUC-1 MEL-2 COL-1 KB KB-V ()

0.2 0.1 0.9 1.3 0.6 0.3 0.4

KB-V (+) P-388 A-431 LNCaP ZR-75-1 U-373

0.3 0.03 0.5 0.2 0.2 0.05

Key to cell lines used: BC1, human breast cancer; HT-1080, human fibrosarcoma; LUC-1, human lung cancer; MEL-2, human melanoma; COL-1, human colon cancer; KB, human oral epidermoid carcinoma; KB-V (+), multidrug-resistant KB assessed in the presence of vinblastine (1 lg/mL); KB-V (), multidrug-resistant KB assessed in the absence of vinblastine; P-388, murine lynphoid neoplasm; A-431, human epidermoid carcinoma; LNCaP, hormone-dependent human prostate cancer; ZR-75-1, hormone-dependent human breast cancer; U-373, human glioblastoma.

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

O

O

O

MeO

O

O

123 Cepacin A

OH O

Et

O

MeO

O

O

125 Wyerone epoxide O

OH

O

H

OR

127 Aporpinone B, R = H 128 1'-Ac Aporpinone B, R = Ac

Et 126 Wyerol epoxide

O

124 Cepacin B

O

Phytotoxic polyacetylene (129) was isolated from the roots of Russian knapweed (Acroptilon repens, Asteraceae). Phytotoxic polyacetylene showed phytotoxic activity against Arabidopsis thaliana seedlings [185]. Water and ethanol extracts of A. repens contained polyphenols and acetylenic compounds. The extracts had a strong reducing power and a superoxide/hydroxyl radical-scavenging effect, and the capacity of ethanol extract was more effective than that of water extract. Both extracts had a reducing lipid peroxidation rate above 47%. The extracts also had strong sodium nitrite scavenging and nitrosamine synthesis disconnection capacities. The water extract presented a 60.4% scavenging rate for sodium nitrite, whereas the ethanol extract presented a 86.5% rate of nitrosamine synthesis disconnection. The ethanol extract of A. repens may be used as both an antioxidant and an anticancer agent, with many effects, such as eliminating free rad-

H

O

O

O

5. Thiophene and dithiine epoxides

H

OH

O

S

O

129 S

O O

O

S

E

OMe Z

130

OMe O

O

135

Z S

O

S

S

131 O

S

136 Thiarubrin D S

O

S

132 O

S S O

137 S

133 S 138

S 134

75

S

76

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

icals in organisms, reducing lipid peroxidation, delaying aging, and preventing cardiovascular diseases and cancer [186]. The hexane fraction from the roots of Echinops ellenbeckii from Ethiopia yielded many acetylenic thiophenes, including compound 129 [187], which was also found in the roots and green parts of 16 Echinops species [188]. This compound was also detected in the green parts of Russian knapweed (A. repens) and globe artichoke (Cynara scolymus) [189]. Thiophene oxirane (130), which was found in the genus Echinops [190], and (131) were present in the genus Geigeria [191]. The roots of Ambrosia chamissonis, collected in the Queen Charlotte Islands, British Columbia, were found to contain thiophene D (132) and thiarubrine D (also known as thiarubrine A epoxide, 138) [192,193]. Thiarubrine D from A. chamissonis inhibited C. albicans growth and showed good anti-HIV activity in micromolar concentrations [194,195]. Rare and unusual photosulphides 133 and 134 were obtained from thiarubrines isolated from the roots of A. chamissonis (Asteraceae) by visible-light irradiation [196]. Foeniculacin (aromatic acetylenic epoxide, 135) was detected in the stem extract of Argyranthemum foeniculaceum [197], which is endemic to the Canary Islands. Extracts from Argyranthemum adauctum, A. foeniculaceum and Argyranthemum frutescens showed antimicrobial activities against Gram-positive and Gram-negative bacteria and cytotoxic activities against HeLa and Hep-2 cell lines [198]. The roots of giant ragweed (Ambrosia trifida) were reported to produce thiarubrine derivatives 137 and 138 [199].

should not be freely used in alternative medicine, although their anti-proliferative activities may suggest anticarcinogenic properties. Small amounts of the biogenetically interesting triacetylene compound 145 [207], which was also found in South African Helichrysum species [208], were yielded from the roots of several species of Anaphalis and Gnaphalium. Chrysindin B (146), which is a diacetylenic oxirane, was isolated from the flowers of C. indicum [209]. O O O

O 141 R = H 142 R = Ac

H trans-(-)-Nitidon 139

O

O H

OH

O O 143

O

O H

OH

CHO

O

R

H

cis-(+)-Nitidon 140

OR

O 144 R = OH 145 R = Cl

O

HO

OH

O

6. Pyrane and macrocyclic epoxides

O

H

O

Bioactive acetylenic epoxides (139–148) were isolated from leaves or roots of some plants, fungi, and lichens. Nitidon (139), a highly oxidised pyranone derivative produced by the Junghuhnia nitida (Meruliaceae) corticioid fungus, was isolated, and several of its biological activities were evaluated. Compound 140 exhibited antibiotic and cytotoxic activities and induced the morphological and physiological differentiation of tumour cells at nanomolar concentrations [200]. The first total synthesis of naturally occurring ()-nitidon (139) and its enantiomer (140) was reported. Both enantiomers of nitidon were found to exhibit significant cytotoxic activities against human cancer cell lines in vitro [201]. J. nitida is a fungus that breaks down wood deciduous trunks by a white rot [202]. Unusually, C14 polyacetylene epoxides (141–143) were found in extracts of Trachelium caeruleum (also known as Hamer Pandora or Blue Throatwort) [203]. Compound (144) was detected in Helichrysum serpyllifolium essential oil [204]. Helichrysum essential oil displayed antispasmodic, anticoagulant, antiallergenic, antiphlogistic, and anti-inflammatory properties. Aquatic and ethanol extracts of Helichrysum arenarium exhibited significant antiproliferative activities towards two human breast-cancer cell lines (MDA-MB-361 and MDA-MB-453) and towards a human cervix carcinoma cell line (HeLa) [205]. Helichrysum species have been used in folk medicine for thousands of years worldwide. The genus Helichrysum (Asteraceae), the flower that gives the ‘‘Everlasting’’ and ‘‘Immortal’’ essential oils and is known by the names Helichrysum angustifolium and Helichrysum italicum, is a European herb native to France, Italy, and a few neighbouring countries. The in vitro cytogenetic effects of nine Helichrysum taxa used in Turkey folk medicine on human lymphocytes were reported [206]. The inhibitory effects of Helichrysum stoechas subsp. barrelieri, H. armenium subsp. armenium, H. armenium subsp. araxinum, H. plicatum subsp. plicatum, H. compactum, and H. artvinense on the mitotic index and on replication index indicate that these taxa can have genotoxic and mutagenic effects. Therefore, these taxa

HO

O

O

146 Chrysindin B OH

147 Ivorenolide A O

O

O

148 Enantiomer

Ivorenolide A (147), which is a novel 18-membered macrolide featuring conjugated acetylenic bonds and five chiral centres, was isolated from Khaya ivorensis. Aqueous extracts of the Kh. ivorensis stem-bark showed antiplasmodial activities. Both compound 147 and its synthetic enantiomer (148) showed potent and selective immunosuppressive activities [210]. 7. Cyclohexanoid epoxides Cyclohexanoids, which occur in bacteria, fungi, higher plants, and molluscs, possess a wide range of bioactivities (e.g., anticancer, antifungal, and/or antibacterial) [211,212]. Acetylenic epoxy cyclohexanoids (149–159) were isolated from the basidiomycete Hexagonia speciosa (family Polyporaceae), which was collected in the tropical and subtropical zones of China, such as in the Hainan and Yunnan Provinces. Five human cancer cell lines, human myeloid leukaemia HL-60, hepatocellular carcinoma SMMC-7721, lung cancer A-549, breast cancer MCF-7, and colon cancer SW480 cells, were used in the cytotoxic assay. Speciosin B (150) showed significant inhibitory activity against the five cell lines, with IC50 values of 0.23 lM (HL-60), 0.70 lM (SMMC-7721), 3.30 lM (A-549), 2.85 lM (MCF7), and 2.95 lM (SW480). The other compounds were inactive (IC50 values > 40 lM) [213,214]. The metabolite 159 showed activity against phytopathogens and plant growth promoting activity,

77

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

properties that are also expressed in vivo by ectotrophic fungi [215]. Compound 160 was found in the essential oil of the flowers of Dendranthema morifolium [216].

O

O O

O

OH

O

OH

O

OH

149 Speciosin A

OH

150 Speciosin B

151 Speciosin C OH

OH

OH

O

OR

O

O

O

OH

OH

OH

153 Speciosin E, R = H 154 Speciosin F, R = Me

152 Speciosin D R

OH O

OH

The antibiotic known as oxirapentyn A (180) was produced by the fungus Beauveria feline. This antibiotic displayed antibacterial activity against S. aureus and S. faecalis. The LD50 (i.p. in mice) of 180 was 6.25 mg/kg [233]. In addition, this antibiotic showed weak growth inhibition against S. aureus and B. subtilis, with MICs of 140 and 150 lM, respectively [234]. Two highly oxygenated chromene derivatives, oxirapentyns B (181) and C (182), were isolated from the lipophilic extract of the marine-derived fungus Isaria felina KMM 4639 [234]. The oxirapentyns (181 and 182) were assayed for their cytotoxic activities against T-47D, SK-Mel-5 and SK-Mel28 cell lines and CD-I mouse splenocytes. Oxirapentyn A (126) exhibited weak cytotoxicity against the T-47D, SK-Mel-5, and SK-Mel-28 cell lines, with IC50 values of 25, 19, and 17 lM, respectively. The inhibitory activities of compounds 180–182 against S. aureus ATCC 21027, B. subtilis ATCC 10702, E. coli ATCC 15034, P. aeruginosa ATCC 27853, and C. albicans KMM 453 were also reported.

155 Speciosin L

OH O

O O

OR1

OH

O

O

OH

R

O

R

O

HO OH 156 Speciosin M, R = H, R1 = Ac 157 Speciosin N, R = OH, R1 = H 158 Speciosin O, R = OH, R1 = Ac

OH 159

162 R = Me 163 R = Et

161

160

164 R = Me 165 R = n-Pr

OAc

OAc

O

The minor compound 161, along with allenic ketones, was found in the extract of grasshoppers [217]. Two natural analogues of 1-ethynyl-1-cyclohexene epoxides, 162 and 164, were prepared [218]. Epoxides 163 and 165 were isolated from crambe seed oil (Crambe abyssinica) [219]. Two epoxides, 166 and 167, with potential antineoplastic and/or chemopreventive activities could be used as potential starting material for the synthesis of C22-acetylenic and allenic carotenoids [220]. Synthesised 9-cis-epoxycarotenoid dioxygenase inhibitors (168 and 169) were found to be regulators of ABA (abscisic acid) biosynthesis in plants [221]. Bioactive 1,2bis(2-oxocyclohexyl)-ethane (170), which contained two epoxy groups and a triple bond, was prepared [222]. A bioactive epoxide with a sesquicarene skeleton (171) was synthesised [223]. Two fungicides (172 and 173) against an oomycete, Phytophthora infestans, were prepared and used [224]. Bioactive 1,2-epoxy-4-cyclohexyl-2-methyl-3-butyne derivatives (174–176) were prepared [225]. ()-Harveynone (177), also known as ()-PT toxin, which is a naturally occurring anticancer agent, was isolated from the tea gray blight fungi, Pestalotiopsis longiseta and Pestalotiopsis theae [226]. Harveynone from Curvularia harveyi (a hyphomycete (mould) fungus, IFO 30129) at 3.2–12.5 lg/mL inhibited cell division in sea urchin eggs [227] and inhibited spindle formation (a microtubule-related function) in sea urchins [228]. Harveynone from Camellia sasanqua leaves showed antibacterial activity [229]. Asperpentyn (178), which was produced by a culture of Aspergillus duricaulis [230] and was isolated from the mangrove-derived fungus Pestalotiopsis sp. PSU-MA69, displayed weak antifungal activity against C. albicans and Cryptococcus neoformans [231]. Compound 179, which is a PAK3 kinase inhibitor, inhibited HeLa cancer cells [232].

O

AcO

O

AcO 167

166 O

R O

HO

O

168 R = SPh 169 R = NHPh

O

O

O

170 171 O

O O

O

O

OH

172

173

R 174 R = H 175 R = OH 176 R = OOH

The antimitotic enynylcyclohexenone named tricholomenyn A (183) was isolated from the fruiting bodies of Tricholoma acerbum (also known as Bitter Knight or as Gerippter Ritterling) [235]. Tricholomenyns C (184) and D (185), which were found in extracts of the fruiting bodies of T. acerbum and of other species of the genus Tricholoma, are the first naturally occurring dimeric dienyne geranyl cyclohexenones [236]. The tricholomenyns efficiently inhibited mitosis in T-lymphocyte cultures and were potent anticancer agents.

78

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

O

OH

O

O

O

O

OH

OH

177 (+)-Harveynone

H

179

O

O

O

O

O

178 Asperpentyn

O

O AcO

OH

AcO

180 Oxirapentyn A

O

H

OH

181 Oxirapentyn B

O

Epstein-Barr virus activation in Raji cells (IC50 0.5 lM), with the effect being comparable to or even stronger than that of curcumin, which is a well-known antioxidative chemopreventer from turmeric. Diacetylenic epoxide 189 was detected in the extract of A. lactiflora (family Compositae) [241] and was found in the roots of Artemisia selengensis [242]. The cytotoxic compound lactiflorasyne (191), which contains a spiro system, was isolated from the flowers and leaves of A. lactiflora [240,243,244]. The roots of Tanacetum parthenium contained a cis-C13-spiroketal enol ether epoxide (192) [245], which was also isolated from Chinese Artemisia species [246]. Several acetylenic epoxides (193–197) and ponticaepoxide were isolated from Chrysanthemum monspeliensis, Chrysanthemum leptophyllum (both in the Asteraceae family) and from Pentzia grandiflora (syn: Matricaria grandiflora and Oncosiphon grandiflorus, Anthemideae) [247].

OH

H

HO

O AcO

O

O

186

182 Oxirapentyn C

O O

O

O

O O R

OAc O

OAc O

183 Tricholomenyn A

O O

O

O

O

OH

O

O

195 O O

O O

O

191 Lactiflorasyne

OAc

O

O

O

184 Tricholomenyn C O

194 O

O

COOH

HO OAc

O O

O

O

O

O

O

187 R = OAc 188 R = O-iBu 189 R = H 190 R = H (6,7-epi)

O

O

O

O

O

193

COOH

O

192

O

O

O O

O

HO

O

OAc 185 Tricholomenyn D

196

O O

197

8. Spiroketal enol ether acetylenic epoxides 9. Marine acetylenic halogenated epoxides Acetylenic epoxides 186 and 187, which are inhibitors of HL-60 cells, were isolated from the leaves of Artemisia lactiflora (Compositae) from Thailand [237–239]. Natural epoxy acetylenes 188, 189, and 190 were evaluated for their ability to inhibit 12-lipoxygenase, and 189 and 190 showed moderate activity at 30 lg/mL. Compound 188 was tested on a series of colorectal and breast cancer cell lines; its IC50 values ranged from 5.8 to 37.6 lg/mL. The inhibitory effects of a diacetylenic spiroketal enol ether epoxide (AL-1 (188) from white mugwort, Asteraceae; A. lactiflora) on a variety of tumour promoter-induced biological responses, such as oxidative stress and tumour promotion in ICR mouse skin, were reported [240]. AL-1 (188) strongly inhibited tumour promoter-induced

Marine red algae of the genus Laurencia (order Ceramiales, family Rhodomelaceae) are widely distributed in temperate and in tropical waters, and in some areas, these algae compose a large component of the algal biomass. These algae are one of the most prolific producers of secondary metabolites in intertidal habitats. The Laurencia species contain unusual glycerolipids [38,248], arsenolipids [249,250], halogenated fatty acids, and other compounds [251–255]. Crude extracts of some Laurencia species showed cytotoxic activities against the U937 tumour cell line in the range 0.5–40 lg/mL [256] and strong activities against Leishmania in vitro [257]. The chemistry of Laurencia species is an

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

interesting topic of research that never fails to offer the possibility of discovering fascinating and novel structures and biologically active metabolites. Species of Laurencia have produced more than 200 secondary metabolites that exhibited cytotoxic activities against various cancer cell lines and/or showed antiviral, antibacterial, antimalarial, antifouling, antifungal, antioxidant, and other activities [251,258–260]. Acetylenic polyethers and aliphatic oxygenated metabolites produced by Laurencia species have displayed different biological activities [259,261]. Several metabolites were identified as acetylenic epoxides. Thus, laureepoxide (198) and laureoxolane (199) were isolated from Laurencia nipponica [262,263]. Rogioloxepane B (200), isorogioloxepane B (201), and metabolite 202 were found in the red seaweed Laurencia microcladia [264,265]. Compound 201 demonstrated phosphatase inhibition [3]. Rogiolenyne A (203) has been found in the red seaweed L. microcladia, which was collected off the torrent Il Rogiolo, south of Livorno [265]. Oxirane (204), an analogue of a natural compound, was prepared from the corresponding mannopyranosyl-acetylenes [266]. The halogenated vinyl acetylene poiteol (205) was obtained from the marine red algae Laurencia poitei and Laurencia snyderae [267]. Epoxyrhodophytin (206) and several acetylenes were isolated from Laurencia obtusa and from other Laurencia species [267,268]. Acetylenic metabolites 207 and 208 were isolated from the red seaweed Laurencia pinnatifida [269].

Br H

OH O

O

O

H Br

H

H

198 Laureepoxide O

O Cl

H

H

O

Z

E

O

Br

O

Z

Br

H

Z

Br H

200 Rogioloxepane B

H

201 Isorogioloxepane B

O

202 Z

HO

O Cl

H

O

Br

O

199 Laureoxolane O

Cl

Et

H Br

O

O

Cl H

O O Et

Et H 203 Rogioleneyne A

Br

H 204

205 Poiteol

Br

Br

E H O O

O Z

Cl 206 Epoxyrhodophytin

H

O

Cl 207 (E) 208 (Z)

H E or Z

79

10. Acetylenic Epoxy Sterols Acetylenic sterols are known in nature. Acetylenic sterols were isolated from plants and marine invertebrates. Acetylenic sterols called gelliusterol A–D were isolated from an unidentified species of sponge, Gellius sp. [270]. Steroids containing an atypical acetylenic unit as a component of the side chain were obtained from extracts of the sponge Calyx nicaeensis, where 26,27-bis-norcholest-5-en-23-yn-3b-ol and cholest-5-en-23-yn3b-ol were minor components. A biological evaluation of gelliusterols A–C was performed on cancer cell lines P-388, HT-29, A-549, DU-145, and MEL-28. Gelliusterols A and B exhibited moderate activities, with IC50 values greater than 1 lg/mL. An activity level of 0.5 lg/mL was observed with gelliusterol C against HT-29, whereas the other cell lines gave IC50 values above 1 lg/mL [271–273]. More recently, three acetylenic sterols, (24R)-5a-stigmast-7en-22-yn-3b-ol, 24,24-dimethyl-5a-cholest-7en-22-yn-3b-ol, and 24,24-dimethyl-5a-cholesta-7,25-dien-22-yn-3b-ol, were isolated from the Gynostemma pentaphyllum plant (also known as southern ginseng, or jiaogulan, family Cucurbitaceae) [274]. Escobarines A (209) and B (210) belong to cassane-type diterpenes that were isolated from the roots of Calliandra californica. Both compounds showed activities against two Mycobacterium tuberculosis strains and displayed cytotoxic activities when evaluated against five tumour cells: colon (HCT-15), breast (MCF-7), leukaemia (K-562 CML), central nervous system (U-251 Glio), and prostate (PC-3) human tumour cell lines [275]. The acetylenic epoxy sterols norethandrolone 4b,5b-epoxide (211) and norethynodrel-5b,10b-epoxide (212) were obtained by a photochemical oxidation of norethisterone [276,277]. Both compounds were toxic to Walker cells [278]. The cytotoxic effects of norethindrone-4b,5b-epoxide (213) to Walker cells in culture and to rat liver cells in vivo were demonstrated [278]. Neither the epoxides (213 and 214) of the parent steroids nor their epoxides were mutagenic in the Ames bacterial system. Both inhibited glutathione S-transferase [279]. 5,10-Epoxy-19-norpregn-20-yne-3,17-diol (215) was prepared [280]. Steroid 216 inhibited both the effect of dexamethasone on rat thymocytes (90% inhibition at 106 M) and the effect of progesterone on rabbit endometrium [281]. Both in vivo and in vitro, the minor metabolites were epoxy-steroid derivatives 217 and 218, which were obtained from metabolised desogestrel epoxidation by dog, rabbit, and/or human liver microsomes [282]. 16,17-Epoxy-pregn-4-en-20-yn-3-one (219) was synthesised [283]. The 5,6-Epoxy-6-ethynyl-cholestan derivatives 220–222 were obtained from 3b-acetoxy-6-oxosteroids [284]. The synthesis of a new C-ring steroidal derivative (223) from D9-pregnyne was described [285]. The neuro-sterol 224 was prepared and found to have anti-apoptotic, neuroprotective, and neurogenic properties that act on the nervous system, with applications in the treatment and/or prevention or amelioration of neurodegenerative diseases related to neuronal apoptosis or neuronal injury or in conditions related to or resulting from apoptosis, including but not limited to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, amyotrophic lateral sclerosis, retinal degeneration and detachment, peripheral neuropathy caused by genetic abnormalities, diabetes, polio, herpes, AIDS, chemotherapy, brain trauma or ischemia, and stroke [286].

80

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

O

H O

O

H MeO MeO

O 217

H O

R1

H

H OR

221 R = H 222 R = Ac H OH

H

OH

O

H

H

223 H H H

O 219

H

O

O H H

H

H

O

H

O 213 R = H, R1 = Et 214 R = Ac, R1 = Me

O

H

218

H

H

H H

HO3SO

H H

H

RO

OH

Et

O H

212

H

O

OH

H

H

OH

H H

H

H

Et

H

H

211

H H

O H

220

H

216

H H

O

O

H

O

OH

H

OH

O

O

215

209 Escobarine A R = CHO 210 Escobarine B R = CH2OH

O

H

H

HO

H

H

H H

H

R

H

H

OH

H

AcO 224

11. Vitamin D3 derivatives Several acetylenic epoxides of vitamin D3 derivatives were identified and reported in some recent publications. The vitamin D3 compounds (225–227) with a cyclic ether side chain have been identified as metabolites of 3-epivitamin D3 produced via a tissue-specific metabolic pathway that catalyses the formation of a cyclic ether structure [287]. Epoxy acetylenic derivatives of vitamin D3 (225–227) showed anticancer activities against human promyeloid leukaemia (HL-60 cells), human osteosarcoma MG-63 cells, and human breast cancer cells (incorporation of thymidine in MCF-7 cells) [288]. Synthetic and semisynthetic analogues of vitamin D (228 and 229) have shown transcriptional activity [289]. Isolated epoxy compounds 230–232 can be used for treating immune disorders, such as diabetes mellitus, multiple sclerosis, graft rejection, etc.; hyperproliferative disorders, such as cancer and psoriasis; and bone-related disorders, such as osteoporosis [290].

12. Epoxy acetylenic carotenoids Carotenoids contribute significantly to the bright colours of the marine environment, particularly in tropical waters, and serve

different functions. Acetylenic and allenic carotenoids are common in many marine organisms [253]. Acetylenic carotenoids are synthesised de novo only in microalgae [291]. The marine carotenoids pyrrhoxanthin (233), halocynthiaxanthin and derivatives (234–236) and others (237–241) have characteristic structures commonly possessing a monoacetylenic end group and the epoxide end group of 5,6-epoxy carotenoids. Carotenoids with an acetylenic b-end group have accumulated in some invertebrates. In feeding experiments with algal unicultures, fucoxanthin, 190 -hexanoyl-oxyfucoxanthin, diadinoxanthin, and peridinin were resorbed by the bivalves. The hydrolysis of carotenoid acetates, the conversion of allenic to acetylenic end groups, and the conversion of 5,6-epoxides to 5,6-glycols were general metabolic reactions. Fucoxanthin (active ingredient of brown algae) was converted to halocynthiaxanthin. The diacetylenic alloxanthin was a terminal metabolic product. Peridinin (a carotenoid found in red, brown and green algae and in dinoflagellates) was converted to peridininol and to pyrrhoxanthinol [292].

81

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

O

H O

O

H

HO

O

H

R

H

H

HO HO

HO CH2 OH

CH2

CH2

225 R = Me 226 R = H

O

OH

OH

227

228

H H

O H

HO

HO

H

O HO

OH

O

231

CH2 OH

229

O

232

230

OH O O 233 Pyrrhoxanthin

AcO

O O

RO

O

R

OH O

234 Halocynthiaxanthin, R = H 235 Halocynthiaxanthin-3'-acetate, R = Ac

O

O

OH

halocynthiaxanthin is present in marine microalgae. Carotenoid 235 strongly inhibited TPA-induced O2-generation in differentiated HL-60 cells at 25 lM and LPS/IFN-j-induced inflammation in mouse macrophage RAW 264.7 cells at 50 lM [302]. The significant anti-neoplastic effect of the carotenoid was demonstrated on human neuroblastoma GOTO cells in which only 5 lg/mL induced complete cell proliferation arrest [303]. Carotenoid 236 induced apoptosis in human leukaemia, breast, and colon cancer cells, with a concentration-dependent activation of DNA fragmentation and with a 30% decrease in Bcl-2 protein expression at 25 lM [304]. Carotenoid 236 also stimulated DR5 death receptor expression in a dose- and time-dependent manner in colon cancer cells [304,305].

O OH

AcO

236 19'-Acyl-halocynthiaxanthin-3'-acetate

O

Pyrrhoxanthin (233) was isolated for the first time from the marine dinoflagellate Gyrodinium resplendens [293]; from the photosynthetic dinoflagellates Amphidinium carterae (2 strains), Glenodinium sp., Glenodinium splendens, Glenodinium nelsoni, and Glenodinium dorsum [294]; from the clam Corbicula (Chinese freshwater clam) [253,295]; from two molluscans, Tridacna crocea, a giant clam, and Pteraeolidia ianthina, a nudibranch; from a cnidian, Pseudopterogorgia bipinnata, a gorgonian coral [296]; from corals Acropora hyacinthus, Acropora japonica, and Acropora secale; and from the tridacrid clam Tridacna squamosa [297]. Pyrrhoxanthin does not induce DR5 expression in human colorectal cancer DLD1 cells and does not sensitise DLD-1 to TRAIL-induced apoptosis [297]. Halocynthiaxanthin (234 and derivatives 235, 236) was isolated from the ascidian Halocynthia roretzi [298,299] and was found in marine bivalves (e.g., oysters and clams [300–302], suggesting that

OAc

HO

HO

237 Gyroxanthin

O

OH

OAc

O

E or Z O HO

238 Gyroxanthin diester, (E) 239 Gyroxanthin diester, (Z)

O HO

240 Diadinoxanthin A

O HO

241 Diadinoxanthin B

OH

OH

82

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

architectures not available in any other living systems. During the last two decades, many active compounds with an enediyne unit have been isolated and identified from soil bacteria. In 1987, Lederle [311–313] and Bristol-Myers [314,315] groups revealed the unprecedented molecular architecture of a new class of natural products, the so-called enediyne anticancer antibiotics. The enediynes are characterised by the presence of an unsaturated core with two acetylenic groups conjugated to a double bond or to an incipient double bond [316,317]. The enediynes are categorised

Gyroxanthin (237) is the first natural allenic acetylenic carotenoid that has been isolated from the dinoflagellate Gymnodinium galatheanum [306]. Gyroxanthin, which occurs as a diester (19-dodecanoate 30 -acetate) (238, 239), was also detected in the same dinoflagellate. A marine haptophyte flagellate, Chrysochromulina palpebralis, from the Nervion River estuary in the Cantabrian Sea (northern Spain) also contains gyroxanthin (237) and diadinoxanthin A (240) [307].

HO

O HO

O Cl

N

OMe NH

O

O

MeHN

OMe

O

O

O

O

HO O

O O

OH O

O

O

O

NMe2

O

OH

243 Neocarzinostatin

O

OH

242 Kedarcidin

HO O

H

OH

O

OH

OH

O

HN

O

Cl 244 N1999A2

Diadinoxanthin A (240) was isolated for the first time from Euglena gracilis [308]. Isochrysis galbana, Hymenomonas carterae, Prymnesium parvum, Pavlova lutheri, and a Pavlova species all produced diadinoxanthin, b,b-carotene, diatoxanthin, and fucoxanthin in various proportions [309]. Diatoms are ubiquitous and constitute an important group of the phytoplankton community, with a major contribution to the total marine primary production. These microalgae exhibit a characteristic golden-brown colour due to a high amount of the xanthophyll fucoxanthin, which plays a major role in the light-harvesting complex of photosystems. Xanthophyll cycles prevent the photodestruction of cells in excessive light intensities. In diatoms, the diadinoxanthin–diatoxanthin cycle is the most important short-term photoprotective mechanism [171]. Diadinoxanthin A (240) and B (241) were isolated from the common freshwater goby Rhinogobius brunneus [310].

13. Enediyne antibiotics and derivatives Microorganisms produce a large variety of biologically active substances representing a vast diversity of fascinating molecular

COOH O OMe

OH HO

OMe

O

HO

O

OH

245 Dynemicin A

into two subfamilies possessing either 9-membered ring chromophore cores or 10-membered rings. The enediyne antitumour antibiotics, such as dynemicin, kedarcidin, and neocarzinostatin families, have aroused considerable interest because of their exceptional potent inhibitory activity against a wide range of tumour cells, the unique structure of their 1,5-diyne-3-ene core, and their intriguing mode of action [316,317]. Kedarcidin (242) showed antitumour activity against implanted P388 leukaemia (3.3 lg/mL/kg) and B16 melanoma (2 lg/kg) cells in mice. Kedarcidin was also effective against Gram-positive bacteria but not against Gram-negative bacteria [318,319]. Neocarzinostatin (243) showed antibacterial activity against the following Gram-positive organisms: B. subtilis, 32 lg/mL; S. aureus, 16 lg/mL; S. aureus, 32 lg/mL; S. aureus, 8 lg/mL; S. aureus, 16 lg/mL; Sarcina lutea, 2 lg/mL; and S. lutea, 2 lg/mL. In mice with ascetic sarcoma 180, 3.2 mg/kg was tolerable daily. The LD50 was 30 mg/kg. In doses ranging from 0.1 to 3.2 mg/kg/day, neocarzinostatin inhibited tumour growth with a therapeutic

83

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

index of 32; 0.8–3.2 mg/kg/day ranges gave 100% survival. Doses of 0.2–3.2 mg/kg/day in leukaemia SN-36-bearing mice significantly prolonged animal survival. Antibiotic N1999A2 (244) strongly inhibited the growth of various tumour cell lines (with IC50 values varying from 1012 to 108 M) and of bacteria [320]. Dynemicin A (245), an antibiotic with the 1,5-diyn-3-ene and anthraquinone subunit, was isolated from the culture broth of Micromonospora chersina sp. nov. M956-1 [313]. Dynemicin A was particularly active against Gram-positive bacteria and prolonged the life span of mice inoculated with P388 leukaemia. In addition, this compound displayed significant activity against P388 leukaemia and 316 melanoma in mice. Uncialamycin (246), which is an enediyne antibiotic, was isolated from cultures of an undescribed streptomycete obtained from the surface of a British Columbia lichen [321,322]. Uncialamycin exhibits potent in vitro antibacterial activity against Gram-positive and Gram-negative human pathogens, including Burkholderia cepacia, which is a major cause of morbidity and mortality in patients with cystic fibrosis. Both uncialamycin and its triacetate analogue (247) were shown to inhibit bacterial growth and to kill cancer cells [321,322]. An antibiotic, deoxydynemicin A (248), was produced together with dynemycin A (245), in the culture broth of Micromonospora globosa. The production, isolation, properties, structure, and biological activities of 248 and 245 were reported. Compound 248 had potent antibacterial activity, similar to 245, and specifically inhibited Gram-positive bacteria at extremely low doses [323].

value of 5.0  106 M against a variety of cancer cell lines in vitro [324]. Several dynemicin analogues (256–259 and 264) were prepared and used as DNA cleaving, cytotoxic, and/or antitumour agents [327]. Two diastereoisomeric simplified dynemicin analogues (260 and 261) were prepared [328], and one of these derivatives showed activity against plasmid DNA. Quinone imine enediynes (262, 263, 268), which possess cytotoxic activity towards cancer cells, were prepared for use as antitumour agents [329–331]. Simple analogues (265 and 266) as an antitumour antibiotic were prepared [332]. Several antitumour agents of water-soluble enediyne compounds, including (269–271) related to dynemicin A, were synthesised and studied of DNA-cleaving, and in vivo antitumour activity [333]. Authors found that the water-soluble compounds, in which the tert-amines, such as the 2-(dimethylamino)ethyl, 2(pyrrolidino)ethyl, or 1-azabicyclo[3.3.0]oct-5-ylmethyl group, were attached, showed not only enhanced in vivo antitumour activity but also decreased toxicity compared with the corresponding 9-acetoxy enediyne compounds.

R N

H

R1

H

O R1

O

H

HN

O

OH

OR1

O

HN

OMe

O

NO2

N

OH

O

N

O

O OH

O

O

OMe OMe

OH 257 O

260

O

PhO

OH

N

OAc O OAc

N

O

R R1

H H

O

269 R = H(OAc), R1 = OAc (H), X = 4-Cl 270 R = H(OAc), R1 = OAc (H), X = 2-NO2 271 R = H, R1 = OAc, X = 4-NO2

O OMe

OH

H

O O

COOR

258 R = H 259 R = Me

N

H

N

O

O H

O

268 H

O

OH

N

OMe

254 R = H 255 R = OH

O

256

PhO

H

X

R

H

N

O

R1

OMe O

N

R

O

OR 252 R = H 253 R = Ac

H

O

H

N

PhO

O

HO

249 R = H, R1 = Me 250 R = COOPh, R1 = OH 251 R = COOPh, R1 = OMe

O

O

H

N

OH

O

O

265 R = H, R1 = OH 266 R = OH, R1 = H

PhO

O

O 264

267

O

248 Deoxydynemicin A

O

R 1O R

N

OH

O

H

O O

OR

OMe H

PhSO2

OR 2 246 (26R)-Uncialamycin, R = R1 = R2 = H 247 R = R1 = R2 = Ac

EtO

COOH O

COOR O

O

R2 O 262 R = R1 = H, R2 = OH 263 R = Me, R1 = OAc, R2 = H

H

H

N

O

261

Dynemicin analogues (249–255, and 267), which are bactericides and antitumour agents, have been prepared [324–326]. Compound 254 exhibited an IC50 value of 6.3  106 M against a variety of cancer cell lines in vitro, and compound 255 exhibited an IC50

14. Miscellaneous compounds Compound 272 was detected by pyrolysis gas chromatography mass spectrometry in an extract of bamboo leaves [334]. A tetranortriterpenoid derivative, namely, munronin E (273), was isolated from the methanolic extract of the whole bodies of Munronia henryi and exhibited moderate antifeeding activity against Pieris brassicae [335]. Compound 274 was isolated from Swietenia mahagonia, Honduras mahogany. The occurrence of this compound in the family Meliaceae was reported by Wakabayashi et al. [336]. Two metabolites, 275 and 276, were found in an extract of the flowering plant Cirsium sp. (family Asteraceae) [337]. Aromatic compound 277 was prepared and inhibited the development of insects and of acarids [338].

84

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

O

O

was detected in A. sinensis. The same compound was also detected in the volatile oil of the fresh leaves of Hyptis spicigera [342]. The volatile oil demonstrated in vitro anti-trypanosoma activity against Trypanosoma brucei. This activity showed the volatile oils from H. spicigera leaves to be a potential trypanocide. Angelicol B (281) was isolated from Angelica keiskei (better known by the Japanese name of Ashitaba) and showed a-glucosidase inhibitory activity [343].

H

OAc

O

H

Me O OH

H

H

272

CH2

H

O

O

O O

274

OH

O

273 Munronin E

O

OH

O O

275 R = H 276 R = Ac

OR O MeO H

PhO

O

O

H

277

HO

OMe

O

279

H

OH H

O

O 280

O

O

281 Angelicol B

OH

AcO

295

O

HO

H O

O

O

278

H

AcO

296

The petroleum ether extract of P. ginseng showed a significant inhibition of the diacylglycerol acyltransferase enzyme from rat liver microsomes. Bioactivity-guided fractionation led to the isolation of compound 278 [339]. An IC50 value of 9 lg/mL was obtained. 3-Ethynyl-a,a-dimethyl-2-oxiranemethanol (279) was found in odour compounds [340]. O

O

O O

O O

O

H HO

H O

O

OAc

OH

O

COOH

283 R = OMe 284 R = CH=CHCOOH 285 R = CH=CHCOOMe O

O

O

OMe

Ph 286

O

HO

O

R

HO

O

CHO

H

. H

H 292

HO

O

Ph

OH O

293 Ph

H H

O

H

O

291 Ph

.

288

289 R = OH 290 R = CHO

N N N H

H

287

OMe O

Ph

O

O

282

O

OH

AcO

R

O

MeO

H

O

N H

Cl

O SMe

N

294

The quality and content of the volatile oils in the traditional Chinese medicine (TCM) Angelica sinensis and Ligusticum chuanxiong were analysed using GC–MS [341]. The chemical material basis of the two TCM was discussed according to the comparison of the similarities and differences of volatile oils. Compound 280

N 297

N N

The biologically active natural aromatic acid 282 was identified from the culture medium of the fungus Eutypa lata [344]. Wyerone benzene analogues, the epoxide derivatives 283–285, were prepared [345]. Photoadduct 286 was prepared by irradiation of 1,4diphenyl-1,3-butadiyne and di-Me fumarate in deaerated THF [346]. Several acetylenic antibiotic analogues containing epoxy group(s) (287–293) were prepared and showed activity against Gram-negative and Gram-positive organisms [347]. Compound 294 was synthesised through a multi-step process and showed 80–100% efficacy against blotch Septoria nodorum at concentrations of 20–200 ppm [348]. Dimeric analogues of mono- and diterpenes 295 and 296 and alkaloid 297 were prepared by the addition of alkynes to ketonecontaining mono- and diterpenes or alkaloidal ketones [349]. Among the drugs targeting microtubule functions by interfering with tubulin subunits, epothilones represent a class of anticancer agents that recently entered clinical development. True natural epothilones do not contain an acetylenic moiety [350,351]. Epothilone acetylenic analogues were a new type of antitumour drugs that could induce the promotion of tubulin heterodimers into microtubule polymers, stabilise microtubules against depolymerization, and induce mitotic cell cycle arrest and, eventually, apoptosis. The epothilone acetylenic analogues that were being developed or were developed (298–302) had high potential to become effective antitumour agent candidates.

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

Epothilone derivatives 298 and 299, with epoxy and acetylenic groups, were synthesised and were suitable for the treatment of malignant ovarian, stomach, colon, adrenal, breast, lung, head and neck tumours, malignant melanomas, and acute lymphocytic and myelocytic leukaemia [352]. Two epothilone derivatives, 300 and 301, were prepared and used as anticancer drugs against lung cancer cells (NSCLC and SCLC) [353]. Epothilone derivative 302 was prepared and used for the treatment of brain disease [354].

S

S

N O

O

N

OH

O

O

O

Me

Me

OH

O Me

O

Me

OH

OH

298

299

O

R S N O O

N OH

O

O

O

Me

O

Me

O

O

OH 300 R = H 301 R = NH2

OH

OH H

302

H

15. Concluding remarks Terrestrial and marine secondary metabolites are unique sources for pharmaceuticals, food additives, flavours, and for other industrial materials. The accumulation of such metabolites often occurs in plants subjected to stresses, including various elicitors or signal molecules. Currently, more than 250 epoxy acetylenic lipids and related compounds have been isolated from living organisms. Natural, semi-synthetic, and synthetic acetylenic epoxides and their analogues and derivatives have been discovered and/or synthesised and evaluated for their biological activity. Inspired by the intriguing biological activities of many acetylenic natural products, polyyne moieties are now introduced in compounds that have pharmacological activity. The many functionalised acetylenic oxiranes thus obtained exhibit an impressive array of activities, such as enzyme inhibitor activities, cytotoxic, or antiviral activities. Without doubt, other important new acetylenic oxiranes possessing important biological activities will soon be discovered. Conflict of interest The authors declare no competing financial interest. References [1] Dembitsky VM. Anticancer activity of natural and synthetic acetylenic lipids. Lipids 2006;41:883–924.

85

[2] Dembitsky VM, Levitsky DO. Acetylenic terrestrial anticancer agents. Nat Prod Commun 2006;1:405–29. [3] Dembitsky VM, Levitsky DO, Gloriozova TA, Poroikov VV. Acetylenic aquatic anticancer agents and related compounds. Nat Prod Commun 2006;1:773–811. [4] Minto RE, Blacklock BJ. Biosynthesis and function of polyacetylenes and allied natural products. Prog Lipid Res 2008;2008(47):233–306. [5] Carballeira NM. New advances in fatty acids as antimalarial, antimycobacterial and antifungal agents. Prog Lipid Res 2008;47:50–61. [6] Bador P, Paris J. Acetylenic enzymic inhibitors: chemotherapeutic interest. Pharm Acta Helv 1990;65:305–10. [7] Siddiq A, Dembitsky V. Acetylenic anticancer agents. Anti-Cancer Agents Med Chem 2008;8:132–70. [8] Kuklev DV, Domb AJ, Dembitsky VM. Bioactive acetylenic metabolites. Phytomedicine 2013;20:100–15. [9] Christensen LP. Acetylenes and related compounds in Anthemideae. Phytochemistry 1992;31:7–49. [10] Christensen LP, Jakobsen HB. Polyacetylenes: distribution in higher plants, pharmacological effects and analysis. Chromatogr Sci Ser 2008;99:757–816. [11] Christensen LP, Lam J. Acetylenes and related compounds in Cynareae. Phytochemistry 1990;29:2753–85. [12] Christensen LP, Lam J. Acetylenes and related compounds in Heliantheae. Phytochemistry 1991;30:11–49. [13] Christensen LP, Lam J. Acetylenes and related compounds in Asteraae. Phytochemistry 1991;29:2453–76. [14] Pan Y, Lowary TL, Tykwinski RR. Naturally occurring and synthetic polyyne glycosides. Can J Chem 2009;87:1565–82. [15] Jakupovic J, Chau-Thi TN, Fischer NH. Isomeric epoxides of matricaria ester from Erigeron philadelphicus. Phytochemistry 1986;25:1223–4. [16] Menelaou MA, Foroozesh M, Williamson GB, Fronczek FR, Fischer Helga D, Fischer NH. Polyacetylenes from Chrysoma pauciflosculosa: effects on Florida sandhill species. Phytochemistry 1992;31:3769–71. [17] Rose AF, Butt BA, Jermy T. Antifeedants for the Colorado potato beetle, Leptinotarsa decemlineata. Part 2. Polyacetylenes from the rabbitbrush Chrysothamnus nauseosus. Phytochemistry 1980;19:533–6. [18] Jordon-Thaden IE, Louda SM. Chemistry of Cirsium and Carduus: a role in ecological risk assessment for biological control of weeds? Biochem Syst Ecol 2003;31:1353–96. [19] Bohlmann F, Zdero C, Robinson H, King RM. Polyacetylenic derivatives. Part 253. New acetylenic derivatives from Chrysothamnus parryi. Phytochemistry 1979;18:1519–21. [20] Mikolajczak KI, Smith Jr CR, Bagby MO, Wolff IA. A new type of naturally occurring polyunsaturated fatty acid. J Org Chem 1964;29:318–22. [21] Patil AD, Chan JA, Lois-Flamberg P, Mayer RJ, Westley JW. Novel acetylenic acids from the root bark of Paramacrolobium caeruleum: inhibitors of 3hydroxy-3-methyl-glutaryl coenzyme A reductase. J Nat Prod 1989;52:153–61. [22] Evans J, Nathaniel D, Charleson S, Léveillé C, Zamboni R, Leblanc Y, et al. Neutrophil LTA4 hydrolases and leukotriene B4 receptors: effects of leukotriene epoxides and their enzymatic products. Prostaglandins Leukot Med 1986;23:167–71. [23] Bohlmann F, Ziesche J, Robinson H, King RM. Polyacetylene compounds. Part 256. New amides from Spilanthes alba. Phytochemistry 1980;19:1535–7. [24] Boonen J, Baert B, Burvenich C, Blondeel P, De Saeger S, De Spiegeleer B. LC– MS profiling of N-alkylamides in Spilanthes acmella extract and the transmucosal behaviour of its main bio-active spilanthol. J Pharm Biomed Anal 2010;53:243–9. [25] Nagashima M, Nakatani N. LC–MS analysis and structure determination of pungent alkamides from Spilanthes acmella L. flowers. Lebensm Wiss Technol 1992;25:417–21. [26] Martin R, Becker H. Amides and other constituents from Acmella ciliate. Phytochemistry 1985;24:2295–300. [27] Bohlmann F, Hartono L, Jakupovic J. Highly unsaturated amides from Salmea scandens. Phytochemistry 1985;24:595–6. [28] Rios-Chavez P, Ramirez-Chavez E, Armenta-Salinas C, Molina-Torres J. Acmella radicans var. radicans: in vitro culture establishment and alkamide content. In Vitro Cell Dev Biol 2003;39:37–41. [29] Rezanka T, Dembitsky VM. Novel brominated lipidic compounds from lichens of Central Asia. Phytochemistry 1999;51:963–8. [30] Liers C, Ullrich R, Hofrichter M, Minibayeva FV, Beckett RP. A heme peroxidase of the ascomyceteous lichen Leptogium saturminum oxidizes high-redox potential substrates. Fungal Genet Biol 2011;48:1139–45. [31] Dembitsky VM. Oxidation, epoxidation and sulfoxidation reactions catalysed by haloperoxidases. Tetrahedron 2003;59:4701–20. [32] Diaz E-M, Sacristan M, Legaz M-E, Vicente C. Isolation and characterization of a cyanobacterium-binding protein and its cell wall receptor in the lichen Peltigera canina. Plant Signal Behav 2009;4:598–603. [33] Dembitsky VM, Rezanka T. Metabolites produced by nitrogen-fixing Nostoc species. Folia Microbiol 2005;50:363–91. [34] Czeczuga B, Semeniuk A, Czeczuga-Semeniuk E. Phycobiliprotein in the cells of Nostoc sp. – a cyanobiont of various lichen species of the genus Peltigera. Curr Top Phytochem 2011;10:17–27. [35] Laufer Z, Beckett RP, Minibayeva FV, Luthje S, Bottger M. Occurrence of laccases in lichenized ascomycetes of the Peltigerineae. Mycol Res 2006;110:846–53. [36] Dembitsky VM. Lipids of lichens. Prog Lipid Res 1992;31:373–97.

86

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

[37] Dembitsky VM, Bychek IA, Shustov MV, Rozentsvet OA. Phospholipid and fatty acid composition of some lichen species. Phytochemistry 1991;30:837–9. [38] Dembitsky VM. Betaine ether-linked glycerolipids: chemistry and biology. Prog Lipid Res 1996;35:1–51. [39] Hirakura K, Mihashi H, Fujihashi T, Okuma T. Isolation of acetylene compounds from Panax ginseng C.A. Meyer and preparation of their derivatives as antitumor agents. Japanese Patent: Jpn. Kokai Tokkyo Koho, 13 pp., JP 04264044 A; 1992 [40] Hirakura K, Takagi H, Morita M, Nakajima K, Niitsu K, Sasaki H, et al. Cytotoxic activity of acetylenic compounds from Panax ginseng. Nat Med (Tokyo) 2000;54:342–5. [41] Girard Y, Rokach J. Leukotriene antagonists and their pharmaceutically acceptable salts. Patent: EP 1984-309045 Eur. Pat. Appl., 102 pp.; 1985. [42] Speijer D. Evolutionary aspects of RNA editing. Nucleic Acids Mol Biol 2008;20:199–227. [43] Dembitsky VM, Rezanka T, Spizek J. Secondary metabolites of slime molds (myxomycetes). Phytochemistry 2005;66:747–69. [44] Ishibashi M. Isolation of bioactive natural products from Myxomycetes. Med Chem 2005;1:575–90. [45] Ishibashi M, Arai MA. Bioactive natural products from Myxomycetes having effects on signaling pathways. Heterocycles 2012;85:1299–332. [46] Hashimoto T, Akazawa K, Tori M, Kan Y, Kusumi T, Takahashi H, et al. Three novel polyacetylene triglycerides, lycogarides A–C, from the myxomycete Lycogala epidendrum. Chem Pharm Bull 1994;42:1531–3. [47] Hashimoto T, Tori M, Oonishi A, Asakawa Y. Structures of new polyacetylene triglycerides and dibenzocarbazoles from the myxomycetes Lycogala epidendrum. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1990;32:79–86. [48] Buchanan MS, Hashimoto T, Asakawa Y. Acylglycerols from the slime mold Lycogala epidendrum. Phytochemistry 1996;41:791–4. [49] Gunstone FD, Sealy AJ. Fatty acids. XII. The acetylenic acids of isano (boleko) oil. J Chem Soc 1965;6:5772–8. [50] Nareeboon P, Komkhunthot W, Lekcharoen D, Wetprasit N, Piriyapolsart C, Sutthivaiyakit S. Acetylenic fatty acids, triglyceride and triterpenes from the leaves of Hymenodictyon excelsum. Chem Pharm Bull 2009;57:860–2. [51] Jagdishprasad P, Rao NS. Anticoagulant and anti-inflammatory and sunscreening effects of Hymenodictyon excelsum. Indian J Pharm 1998;20:221–2. [52] Dembitsky VM, Rezanka T. Distribution of acetylenic acids and polar lipids in some aquatic bryophytes. Phytochemistry 1995;40:93–7. [53] Spitzer V, Tomberg W, Hartmann R, Aichholz R. Analysis of the seed oil of Heisteria silvanii (Olacaceae) – a rich source of a novel C18 acetylenic fatty acid. Lipids 1997;32:1189–200. [54] Jie MSF, Lie K, Fu X, Lau MML, Chye ML. Lipase-catalyzed hydrolysis of TG containing acetylenic FA. Lipids 2002;37:997–1006. [55] Jie MSF, Lie K, Lam CC. 13C-NMR studies of polyunsaturated triacylglycerols of type AAA and mixed triacylglycerols containing saturated, acetylenic and ethylenic acyl groups. Chem Phys Lipids 1995;78:1–13. [56] Anderson WH, Gellerman JL, Schlenk H. Acetylenic acids from mosses. Lipids 1975;10:501–2. [57] Anderson B, Anderson WH, Chipault JR, Ellison EC, Fenton SW, Gellerman JL, et al. 9,12,15-Octadecatrien-6-ynoic acid, new acetylenic acid from mosses. Lipids 1974;9:506–11. [58] Jamieson GR, Reid EH. Lipids of Fontinalis antipyretica. Phytochemistry 1976;15:1731–4. [59] Gellerman JL, Anderson WH, Schlenk H. Synthesis and function of 9,12,15octadecatrien-6-ynoic acid in the moss Ceratodon purpureus. Biochemistry 1977;16:1258–62. [60] Kohn G, Demmerle S, Vandekerkhove O, Hartmann E, Beutelmann P. Distribution and chemotaxonomic significance of acetylenic fatty acids in mosses of the Dicranales. Phytochemistry 1987;26:2271–5. [61] Kohn G, Hartmann E, Stymne S, Beutelmann P. Biosynthesis of acetylenic fatty acids in the moss Ceratodon purpureus. J Plant Physiol 1994;144:265–7. [62] Dembitsky VM, Rezanka T. Acetylenic fatty acids of the Dicranaceae. Phytochemistry 1994;36:685–9. [63] Dembitsky VM, Rezanka T. Distribution of diacylglycerylhomoserines, phospholipids and fatty acids in thirteen moss species from Southwestern Siberia. Biochem Syst Ecol 1995;23:71–8. [64] Dembitsky VM, Rezanka T, Bychek IA, Afonina OM. Polar lipid and fatty acid composition of some bryophytes. Phytochemistry 1993;33:1009–14. [65] Dembitsky VM, Rezanka T, Bychek IA, Afonina OM. Acetylenic acids and lipid compositions of some mosses from Russia. Phytochemistry 1993;33:1021–7. [66] Dembitsky VM. Lipids of bryophytes. Prog Lipid Res 1993;32:281–356. [67] Dembitsky VM, Rezanka T. Distribution of acetylenic acids and polar lipids in some aquatic bryophytes. Phytochemistry 1995;40:93–7. [68] Yun YS, Lee SY, Kim BS, Yun TK. Studies on the mechanism of action of the cytotoxic fractions from Korean ginseng roots. II. Effects of ethyl acetate fraction from Korean ginseng roots on the biosynthesis of macromolecules in mammalian neoplastic cells. Han’guk Saenghwa Hakhoechi 1980;13:219–34. [69] Sohn J, Lee CH, Chung DJ, Park SH, Kim I, Hwang WI. Effect of petroleum ether extract of Panax ginseng roots on proliferation and cell cycle progression of human renal cell carcinoma cells. Exp Mol Med 1998;30:47–51. [70] Yun YS, Lee SY, Kim BS, Yun TK. Studies on the mechanism of action of the cytotoxic fraction from Korean ginseng roots. I. Effects of petroleum ether fraction from Korean ginseng roots on the biosynthesis of macromolecules in mammalian neoplastic cells. Han’guk Saenghwa Hakhoechi 1980;13:203–17.

[71] Oh M, Choi YH, Choi S, Chung H, Kim K, Kim SI, et al. Anti-proliferating effects of ginsenoside Rh2 on MCF-7 human breast cancer cells. Int J Oncol 1999;14:869–75. [72] Matsuzaki P, Akisue G, Salgado OSC, Gorniak SL, Zaidan DML. Effect of Pfaffia paniculata (Brazilian ginseng) on the Ehrlich tumor in its ascitic form. Life Sci 2003;74:573–9. [73] Duda RB, Taback B, Kessel B, Dooley DD, Yang H, Marchiori J, et al. PS2 expression induced by American ginseng in MCF-7 breast cancer cells. Ann Surg Oncol 1996;3:515–20. [74] Lu J-M, Yao Q, Chen C. Ginseng compounds: an update on their molecular mechanisms and medical applications. Curr Vasc Pharmacol 2009;7:293–302. [75] Park JS, Lee TW, Han K. Cell growth inhibitory effect of tissue cultured root of wild Panax ginseng C.A. Mayer extract on various cancer cell lines. Nat Prod Sci 2009;15:1–7. [76] Wong VKW, Cheung SSF, Li T, Jiang Z-H, Wang J-R, Dong H, et al. Asian ginseng extract inhibits in vitro and in vivo growth of mouse lewis lung carcinoma via modulation of ERK-p53 and NF-jB signaling. J Cell Biochem 2010;111:899–910. [77] Ahn BZ, Kim SI. Relation between structure and cytotoxic activity of panaxydol analogs against L1210 cells. Arch Pharm (Weinheim) 1988;321:61–3. [78] Matsunaga H, Katano M, Yamamoto H, Fujito H, Mori M, Takata K. Cytotoxic activity of polyacetylene compounds in Panax ginseng C.A. Meyer. Chem Pharm Bull 1990;38:3480–4. [79] Poplawski J, Wrobel JT, Glinka T. Panaxydol, a new polyacetylenic epoxide from Panax ginseng roots. Phytochemistry 1980;19:1539–41. [80] Kitagawa I, Taniyama T, Shibuya H, Noda T, Yoshikawa M. Chemical studies on crude drug processing. V. On the constituents of ginseng radix rubra (2): comparison of the constituents of white ginseng and red ginseng prepared from the same Panax ginseng root. Yakugaku Zasshi 1987; 107:495–505. [81] Saita T, Katano M, Matsunaga H, Yamamoto H, Fujito H, Mori M. The first specific antibody against cytotoxic polyacetylenic alcohol, panaxynol. Chem Pharm Bull 1993;41:549–52. [82] Alanko J, Kurahashi Y, Yoshimoto T, Yamamoto S, Baba K. Panaxynol, a polyacetylene compound isolated from oriental medicines, inhibits mammalian lipoxygenases. Biochem Pharmacol 1994;48:1979–81. [83] Kim YS, Kim SI, Hahn DR. Effect of polyacetylene compounds from Panax ginseng on macromolecular synthesis by lymphoid leukemia L1210. Yakhak Hoechi 1988;32:137–40. [84] Otsuka H, Komiya T, Fujioka S, Goto M, Hiramatsu Y, Fujimura H. Studies on anti-inflammatory agents. IV. Anti-inflammatory constituents from roots of Panax ginseng C.A. Meyer. Yakugaku Zasshi 1981;101:1113–7. [85] Kim SI, Kang KS, Lee YH. Panaxyne epoxide, a new cytotoxic polyyne from Panax ginseng root against L1210 cells. Arch Pharm Res 1989;12:48–51. [86] Fujiki Y, Sato Y, Ushiyama K. Anticancer agents containing heptadeca-4,6diynes and formulations thereof. Japan Kokai Tokkyo Koho, 6 pp. Japanese Patent: JP 62207234 A2 19870911 Showa; 1987. [87] Fujimoto Y, Honma Y, Sato Y, Ushiyama K. Fungicides containing heptadecadiyne derivatives. Japan Kokai Tokkyo Koho, 5 pp. Japanese Patent: JP 01006201 A2 19890110 Heisei; 1989 [88] Fujimoto Y, Sato M. A new cytotoxic chlorine-containing polyacetylene from the callus of Panax ginseng. Chem Pharm Bull 1988;36:4206–8. [89] Kim SI, Lee YH, Kang KS. 10-Acetyl panaxytriol, a new cytotoxic polyacetylene from Panax ginseng. Yakhak Hoechi 1989;33:118–23. [90] Hirakura K, Takagi H, Morita M, Nakajima K, Niitsu K, Sasaki H, et al. Cytotoxic activity of acetylenic compounds from Panax ginseng. Nat Med (Tokyo) 2000;54:342–5. [91] Saita T, Katano M, Matsunaga H, Kouno I, Fujito H, Mori M. Screening of polyacetylenic alcohols in crude drugs using the ELISA for panaxytriol. Biol Pharm Bull 1995;18:933–7. [92] Lee G, Park H-G, Choi M-L, Kim YH, Park YB, Song K-S, et al. Falcarindiol, a polyacetylenic compound isolated from Peucedanum japonicum, inhibits mammalian DNA topoisomerase I. J Microbiol Biotechnol 2000; 2000(10):394–8. [93] Setzer WN, Gu X, Wells EB, Setzer MC, Moriarity DM. Synthesis and cytotoxic activity of a series of diacetylenic compounds related to falcarindiol. Chem Pharm Bull 2000;48:1776–7. [94] Fujimoto Y, Satoh M, Takeuchi N, Kirisawa M. Cytotoxic acetylene from Panax quinquefolium. Chem Pharm Bull 1991;39:521–3. [95] Fujimoto Y. Panaquinquecols of Panax quinquefolium and their use as anticancer agents. Japan Kokai Tokyo Koho, 9 pp. Japanese Patent: JP 06009418 A2 19940118 Heisei; 1994. [96] Fujimoto Y, Wang H, Satoh M, Takeuchi N. Polyacetylenes from Panax quinquefolium. Phytochemistry 1994;35:1255–7. [97] Fujimoto Y, Wang H, Kirisawa M, Satoh M, Takeuchi N. Acetylenes from Panax quinquefolium. Phytochemistry 1992;31:3499–501. [98] Bae HO, Chae GY, Chung HT, Jang SI, Kwon TO, Lee HS, et al. Acetylene compounds separated from Acanthopanax senticosus and composition containing the same to induce apoptosis. Kongkae Taeho Kongbo, Korean Patent: KP 2003059643 A 20030710; 2003. [99] Kustrak D. Siberian ginseng or the root from taiga – Eleutherococcus senticosus. Farm Glasnik 1993;49:1–7. [100] Kwak TH, Shin MS, Kim JY, Park J-K. Active fraction having anticancer and anti-metastasis isolated from Acanthopanax species and fruits. PCT

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

[101] [102] [103] [104]

[105]

[106]

[107]

[108] [109]

[110]

[111] [112]

[113]

[114] [115]

[116]

[117]

[118]

[119]

[120] [121]

[122] [123]

[124]

[125] [126]

[127] [128] [129] [130]

[131]

International, WO 2003099309 A1 Application: WO 2003-KR1043 20030528, 2003: 43 pp. Nishibe S. Bioactive lignans and flavonoids from traditional medicines. Colloques – Institut National de la Recherche Agronomique 1995;69:113–22. Smith M, Boon HS. Counseling cancer patients about herbal medicine. Patient Educ Couns 1999;38:109–20. Zhang Y, Liu B, Pei Y. Pharmacological action of Acanthopanax senticosus (Rupr. et Maxim.) Harms. Shenyang Yaoke Daxue Xuebao 2002;19:143–6. Zhang Z. Manufacture of traditional Chinese medicine freeze dried powder injection for treating tumors. Faming Zhuanli Shenqing Gongkai Shuomingshu, 15 pp. Chinese Patent: CN 1559454 A 20050105; 2005. Fujihashi T, Okuma T, Hirakura K, Mihashi H. Anticancer agents containing polyacetylenes. Japan Kokai Tokkyo Koho, 14 pp. Japanese Patent: JP 03200736 A2 19910902 Heisei; 1991. Jung V, Thibaut T, Meinesz A, Pohnert G. Comparison of the wound-activated transformation of caulerpenyne by invasive and noninvasive Caulerpa species of the Mediterranean. J Chem Ecol 2002;28:2091–5. Bae KH, Jung HJ. Biological polyacetylenes from Gymnaster koraiensis (Nakai) Kitamura. Recent advances in natural products research. In: Proceedings of the international symposium on recent advances in natural products research, 3rd, Seoul, Republic of Korea, Nov. 1999;19. p. 37–41. Metwally MA, King RM, Robinson H. An acetylenic epoxide and a ferulate from Coreopsis longula. Phytochemistry 1985;24:182–3. Borchardt JR, Wyse DL, Sheaffer CC, Kauppi KL, Fulcher G, Ehlke NJ, et al. Antimicrobial activity of native and naturalized plants of Minnesota and Wisconsin. J Med Plants Res 2008;2:98–110. Fullas F, Brown DM, Wani MC, Wall ME, Chagwedera TE, Farnesworth NR, et al. Gummiferol, a cytotoxic polyacetylene from the leaves of Adenia gummifera. J Nat Prod 1995;1995(58):1625–8. Takamura H, Wada H, Lu N, Kadota I. Total synthesis and absolute configuration of ()-gummiferol. Org Lett 2011;13:3644–7. Takamura H, Wada H, Lu N, Ohno O, Suenaga K, Kadota I. Total synthesis, structural elucidation, and structure–cytotoxic activity relationship of ()gummiferol. J Org Chem 2013;78:2443–54. Takahashi A, Endo T, Nozoe S. Repandiol, a new cytotoxic diepoxide from the mushrooms Hydnum repandum and H. repandum var. album. Chem Pharm Bull 1992;40:3181–4. Nozoe S, Takahashi A, Endo T. Preparation of repandiol derivatives as antitumor agents. Jpn. Kokai Tokkyo Koho, JP 05247017 A 19930924, 1993. Millard JT, Katz JL, Goda J, Frederick ED, Pierce SE, Speed TJ, et al. DNA interstrand cross-linking by a mycotoxic diepoxide. Biochimie 2004;86:419–23. Bohlmann F, Knoll KH, Robinson H, King RM. Naturally occurring terpene derivatives. Part 246. New guaianolides from Cacosmia rugosa. Phytochemistry 1980;19:599–602. Czerson H, Bohlmann F, Stuessy TF, Fischer NH. Sesquiterpenoid and acetylenic constituents of seven Clibadium species. Phytochemistry 1979;18:257–60. Jones ERH, Barley GC, Day AC, Graf U, O’Neill I, Tachikawa R, et al. Natural acetylenes. XXXIII. Biogenesis of the C9 diacetylenic triol from the fungus Clitocybe rhizophora. J Chem Soc 1971;19:3308–13. Bohlmann F, Ahmed M, King RM, Robinson H. Polyacetylenic compounds. Part 262. Acetylenic compounds from Bidens graveolens. Phytochemistry 1983;22:1281–3. Bohlmann F, Banerjee S, Jakupovic J. 3-Propyl-8-hydroxy-6methoxyisocoumarin from Solidago multiradiata. Planta Med 1984;50:201. Chialva F, Gabri G, Liddle PAP, Ulian F. Qualitative evaluation of aromatic herbs by direct head-space (GC)2 analysis. Applications of the method and comparison with the traditional analysis of essential oils. World Crops 1982;7:183–95. Ichihara K, Noda M. Distribution and metabolism of polyacetylenes in safflower. Biochim Biophys Acta 1977;487:249–60. Tietjen KG, Matern U. Induction and suppression of phytoalexin biosynthesis in cultured cells of safflower Carthamus tinctorius L., by metabolites of Alternaria carthami Chowdhury. Arch Biochem Biophys 1984;229:136–44. Magalhaes AF, Magalhaes EG, Vieira DM. Synthesis of wyerone benzene analog, its epoxide derivative and other a-alkynylcarbonyl compounds. Quim Nova 1987;10:189–93. Zeng H, Zeng Z, Yang D, Lai X. Volatile chemical constituents from traditional Chinese medicine Pochai pills. Yaowu Shengwu Jishu 2002;9:359–63. Liang B, Zheng C. Chemical constituents of volatile oil from the fruits and shells of Alpinia oxyphylia Miq. Tianran Chanwu Yanjiu Yu Kaifa 1992;4:18–26. Yano K. A new acetylenic alcohol from Cirsium japonicum. Phytochemistry 1980;19:1864–6. Takaishi Y, Okuyama T, Masuda A, Nakano K, Murakami K, Tomimatsu T. Acetylenes from Cirsium japonicum. Phytochemistry 1990;29:3849–52. Takasugi M, Kawashima S, Katsui N, Shirata A. Two polyacetylenic phytoalexins from Arctium lappa. Phytochemistry 1987;26:2957–8. Bohlmann F, Ziesche J. Naturally occurring terpene derivatives. Part 253. New guaianolides and acetylenic compounds from Ptilostemon species. Phytochemistry 1980;19:692–6. Andersen AB, Lam J, Wrang P. Polyunsaturated compounds of Centaurea scabiosa. Phytochemistry 1977;16:1829–31.

87

[132] Jung V, Thibaut T, Meinesz A, Pohnert G. Comparison of the wound-activated transformation of caulerpenyne by invasive and noninvasive Caulerpa species of the Mediterranean. J Chem Ecol 2002;28:2091–105. [133] Amico V, Oriente G, Piattelli M, Tringali C, Fattorusso E, Magno S, et al. Caulerpenyne, an unusual sesquiterpenoid from the green alga Caulerpa prolifera. Tetrahedron Lett 1978;38:3593–6. [134] Valls R, Lemee R, Piovetti L, Amade P, Bouaicha N. Determination of caulerpenyne, a toxin of the green alga Caulerpa taxifolia. Acta Bot Gallica 1995;142:131–5. [135] Guerriero A, Marchetti F, D’Ambrosio M, Senesi S, Dini F, Pietra F. New ecotoxicologically and biogenetically relevant terpenes of the tropical green seaweed Caulerpa taxifolia which is invading the Mediterranean. Helv Chim Acta 1993;76:855–64. [136] Lemee R, Pesando D, Durand-Clement M, Dubreuil A, Meinesz A, Guerriero A, et al. Preliminary survey of toxicity of the green alga Caulerpa taxifolia introduced into the Mediterranean. J Appl Phycol 1993;5:485–93. [137] Jung HJ, Min BS, Park JY, Kim YH, Lee HK, Bae KH. Gymnasterkoreaynes A–F, cytotoxic polyacetylenes from Gymnaster koraiensis. J Nat Prod 2002;65:897–901. [138] Guerriero A, Meinesz A, D’Ambrosio M, Pietra F. Isolation of toxic and potentially toxic sesqui- and monoterpenes from the tropical green seaweed Caulerpa taxifolia which has invaded the region of Cap Martin and Monaco. Helv Chim Acta 1992;75:689–95. [139] Weathers PJ, Arsenault PR, Covello PS, McMickle A, Teoh KH, Reed DW. Artemisinin production in Artemisia annua: studies in planta and results of a novel delivery method for treating malaria and other neglected diseases. Phytochem Rev 2011;10:173–83. [140] Rabe SZT, Mahmoudi M, Ahi A, Emami SA. Antiproliferative effects of extracts from Iranian Artemisia species on cancer cell lines. Pharm Biol 2011;49:962–9. [141] Zhai D-D, Supaibulwatana K, Zhong J-J. Inhibition of tumor cell proliferation and induction of apoptosis in human lung carcinoma 95-D cells by a new sesquiterpene from hairy root cultures of Artemisia annua. Phytomedicine 2010;2010(17):856–61. [142] Manns D, Hartmann R. Annuadiepoxide, a new polyacetylene from the aerial parts of Artemisia annua. J Nat Prod 1992;55:29–32. [143] Robbins WJ, Kavanagh F, Hervey A. Antibiotic substances from Basidiomycetes. II. Polyporus biformis. Proc Natl Acad Sci USA 1947;33:176–82. [144] Anchel M, Cohen MP. Biformin. I. Its characterization as a polyacetylenic 9carbon glycol. J Biol Chem 1954;208:319–26. [145] Kavanagh F. Activities of twenty two antibacterial substances against nine species of bacteria. J Bacteriol 1947;54:761–6. [146] Dagne E, Asmellash S, Abate D. An antifungal polyacetylenic compound from the culture filtrate of the fungus Trametes pubescens. J Nat Prod 1994;57:390–2. [147] Kuropka G, Neugebauer M, Glombitza KW. Essential oils of Achillea ptarmica. Planta Med 1991;57:492–4. [148] Bohlmann F, Arndt C, Bornowski H, Jastrow H, Kleine KM. Polyacetylenic compounds. XXXVIII. New polyynes from the tribe Anthemideae. Berichte 1962;95:1302–7. [149] Bruno W, Otmar H, Harald G. Polyacetylenes from the Artemisia ‘Vulgares’ group. Phytochemistry 1989;28:2687–91. [150] Dan DZ, Jian JZ. Simultaneous analysis of two bioactive compounds in Artemisia annua L. hairy root cultures by reversed-phase. J Biotechnol 2008;136:S350–8. [151] Dou D, Liu P, Kang T. Method for preparing Oplopanax leaf total saponin extract with antitumor effect. 8 pp. Chinese Patent: Faming Zhuanli Shenqing CN 101732377 A; 2010. [152] Yang MC, Kwon HC, Kim Y-J, Lee KR, Yang HO. Oploxynes A and B, polyacetylenes from the stems of Oplopanax elatus. J Nat Prod 2010;73:801–5. [153] Yadav JS, Boyapelly K, Alugubelli SR, Pabbaraja S, Vangala JR, Kalivendi SV. Stereoselective total synthesis of (+)-oploxyne A, ()-oploxyne B, and their C10 epimers and structure revision of natural oploxyne B. J Org Chem 2011;76:2568–76. [154] Wrang PA, Lam J. Polyacetylenes from Chrysanthemum leucanthemum. Phytochemistry 1975;14:1027–35. [155] Kim C, Kim M-C, Kim S-M, Nam D, Choi S-H, Kim S-H, et al. Chrysanthemum indicum L. extract induces a Apoptosis through suppression of constitutive STAT3 activation in human prostate cancer DU145 Cells. Phytother Res 2013;2013(27):30–8. [156] Campbell DL. The tea book. Gretna: Pelican Publishing; 1995. p. 223. [157] Lam J, Kaufmann F. Chemical constituents of the genus Dahlia. VI. Polyacetylenic C14-epoxide and C14-tetrahydropyranyl compounds from Dahlia scapigera. Phytochemistry 1971;10:1877–80. [158] Jung MY, Yang SM, Lee IS, Jung MH, Lee SC, Choi SJ, et al. Coffee powder containing lotus root and rice and its manufacture method. Korean Patent: Repub. Korean Kongkae Taeho Kongbo, 17 pp., R 2010122217 A; 2010. [159] Bohlmann F, Moench H. Polyacetylene compounds. CXXXIII. New polyyne epoxides from Centaurea deusta. Chem Ber 1967;100:1944–8. [160] Cambie RC, Gardner JN, Jones ERH, Lowe G, Read G. Chemistry of the higher fungi. XIV. Polyacetylenic metabolites of Poria sinuosa. J Chem Soc 1963:2056–64.

88

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

[161] Seshimoto F, Hong SW, Nakajyo H, Shigemori H. New antibacterial polyacetylenes from sunflower (Helianthus annuus L.) seedlings. Heterocycles 2011;83:1067–76. [162] Yamazoe S, Hasegawa K, Shigemori H. Structure–activity relationship of acetylenes from galls of Hedera rhombea as plant growth inhibitors. Z Naturforsch 2006;61C:536–40. [163] Yamazoe S, Hasegawa K, Suenaga K, Shigemori H. Growth inhibitory polyacetylenes from galls of Hedera rhombea bean. Nat Prod Commun 2006;1:87–94. [164] Camps F, Fabrias G, Gasol V, Guerrero A, Nernandez, Montoya. Analogs of sex pheromone of processionary moth, Thaumetopoea pityocampa: synthesis and biological activity. J Chem Ecol 1988;14:1331–46. [165] Bohlmann F, Gerke T, King RM, Robinson H. Polyacetylenic compounds. 266. New C17 acetylenic compounds from Solidago spathulata DC. Liebigs Ann Chem 1983;4:714–6. [166] Saito Y, Iwamoto Y, Okamoto Y, Gong X, Kuroda C, Tori M. Four new guaianolides and acetylenic alcohol from Saussurea katochaete collected in China. Nat Prod Commun 2012;7:447–50. [167] Bohlmann F, Fanghaenel L, Wotschokowsky M, Laser J. Polyacetylene compounds. CLIV. Isolation of additional acetylene compounds from Aethusa cynapium and biosynthesis of the main components. Chem Ber 1968;101:2510–8. [168] Bohlmann F, Rode KM, Zdero C. Polyacetylene compounds. CXXI. Polyynes from Helenieae tribe. Chem Ber 1967;100:537–41. [169] Bohlmann F, Sinn H. Polyacetylenic compounds. XIV. Reaction of polyenynes with ozone and peracids. Chem Ber 1955;88:1869–77. [170] Venus-Danilova ED, Printseva ZV. Transformations of acetylenic c-glycols. IV. Isomerization of unsym-methyldi-p-tolylbutynediol (1,1-di-p-tolyl-2pentyne-1,4-diol). Zh Obshch Khim 1956;26:2170–4. [171] Bernard D, Doutheau A, Gore J, Moulinoux J, Quemener V, Chantepie J, et al. cAmino a-acetylenic epoxides. Preparation and biological activity due to an aldehyde reductase inhibition. Tetrahedron 1989;45:1429–39. [172] Israel M, Dudak RM, Donovan GJ. Acetylenic epoxy amino compounds. US Patent: US 1963-285898, 2 pp.; 1966. [173] Grandjean D, Pale P, Chuche J. First total synthesis of optically pure methyl (2Z,8S,9R)-8,9-epoxydeca-4,6-diyn-2-en-10-hydroxy-1-oate and its acetate, two naturally-occurring antifeedants. Tetrahedron Lett 1992;33:5355–8. [174] Wang B. (3R,9R,10R)-9,10-epoxy-1-heptadecene-4,6-diyn-3-ol, and medical application as antitumor agents. Chinese Patent: CN 102382078 A. Faming Zhuanli Shenqing, 13pp.; 2012. [175] Kim S-I, Lee Y-H, Ahn B-Z. Synthesis of Ginseng diyne analogs and their antiproliferative activity against L1210 cells. Arch Pharm (Weinheim) 1999;332:133–6. [176] Kibina IYu, Shchelkunov AV. Polyacetylene epoxides – analogs of natural compounds. I. Synthesis of the epoxydiacetylene alcohol 2,7-dimethyl-1,2epoxy-3,5-octadiyn-7-ol using the Chodkiewicz–Cadiot reaction. Deposited Doc. VINITI 139–75 (USSR), 1974:10pp. [177] Golodova KG, Yakimovich SI. Stereochemistry of acetylene a-oxides. Khim Geterotsikl Soed 1974;1:19–21. [178] Malinovskii MS, Skrodskaya TS, Yudasina AG, Khmel MP, Larionova VG, Krivosheeva NG, et al. Studies in the field of acetylenic epoxides. Tezisu Dokl. Vses. Konf. Khim. Atsetilena, 5th, USSR; 1975. p. 82–83. [179] Koenig WA, Lutz S, Wenz G, Goergen G, Neumann C, Gaebler A, et al. Gas chromatographic determination of the enantiomeric composition of epoxy alcohols. Angew Chem 1989;101:180–1. [180] Sustmann R, Mueller W, Roth WR, Wittich D. An analysis of the electronic structure of 6,7-dimethyl-3-oxabicyclo[3.2.0]hepta-1,4,6-triene. Chem Ber 1985;118:3939–43. [181] Van Duuren BL, Goldschmidt BM, Katz C, Seidman I, Paul JS. Carcinogenic activity of alkylating agents. J Natl Cancer Inst 1974;53:695–700. [182] Parker WL, Rathnum ML, Seiner V, Trejo WH, Principe PA, Sykes RB. Cepacin A and cepacin B, two new antibiotics produced by Pseudomonas cepacia. J Antibiot 1984;37:431–40. [183] Hargreaves JA, Mansfield JW, Coxon DT, Price KR. Wyerone epoxide as a phytoalexin in Vicia faba and its metabolism by Botrytis cinerea and B. fabae in vitro. Phytochemistry 1976;15:1119–21. [184] Levy LM, Cabrera GM, Wright JE, Seldes AM. 5H-Furan-2-ones from fungal cultures of Aporpium caryae. Phytochemistry 2003;62:239–43. [185] Quintana N, Weir TL, Du J, Broeckling CD, Rieder JP, Stermitz FR, et al. Phytotoxic polyacetylenes from roots of Russian knapweed (Acroptilon repens (L.) DC.). Phytochemistry 2008;69:2572–8. [186] Tursun K, Zhan R, Zhang H, Ababakri S. Study on antioxidant activity of Acroptilon repens. Shengwu Jishu Tongxun 2010;21:406–12. [187] Hymete A, Rohloff J, Kjoesen H, Iversen T-H. Acetylenic thiophenes from the roots of Echinops ellenbeckii from Ethiopia. Nat Prod Res 2005;19:755–61. [188] Lam J, Christensen LP, Thomasen T. Thiophene derivatives from Echinops species. Phytochemistry 1991;30:1157–9. [189] Stevens KL, Witt SC, Turner CE. Polyacetylenes in related thistles of the subtribes Centaureinae and Carduinae. Biochem Syst Ecol 1990;18:229–32. [190] Bohlmann F, Arndt C, Kleine KM, Bornowski H. Polyacetylene compounds. LXIX. The acetylene compounds of the genus Echinops. Chem Ber 1965;98:155–63. [191] Bohlmann F, Zdero C, Ahmed M. Naturally occurring terpene derivatives. Part 422. New sesquiterpene lactones, geranyllinalol derivatives, and other constituents from Geigeria species. Phytochemistry 1982;21:1679–91.

[192] Ellis S, Balza F, Towers GHN. A dithiacyclohexadiene polyyne alcohol from Ambrosia chamissonis. Phytochemistry 1993;33:224–6. [193] Balza F, Lopez I, Rodriguez E, Towers GHN. Dithiacyclohexadienes and thiophenes from Ambrosia chamissonis. Phytochemistry 1989;28:3523–4. [194] Hudson JB, Balza F, Harris L, Towers GHN. Light-mediated activities of thiarubrines against human immunodeficiency virus. Photochem Photobiol 1993;57:675–80. [195] Towers GHN, Balza F, Lopez-Bazzochi I, Bruening RC, Abramowski Z. Thiarubrine antifungal and antibiotic agents. Patent PCT Int. Appl., WO 9109027 A1, 42 pp.; 1991. [196] Page JE, Block E, Towers GHN. Visible-light photochemistry and phototoxicity of thiarubrines. Photochem Photobiol 1999;70:159–65. [197] Gonzalez AG, Bermejo Barrera J, Diaz JG, Zaragoza Garcia T, De Paz PP. Distribution of acetylenes and sesquiterpene lactones in Argyranthemum from Tenerife. Biochem Syst Ecol 1987;16:17–21. [198] Gonzalez AG, Estevez-Reyes R, Estevez-Braun A, Ravelo AG, Jimenez IA, Bazzocchi IL, et al. Biological activities of some Argyranthemum species. Phytochemistry 1997;45:963–7. [199] Lu T, Parodi FJ, Vargas D, Quijano L, Mertooetomo ER, Hjortso MA, et al. Sesquiterpenes and thiarubrines from Ambrosia trifida and its transformed roots. Phytochemistry 1993;33:113–6. [200] Gehrt A, Erkel G, Anke T, Sterner O. Nitidon, a new bioactive metabolite from the basidiomycete Junghuhnia nitida. Z Naturforsch 1998;53C:89–92. [201] Bellina F, Carpita A, Mannocci L, Rossi R. First total synthesis of naturally occurring ()-nitidon and its enantiomer. Eur J Org Chem 2004;12:2610–9. [202] Westphalen MC, Reck MA, Borges da Silveira RM. The genus Junghuhnia in Brazil. Nova Hedwigia 2011;94:209–20. [203] Bentley RK, Higham CA, Jenkins JK, Jones ERH, Thaller V. Natural acetylenes. XLIV. C14 polyacetylenes from Trachelium caeruleum (Campanulaceae). J Chem Soc Perkin Trans 1 1974;16:1987–91. [204] Bohlmann F, Zdero C. Naturally occurring coumarins. 18. New obliquin derivatives from Helichrysum serpyllifolium. Phytochemistry 1980;19:331–2. [205] Stanojkovic TP, Konic-Ristic A, Juranic ZD, Savikin K, Zdunic G, Menkovic N, et al. Cytotoxic and cell cycle effects induced by two herbal extracts on human cervix carcinoma and human breast cancer cell lines. J Med Food 2010;13:291–7. [206] Eroglu HE, Aksoy A, Hamzaoglu E, Budak U, Albayrak S. Cytogenetic effects of nine Helichrysum taxa in human lymphocytes culture. Cytotechnology 2009;59:65–72. [207] Bohlmann F, Arndt C, Zdero C. Polyacetylene compounds. CII. New enol ether polyynes from Anaphalis and Gnaphalium species. Chem Ber 1966;99:1648–51. [208] Bohlmann F, Zdero C, Hoffmann E, Mahanta PK, Dorner W. Naturally occurring terpene derivatives. Part 166. New diterpenes and sesquiterpenes from South African Helichrysum species. Phytochemistry 1978;17:1917–22. [209] Liu L-L, Wang R, Shi Y-P. Chrysindins A–D, polyacetylenes from the flowers of Chrysanthemum indicum. Planta Med 2001;77:1806–10. [210] Zhang B, Wang Y, Yang S-P, Zhou Y, Wu W-B, Tang W, et al. An unprecedented immunosuppressive macrolide from Khaya ivorensis: structural elucidation and bioinspired total synthesis. J Am Chem Soc 2012;134:20605–8. [211] Croteau RB, Davis EM, Ringer KL, Wildung MR. ()-Menthol biosynthesis and molecular genetics. Naturwissenschaften 2005;92:562–77. [212] Croteau R, Loomis WD. Biosynthesis and metabolism of monoterpenes. Int Flavours Food Addit 1975;6:292–6. [213] Jiang M-Y, Li Y, Wang F, Liu J-K. Isoprenylated cyclohexanoids from the basidiomycete Hexagonia speciosa. Phytochemistry 2011;72:923–8. [214] Jiang M-Y, Zhang L, Liu R, Dong Z-J, Liu J-K. Speciosins A–K, oxygenated cyclohexanoids from the basidiomycete Hexagonia speciosa. J Nat Prod 2009;72:1405–9. [215] Kim H-J, Vinale F, Ghisalberti EL, Worth CM, Sivasithamparam K, Skelton BW, et al. An antifungal and plant growth promoting metabolite from a sterile dark ectotrophic fungus. Phytochemistry 2006;67:2277–80. [216] Qin M, Gong J, Gu Y, Liang Z. Volatile constituents in flowers of Dendranthema morifolium cv. Gongju. Zhiwu Ziyuan Yu Huanjing Xuebao 2003;4:54–6. [217] Russell SW, Weedon BCL. Allenic ketone from grasshoppers. Chem Commun 1969;3:85–6. [218] Skrodskaya TS, Yudasina AG, Malinovskii MS, Dolgina AS. 1-Ethynyl-1,2epoxycyclohexane. Ukr Khim Zh 1966;32:604–6. [219] Daxenbichler ME, Van Etten H, Wolff IA. Diastereomeric 1-cyano-2(S)hydroxy-3,4-epithiobutanes from epiprogoitrin of crambe seed. Chem Commun 1966;15:526–7. [220] Ito M, Hirata Y, Tsukida K, Tanaka N, Hamada K, Hino R, et al. Retinoids and related compounds. XI. Synthesis and stereochemistry of (±)-C22-acetylenic and allenic apocarotenals. Chem Pharm Bull 1988;36:3328–40. [221] Abrams SR, Loewen MC, Boyd J, Cutler AJ, Gai Y, Nelson KM. Use of 9-cis epoxycarotenoid dioxygenase inhibitors for regulation of maturation, desiccation tolerance, dormancy, or adaptation to stress in plants or seeds. US Patent: US 20100160166 A1, 30 pp.; 2010. [222] Ghera E, Gibson M, Sondheimer F. Syntheses in the terpene series. XI. Model experiments with sym-dicyclohexylethane derivatives. J Am Chem Soc 1962;84:2953–61. [223] Franck-Neumann M, Geoffroy P, Miesch M, Zaragoza DF. Convergent syntheses in the sesquicarene series using a C7-vinylalkynylcarbene. Tetrahedron Lett 1990;31:4121–4.

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91 [224] Wriede U, Speakman JB, Karl R, Pommer EH, Ammermann E, Wuerzer B. Patent DDR: DE 1987-3707358, Ger. Offen. 22 pp.; 1988. [225] Sosnovskii GM, Chirko AI, Tishchenko IG, Abramov AF. Autoxidation of 1,2epoxy-4-cyclohexyl-2-methyl-3-butyne. Vestsi Akad Navuk BSSR Ser Khim Navuk 1978;5:91–4. [226] Kamikubo T, Ogasawara K. Absolute configuration of (+)-PT-toxin: enantiodivergent synthesis of (+)- and ()-PT-toxins. Heterocycles 1998;47:69–72. [227] Kawazu K, Kobayashi A, Oe K. Cell division-inhibiting harveynones from Curvularia harveyi. Japanese Patent: Jpn. Kokai Tokkyo Koho, 3pp.; 1991. [228] Kobayashi A, Ooe KYS, Kawazu K. Chemical studies of microtubule assembly regulators of microbial origin. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 1989;1989(31):388–95. [229] Nagata T. Tea quality components. Chagyo Kenkyu Hokoku 1990;72:53–8. [230] Muehlenfeld A, Achenbach H. Metabolites of microorganisms. Part 36. Asperpentyn, a novel acetylenic cyclohexene epoxide from Aspergillus duricaulis. Phytochemistry 1988;27:3853–5. [231] Klaiklay S, Rukachaisirikul V, Tadpetch K, Sukpondma Y, Phongpaichit S, Buatong J, et al. Chlorinated chromone and diphenyl ether derivatives from the mangrove-derived fungus Pestalotiopsis sp. PSU-MA69. Tetrahedron 2012;68:2299–305. [232] Baldwin A, Grueneberg D, Harlow E, Xian J, Munger K, Hellner K, et al. Compositions and methods for inhibiting tumor growth and for identifying antitumor agents and tumor survival kinases. PCT Int. Appl. WO 2010141738 A2 20101209, 2010. [233] Takahashi S, Itoh Y, Takeuchi M, Furuya K, Kodama K, Naito A, et al. Isolation and structure of oxirapentyn. J Antibiot 1983;36:418–20. [234] Smetanina OF, Yurchenko AN, Afiyatullov SSh, Kalinovsky AI, Pushilin MA, Khudyakova YV, et al. Oxirapentyns B–D produced by a marine sedimentderived fungus Isaria felina (DC.) Fr. Phytochem Lett 2012;5:165–9. [235] Garlaschelli L, Magistrali E, Vidari G, Zuffardi O. Fungal metabolites. 38. Tricholomenyns A and B, novel antimitotic acetylenic cyclohexenone derivatives from the fruiting bodies of Tricholoma acerbum. Tetrahedron Lett 1995;36:5633–6. [236] Garlaschelli L, Vidari G, Vita-Finzi P. Fungal metabolites. 41. Tricholomenyns C, D, and E, novel dimeric dienyne geranyl cyclohexenones from the fruiting bodies of Tricholoma acerbum. Tetrahedron Lett 1996;37:6223–6. [237] Nakamura Y, Ohto Y, Murakami A, Jiwajinda S, Ohigashi H. Isolation and identification of acetylenic spiroketal enol ethers from Artemisia lactiflora as inhibitors of superoxide generation induced by a tumor promoter in differentiated HL-60 cells. J Agric Food Chem 1998;46:5031–6. [238] Murakami A, Ohigashi H. Cancer preventive potentials of edible plants from subtropical countries. Food Style 1999;3:35–9. [239] Ohigashi H, Nakamura Y, Murakami A. Active components and antitumor effects of tropical Asian foods. Food Style 1998;2:31–5. [240] Nakamura Y, Kawamoto N, Ohto Y, Torikai K, Murakami A, Ohigashi H. A diacetylenic spiroketal enol ether epoxide, AL-1, from Artemisia lactiflora inhibits 12-O-tetradecanoylphorbol-13-acetate-induced tumor promotion possibly by suppression of oxidative stress. Cancer Lett 1999;140:37–45. [241] Ma L, Ge F, Tang C-P, Ke C-Q, Li X-Q, Althammer A, et al. The absolute configuration determination of naturally occurring diacetylenic spiroacetal enol ethers from Artemisia lactiflora. Tetrahedron 2011;67:3533–9. [242] Birnecker W, Wallnoefer B, Hofer O, Greger H. Relative and absolute configurations of two naturally occurring acetylenic spiroketal enol ether epoxides. Tetrahedron 1988;44:267–76. [243] Xu C, Sun X, Yang J, Yu D, Li Q, Zhang Y, et al. The structure of lactiflorasyne isolated from Artemisia lactiflora wall. Yao Xue Xue Bao 1986;21:772–5. [244] Fang H, Hu Q, Ma Y, Sun S, Xu C, Zeng X, et al. Constituents of volatile oils. IV. Chemical constituents of the volatile oil from Bai Hua Hao (Artemisia lactiflora wall). Zhongcaoyao 1984;15:99–101. [245] Stojakowska A, Burczyk J, Kisiel W, Zych M, Banas A, Duda T. Effects of various elicitors on the accumulation and secretion of spiroketal enol ether diacetylenes in feverfew hairy root culture. Acta Soc Bot Poloniae 2008;77:17–21. [246] Tan RX, Wei HX, Cui YX. NMR studies of the regio- and stereoselectivity of 1,3-dipolar cycloaddition of diazomethane to a, b-unsaturated spiroketals from Artemisia species. Spectrosc Lett 1996;29:1035–46. [247] Bohlmann F, Zdero C. Polyacetylenic compounds. 174. New spiro ketal enol ether polyynes from species of the tribe Anthemideae. Chem Ber 1970;103:1879–85. [248] Dembitsky VM, Rozentsvet OA. Distribution of polar lipids in some marine, brackish and freshwater green macrophytes. Phytochemistry 1996;41:483–8. [249] Dembitsky VM, Rezanka T. Natural occurrence of arseno compounds in plants, lichens, fungi, algal species, and microorganisms. Plant Sci 2003;165:1177–92. [250] Dembitsky VM, Levitsky DO. Arsenolipids. Prog Lipid Res 2004;43:403–48. [251] Dembitsky VM, Srebnik M. Natural halogenated fatty acids: their analogs and derivatives. Prog Lipid Res 2002;41:315–67. [252] Dembitsky VM. Bioactive peroxides as potential therapeutic agents. Eur J Med Chem 2008;43:223–51. [253] Dembitsky VM, Maoka T. Allenic and cumulenic lipids. Prog Lipid Res 2007;46:328–75. [254] Dembitsky VM. Biogenic iodine and iodine-containing metabolites. Nat Prod Commun 2006;1:139–75.

89

[255] Dembitsky VM. Natural neo acids and neo alkanes: their analogs and derivatives. Lipids 2006;41:309–40. [256] Mendiola J, Hernández H, Sariego I, González Z, Rojas L, Robles Laurencio R, et al. In vitro antimalarial activity and cytotoxicity against human macrophage cell line of extracts of marine organisms collected in the North West coast of Cuba. Plant. Med., Rev. Cuba Farmaceut. 2004(Supl. Esp):23–8. [257] Sabina H, Tasneem S, Sambreen Kausar Y, Choudhary MI, Aliya R. Antileishmanial activity in the crude extract of various seaweeds from the coast of Karachi, Pakistan. Pak J Bot 2005;37:163–8. [258] Crespo Pereira R, Laneuville Teixeira V. Sesquiterpenes of the marine algae Laurencia lamouroux (Ceramiales, Rhodophyta). Quim Nova 1999;22:369–74. [259] Machado FLDS, Kaiser CR, Costa SS, Gestinari LM, Soares AR. Biological activity of the secondary metabolite from marine algae of the genus Laurencia. Rev Bras Farm 2010;20:441–52. [260] Suzuki M, Vairappan CS. Halogenated secondary metabolites from Japanese species of the red algal genus Laurencia (Rhodomelaceae, Ceramiales). Curr Top Phytochem 2005;7:1–34. [261] Koenig GM, Wright AD. Marine organisms. Producers of pharmacologically active secondary substances. Pharm Unserer Zeit 1997;26:281–8. [262] Fukuzawa A, Kurosawa E. Constituents of marine plants. XXXVIII. Laureepoxide, new bromo ether from the marine red alga Laurencia nipponica Yamada. Tetrahedron Lett 1980;21:1471–4. [263] Fukuzawa A, Aye M, Takaya Y, Fukui H, Masamune T, Murai A. Laureoxolane, a new bromo ether from Laurencia nipponica. Tetrahedron Lett 1989;30:3665–8. [264] Guella G, Mancini I, Chiasera G, Pietra F. On the unusual propensity by the red seaweed Laurencia microcladia of II Rogiolo to form C15 oxepanes: isolation of rogioloxepane A, B, C, and their likely biogenetic acyclic precursor, prerogioloxepane. Helv Chim Acta 1992;75:310–22. [265] Guella G, Pietra F. Rogiolenyne A, B, and C: the first branched marine C15 acetogenins. Isolation from the red seaweed Laurencia microcladia or the sponge Spongia zimocca of Il Rogiolo. Helv Chim Acta 1991;74:47–54. [266] Stichler-Bonaparte J, Bernet B, Vasella A. Oligosaccharide analogues of polysaccharides. Part 25 synthesis of mono- and diethynylated analogues of 2-acetamido-2-deoxy-D-glucopyranose. Helv Chim Acta 2002;85:2235–57. [267] Howard BM, Fenical W, Hirotsu K, Solheim B, Clardy J. The rhodophytin and chondriol natural products; structures of several new acetylenes from Laurencia, and a reassignment of structure for cis-rhodophytin. Tetrahedron 1980;36:171–6. [268] Imre S, Lotter H, Wagner H, Thomson RH. Epoxy-trans-isodihydrorhodophytin, a new metabolite from Laurencia obtuse. Z Naturforsch 1987;42C:507–9. [269] Gonzalez AG, Martin JD, Martin VS, Norte M, Perez R, Ruano JZ, et al. Marine natural products from the Atlantic zone. Part 25. Nonterpenoid C-15 metabolites from the red seaweed Laurencia pinnatifida. Tetrahedron 1982;38:1009–14. [270] Gallimore WA, Kelly M, Scheuer PJ. Gelliusterols A–D, new acetylenic sterols from a sponge, Gellius species. J Nat Prod 2001;64:741–4. [271] Steiner E, Djerassi C, Fattorusso E, Magno S, Mayol L, Santacroce C, et al. Isolation, structure determination and synthesis of new acetylenic steroids from the sponge Calyx nicaaensis. Helv Chim Acta 1977;60:475–81. [272] Onken D, Heublein D. Acetylenated steroids. Pharmazie 1970;25:3–9. [273] Nagahisa A, Spencer RW, Orme-Johnson WH. Acetylenic mechanism-based inhibitors of cholesterol side chain cleavage by cytochrome P-450scc. J Biol Chem 1983;258:6721–3. [274] Akihisa T, Tamura T, Matsumoto T, Kokke WCMC, Yokota T. Isolation of acetylenic sterols from a higher plant. Further evidence that marine sterols are not unique. J Org Chem 1989;54:606–10. [275] Encarnacion-Dimayuga R, Agundez-Espinoza J, Garcia A, Delgado G, MolinaSalinas GM, Said-Fernandez S. Two new cassane-type diterpenes from Calliandra californica with antituberculosis and cytotoxic activities. Planta Med 2006;72:757–61. [276] Thompson RM, Horning EC. Preparation and reactions of norethynodrel epoxide. Possible mechanisms for A-ring aromatization of 19-norsteroids. Steroids Lipids Res 1974;5:133–42. [277] Sedee AGJ, Beijersbergen Van Henegouwen GMJ , Blaauwgeers HJA. Isolation, identification and densitometric determination of norethisterone 4b,5bepoxide after photochemical decomposition of norethisterone. Int J Pharm 1983;15:149–58. [278] White INH, Suzangar M. Cytotoxic effects of norethindrone-4b,5b-epoxide to Walker cells in culture and to rat liver in vivo. Chem Biol Interact 1980;30:355–66. [279] Peter H, Jung R, Bolt HM, Oesch F. Norethisterone 4b,5-oxide and levonorgestrel 4b,5-oxide: formation in rat liver microsomal incubations and interference with microsomal epoxide hydrolase and cytoplasmic glutathione S-transferase. J Steroid Biochem 1981;14:83–90. [280] Ponsold K, Wunderwald M. 5a,10a-Epoxy-17-ethynyl steroids. France Patent: FR 2019734; 1970. [281] Torelli V, Teutsch JG, Philibert D. Preparation of estradienolone derivatives useful as antiglucocorticoids and antiprogestomimetics, and their pharmaceutical formulation. US Patent: US 1985-693682, 41 pp.; 1987. [282] Verhoeven CHJ, Krebbers SFM, Wagenaars GN, Vos RME. In vitro and in vivo metabolism of desogestrel in several species. Drug Metab Dispos 1998;26:927–36. [283] Luu DH. Synthesis, study on characteristics, structure and stereochemistry of the C(17)-center of epimer pair of the 16-keto-17a/b-ethynyl steroids. Tap Chi Phan Tich Hoa, Ly Va Sinh Hoc 2004;9:24–9.

90

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91

[284] Ellis B, Petrow V, Waterhouse B. Modified steroid hormones. XVI. Preparation of some 6-ethynyl steroids. J Chem Soc 1960:2596–602. [285] Luu DH. Synthesis of some new C ring steroidal derivatives. Tap Chi Hoa Hoc 2005;43:250–2. [286] Gravanis A, Calogeropoulou T, Castanas E, Margioris A, Charalambopoulos I, Avlonitis N, et al. Neurosteroid compounds with antiapoptotic, neuroprotective and neurogenic properties. Patent: WO 2008-GB2067, PCT Int. Appl., 62 pp.; 2008. [287] Reddy SG. Cyclic ether vitamin D3 compounds, 1a-hydroxy-3-epivitamin D3 compounds and uses thereof. WO 1998-US10062 PCT Int. Appl., 93pp., 1998. [288] Allewaert K, Zhao X-Y, Zhao J, Glibert F, Branisteanu D, De Clercq P, et al. Biological evaluation of epoxy analogs of 1a,25-dihydroxyvitamin D3. Steroids 1995;60:324–32. [289] Van Baelen H, Convents R, Bouillon R. Activity of vitamin D analogs in cotransfected COS-7 cells. In: Proceedings of the workshop on vitamin D; 1994; 9. p. 77–78. [290] Bouillon R, Vandewalle M, De Clercq PJ. Novel structural analogs of vitamin D. Novel structural analogs of vitamin D. Patent: PCT Int. Appl. WO 1994EP2294, 192 pp.; 1995. [291] Weedon BCL. Allenic and acetylenic carotenoids. Rev Pure Appl Chem 1970;20:51–66. [292] Partali V, Tangen K, Liaaen-Jensen S. Carotenoids in food chain studies. III. Resorption and metabolic transformation of carotenoids in Mytilus edulis (edible mussel). Comp Biochem Physiol 1989;92B:239–46. [293] Loeblich III AR, Smith VE. Chloroplast pigments of marine dinoflagellate Gyrodinium resplendens. Lipids 1968;3:5–13. [294] Johansen JE, Svec WA, Liaaen-Jensen S, Haxo FT. Algal carotenoids. 10. Carotenoids of dinophyceae. Phytochemistry 1974;13:2261–71. [295] Maoka T, Fujiwara Y, Hashimoto K, Akimoto N. Carotenoids in three species of corbicula clams, Corbicula japonica, Corbicula sandai, and Corbicula sp. (Chinese freshwater corbicula clam). J Agric Food Chem 2005;53:8357–64. [296] Skjenstad T, Haxo FT, Liaaen-Jensen S. Algal carotenoids. 27. Carotenoids of clam, coral and nudibranch zooxanthellae in aposymbiotic culture. Biochem Syst Ecol 1984;12:149–53. [297] Maoka T, Akimoto N, Tsushima M, Komemushi S, Mezaki T, Iwase F, et al. Carotenoids in marine invertebrates living along the Kuroshio current coast. Mar Drugs 2011;9:1419–27. [298] Matsuno T, Ookubo M. A new carotenoid, halocynthiaxanthin from the sea squirt, Halocynthia roretzi. Tetrahedron Lett 1981;22:4659–60. [299] Matsuno T, Ookubo M, Nishizawa T, Shimizu I. Carotenoids of sea squirts. 1. New marine carotenoids, halocynthiaxanthin and mytiloxanthinone from Halocynthia roretzi. Chem Pharm Bull 1984;1984(32):4309–15. [300] Hertzberg S, Partali V, Liaaen-Jensen S. Animal carotenoids. 32. Carotenoids of Mytilus edulis (edible mussel). Acta Chem Scand 1988;42B:495–503. [301] Maoka T, Akimoto N, Murakoshi M, Sugiyama K, Nishino H. Carotenoids in clams, Ruditapes philippinarum and Meretrix petechialis. J Agric Food Chem 2010;58:5784–8. [302] Maoka T, Ochi J, Mori M, Sakagami Y. Identification of carotenoids in the freshwater shellfish Unio douglasiae nipponensis, Anodonta lauta, Cipangopaludina chinensis laeta, and Semisulcospira libertine. J Oleo Sci 2012;61:69–74. [303] Nishino H, Tsushima M, Matsuno T, Tanaka Y, Okuzumi J, Murakoshi M, et al. Antineoplastic effect of halocynthiaxanthin, a metabolite of fucoxanthin. Anticancer Drugs 1992;3:493–7. [304] Yoshida T, Maoka T, Das SK, Kanazawa K, Horinaka M, Wakada M, et al. Halocynthiaxanthin and peridinin sensitize colon cancer cell lines to tumor necrosis factor-related apoptosis-inducing ligand. Mol Cancer Res 2007;5:615–25. [305] Konishi I, Hosokawa M, Sashima T, Kobayashi H, Miyashita K. Halocynthiaxanthin and fucoxanthinol isolated from Halocynthia roretzi induce apoptosis in human leukemia, breast and colon cancer cells. Comp Biochem Phys 2006;142C:53–9. [306] Bjørnland T, Fiksdahl A, Skjetne T, Krane J, Liaaen-Jensen S. Gyroxanthin – the first allenic acetylenic carotenoid. Tetrahedron 2000;56:9047–56. [307] Seoane S, Eikrem W, Pienaar R, Edvardsen B. Chrysochromulina palpebralis sp. nov. (Prymnesiophyceae): a haptophyte, possessing two alternative morphologies. Phycologia 2009;48:165–76. [308] Heelis DV, Kernick W, Phillips GO, Davies K. Separation and identification of the carotenoid pigments of stigmata isolated from light-grown cells of Euglena gracilis strain Z. Arch Microbiol 1979;121:207–11. [309] Berger R, Liaaen-Jensen S, McAlister V, Guillard RRL. Algal carotenoids. Part XXII. Carotenoids of Prymnesiophyceae (Haptophyceae). Biochem Syst Ecol 1977;5:71–5. [310] Tsushima M, Mune E, Maoka T, Matsuno T. Isolation of stereoisomeric epoxy carotenoids and new acetylenic carotenoid from the common freshwater goby Rhinogobius brunneus. J Nat Prod 2000;63:960–4. [311] Lee MD, Dunne TS, Chang CC, Siegel M, Morton GO, Ellestad GE, et al. The calicheamicins, a family of extremely potent antitumor antibiotics. Youji Huaxue 1993;13:166–70. [312] Lee MD, Dunne TS, Siegel MM, Chang CC, Morton GO, Borders DB. Calichemicins, a novel family of antitumor antibiotics. 1. Chemistry and partial structure of calichemicin-gamma-1. J Am Chem Soc 1987;109:3464–6. [313] Konishi M, Ohkuma H, Saitoh K, Kawaguchi H, Golik J, Dubay G, et al. Esperamicins, a novel class of potent antitumor antibiotics. I. Physicochemical data and partial structure. J Antibiot 1985;38:1605–9.

[314] Golik J, Clardy J, Dubay G, Groenewold G, Kawaguchi H, Konishi M, et al. Esperamicins, a novel class of potent antitumor antibiotics. 2. Structure of esperamicin-X. J Am Chem Soc 1987;109:3461–2. [315] Golik J, Dubay G, Groenwold G, Kawaguchi M, Konishi M, Krishnan B, et al. Esperamicins, a novel class of potent antitumor antibiotics. 3. Structures of esperamicins-A1, esperamicin-A2, and esperamicin-A1b. J Am Chem Soc 1987;109:3462–4. [316] Jean M, Tomasi S, Van de Weghe P. When the nine-membered enediynes play hide and seek. Org Biomol Chem 2012;10:7453–6. [317] Joshi MC, Rawat DS. Recent developments in enediyne chemistry. Chem Biodivers 2012;9:459–98. [318] Lam KS, Hesler GA, Gustavson DR, Crosswell AR, Veitch JM, Forenza S, et al. Kedarcidin, a new chromoprotein antitumor antibiotic. 1. Taxonomy of producing organism, fermentation and biological-activity. J Antibiot 1991;44:472–8. [319] Zein N, Casazza AM, Doyle TW, Leet JE, Schroeder DR, Solomon W, et al. Selective proteolytic activity of the antitumor agent kedarcidin. Proc Natl Acad Sci USA 1993;90:8009–12. [320] Takeshita M, Kappen LS, Grollman AP, Eisenberg M, Goldberg IH. Strand scission of deoxyribonucleic acid by neocarzinostatin, auromomycin, and bleomycin: studies on base release and nucleotide sequence specificity. Biochemistry 1981;20:7599–606. [321] Davies JE, Anderson RJ, Wang H, Warabi K, Huang XH. Uncialamycin and analogs for pharmaceuticals. Patent: PCT Int. Appl. WO 2007038868 A2, 39 pp.; 2007. [322] Davies J, Wang H, Taylor T, Warabi K, Huang X-H, Andersen RJ. Uncialamycin, a new enediyne antibiotic. Org Lett 2005;7:5233–6. [323] Shiomi K, Iinuma H, Naganawa H, Hamada M, Hattori S, Nakamura H, et al. New antibiotic produced by Micromonospora globosa. J Antibiot 1990;43:1000–5. [324] Smith AL, Hwang CK, Wenderborn SV, Nicolaou KC, Schreiner EP, Stahl W, et al. Preparation of dynemicin analogs as bactericides and antitumor agents. US Patent: US 1992-939104, 114 pp.; 1994. [325] Nicolaou KC, Chen JS, Dalby SM. From nature to the laboratory and into the clinic. Bioorg Med Chem 2009;17:2290–303. [326] Nicolaou KC, Dai WM. Molecular design and chemical synthesis of potent enediynes. 2. Dynemicin model systems equipped with C-3 triggering devices and evidence for quinone methide formation in the mechanism of action of dynemicin A. J Am Chem Soc 1992;114:8908–21. [327] Myers AG. Preparation of dynemicin analogs for use as DNA cleaving agents, cytotoxic agents, and/or antitumor agents. US Patent: US 1996-598316, 69 pp.; 1998. [328] Guanti G, Riva R. Simplified dynemicin analogs: diastereoselective synthesis and evaluation of their activity against plasmid DNA. Org Biomol Chem 2003;1:3967–76. [329] Shair MD, Yoon T, Chou T-C, Danishefsky SJ. Enediyne quinonimines: smaller, biologically active dynemicin analogs. Angew Chem 1994;106:2578–80. [330] Shair MD, Yoon TY, Mosny KK, Chou TC, Danishefsky SJ. The total synthesis of dynemicin a leading to development of a fully contained bioreductively activated enediyne prodrug. J Am Chem Soc 1996;118:9509–15. [331] Shair MD, Yoon TY, Danishefsky SJ. Total synthesis of (±)-dynemicin A. Angew Chem Int Ed Engl 1995;34:1721–9. [332] Wender PA, Kelly RC, Beckham S, Miller BL. Studies on DNA-cleaving agents: computer modeling analysis of the mechanism of activation and cleavage of dynemicin–oligonucleotide complexes. Proc Natl Acad Sci USA 1991;88:8835–9. [333] Unno R, Michishita H, Inagaki H, Suzuki Y, Baba Y, Jomori T, et al. Synthesis and antitumor activity of water-soluble enediyne compounds related to dynemicin A. Bioorg Med Chem 1997;5:987–99. [334] Zhang Z-F, Zhou X-Y, Ma Q-Z. Analysis on health risk of extractives of bamboo leaves by Py-GC–MS. Key Eng Mater 2011;480–481:238–41. [335] Qi S-H, Chen L, Wu D-G, Ma Y-B, Luo X-D. Novel tetranortriterpenoid derivatives from Munronia henryi. Tetrahedron 2003;59:4193–9. [336] Wakabayashi N, Spencer SL, Waters RM, Lusby WR. A polyacetylene from Honduras mahogany, Swietenia mahagoni. J Nat Prod 1991;54:419–21. [337] Baek N-I, Park JD, Lee YH, Jeong SY, Kim SI. A novel polyacetylene from Cirsium spp. Yakhak Hoechi 1995;39:268–75. [338] Karrer F. Diphenyl ether derivatives. US Patent: US 1975-611731, 15 pp.; 1977. [339] Lee SW, Kim K, Rho M-C, Chung MY, Kim YH, Lee S, et al. New polyacetylenes, DGAT inhibitors from the roots of Panax ginseng. Planta Med 2004;70:197–200. [340] Ray A, Boyle SM. In silico screening method for identifying ligands for odor receptors and olfactory neurons for use as repellents in traps or other media. Patent: WO 2011-US32804, 192 pp., PCT Int. Appl.; 2011. [341] Chen L-X, Wang L. Comparative study on the composition of volatile oil and the efficacy of Angelica sinensis and Ligusticum chuanxiong. Henan Shifan Daxue Xuebao, Ziran Kexueban 2012;40:103–8. [342] Ladan Z, Amupitan JO, Oyewale OA, Okonkwo EM, Ladan EO, Odjobo B, et al. Chemical composition and biological activity of the volatile oils of Hyptis spicigera against Trypanosoma brucei brucei, (Tbb) found in Northern Nigeria. Afr J Pure Appl Chem 2011;5:53–8. [343] Luo L, Wang R, Wang X, Ma Z, Li N. Compounds from Angelica keiskei with NQO1 induction, DPPH scavenging and a-glucosidase inhibitory activities. Food Chem 2012;131:992–8.

D.V. Kuklev, V.M. Dembitsky / Progress in Lipid Research 56 (2014) 67–91 [344] Tsoupras G, De Angelis P, Zesiger T, Renaud JM, Tabacchi R. Biologically active phytotoxic acetylenic acid was isolated from the culture filtrate of Eutypa lata. Bioact Mol 1988;7:93–100. [345] Magalhaes AF, Magalhaes EG, Vieira DM. Synthesis of wyerone benzene analog, its epoxide derivative and other a-alkynylcarbonyl compounds. Quim Nova 1987;10:189–93. [346] Lee SJ, Shim SC. Photochemistry of conjugated polyacetylenes: photoreaction of 1,4-diphenyl-1,3-butadiyne with dimethyl fumarate. Tetrahedron Lett 1990;31:6197–200. [347] Bisacchi GS, Koster WH. Acetylenic antibiotics. US Patent: US 4588828 A; 1986. [348] Beaudegnies R, Murphy KF, Quaranta L, Brunner H-G, Cederbaum F. Fungicidal 2-alkylthio-2-quinolinyl-oxyacetamide derivatives and their preparation. WO 2008-EP7195, PCT Int. Appl., 40 pp.; 2009. [349] Montenegro HE, Ramirez-Lopez P, De la Torre MC, Asenjo M, Sierra MA. Two versatile and parallel approaches to highly symmetrical open and closed natural product-based structures. Chem Eur J 2010;16:3798–814.

91

[350] Ferrandina G, Mariani M, Andreoli M, Shahabi S, Scambia G, Ferlini C. Novel drugs targeting microtubules: the role of epothilones. Curr Pharm Des 2012;18:2793–803. [351] Argyriou AA, Marmiroli P, Cavaletti G, Kalofonos HP. Epothilone-induced peripheral neuropathy: a review of current knowledge. J Pain Symptom Manage 2011;42:931–40. [352] Klar U, Schwede W, Skuballa W, Buchmann B, Schirner M. Preparation of new epothilone derivatives and their pharmaceutical uses. DE 1999-19908767, Ger. Offen., 74 pp.; 2000. [353] Hammer S, Hoffmann J, Sommer A. Methods, kits, and compounds for determining responsiveness to treatment of a pathological disorder by epothilones. Patent: WO 2008-EP5437, 110 pp., PCT Int. Appl.; 2009. [354] Lichtner R, Rotgeri A, Klar U, Hoffmann J, Buchmann B, Schwede W, et al. Use of epothilones in the treatment of brain diseases associated with proliferative processes. Patent: WO 2003-EP2085, PCT Int. Appl., 53 pp.; 2003.