Anticancer compounds from cyanobacterium Lyngbya species: a review.

Antonie van Leeuwenhoek DOI 10.1007/s10482-015-0487-2

REVIEW PAPER

Anticancer compounds from cyanobacterium Lyngbya species: a review Shasank S. Swain . Rabindra N. Padhy . Pawan K. Singh

Received: 15 February 2015 / Accepted: 19 May 2015 Ó Springer International Publishing Switzerland 2015

Abstract The use of synthetic anticancer drugs and other methods followed in cancer therapy have several side effects; and ineffective methods or drugs give a way to the emergence of drug resistant cancer cells, with the intrinsic metastasis as the aftermath. Anticancer efficacy of many cyanobacterial compounds has been claimed in literature. This review considers 144 compounds isolated and characterized from seven species of the non-nitrogen fixing filamentous cyanobacterium Lyngbya, as the source of antineoplastic agents, which have been screened primarily with cancer cell lines. Structure and information of Lyngbya compounds were retrieved from databases, PubChem, ChemSpider and ChEBI. Information and clinical status of Lyngbya compounds are summarized, and those might be the future anticancer drugs for drug-resistant cancer cells even, as complementary/adduct drugs, if pursued thoroughly in pharmacology and pharmaceutics.

S. S. Swain R. N. Padhy (&) Central Research Laboratory, IMS & Sum Hospital, Siksha ‘O’ Anusandhan University, Kalinga Nagar, Bhubaneswar 751003, Odisha, India e-mail: [email protected] P. K. Singh Department of Botany, Banaras Hindu University (BHU), Varanasi 221005, UP, India e-mail: [email protected]

Keywords Cyanobacterium Lyngbya Cyanocompounds Anticancer drugs Clinical status

Introduction For the many known human cancer types, there has been a great increase in synthetic drug treatments, as chemotherapy is the most preferable treatment option. Intrinsically, the development of resistance of multiplying cancer cells to applied drug(s), over the time, renders the treatment regimen ineffective. For example, imatinib and dasatinib are the most preferred synthetic drugs among many, against chronic myeloid leukemia (CML) and colorectal cancer. However, in the accelerated phase of CML and the advanced stage of colorectal cancer, the emerged drug-resistant cancer cells predominate, with eventual metastatic invasion of cancer to internal tissue, resulting in the transfer of patients to hospice (Hochhaus et al. 2007; Gromicho et al. 2011). Moreover, drug-resistant cancer cells need be addressed suitably to overcome the impasse in treatment; most established anticancer drugs cannot be replaced ordinarily, due to sporadic developments of resistant cancer stem cells. Curcumin from the plant Curcuma longa had been shown to control dasatinib resistant cancer stem cells in vitro (Nautiyal et al. 2011); but, synergistic/adduct uses of dasatinib and curcumin or any other natural compound in vivo have not been reported, yet. From this perspective,

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Antonie van Leeuwenhoek

additional antineoplastic agents from other natural sources need to be located and formulated, for the possible use as synergistic/complementary/supplementary/adduct drugs for the several types of cancer. Cyanobacteria have been known to have antineoplastic activity in several preliminary screening attempts, as reviewed (Dixit and Suseela 2013). Cyanobacteria are oxygen evolving photosynthetic prokaryotes with ubiquitous distribution ranging from moist soil to inland fresh water bodies (Dash et al. 2015) and ocean (Kulasooriya 2011). This group has diverse forms, unicellular and branched/un-branched filaments/trichomes; sometimes the latter are with/ without heterocysts (Galhano et al. 2011), and can survive throughout the biosphere, ranging from Antarctic ice fields to thermal springs. In addition, cyanobacteria possess unique secondary metabolites (Dobretsov et al. 2011), and those of several bloomforming species growing in stagnant fresh waters are most often toxic to biota, helping domination on other cyanobacteria, algae and hydrophytes (Jaiswal et al. 2005, 2008; Rodrı´guez-Meizoso et al. 2008; Cheung et al. 2013). Furthermore, cyanobacterial secondary metabolites of bloom-forming species in extracellular secretions eliminate zooplankton and aquatic fauna, during bloom formation. Among bloom-forming taxa, Lyngbya sp. (family Oscillatoriaceae) is noteworthy. It is a non-nitrogen fixing, un-branched filamentous cyanobacterium related to the common marine species, Lyngbya majuscula that causes skin irritation, the ‘seaweed dermatitis’ in man. Information on 144 compounds of 7 well-known species of Lyngbya, isolated, characterized and tested for anticancer activities to date, are presented here. Details on chemical structures of many secondary metabolites of several cyanobacteria, including those of Lyngbya sp. are available in literature. Further, a considerable amount of work has been published on the screening of cyanobacterial compounds to fit into the drug development cascades, as antidiabetic, antimicrobial, antifungal, antiviral, anti-inflammatory, antiulcerative and anticancer aids (Gerwick et al. 1994; Martins et al. 2008; Medina et al. 2008; Mondal et al. 2012; Dixit and Suseela 2013; Natarajan et al. 2013). In the search for suitable anticancer agents, available information on 144 Lyngbya-compounds, retrieved from chemicalstructure databases, PubChem (http://www.ncbi.nlm. nih.gov/pccompound), ChemSpider (http://www. chemspider.com/) and ChEBI (http://www.ebi.ac.uk/

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chebi/) are presented here; and it is anticipated that the information will be useful in pharmacology for anticancer-drug development programmes.

Cyanobacterial compounds and their chemical classification Several classes of peptides, cyclic depsipeptide (CD), cyclic dodecapeptide (CDO), depsipeptide (DP), linear depsipeptide (LD), lipopeptide (LP) and polyketide-peptide (PP) have been isolated and other classes, fatty acid amines (FA), macrolactone (MA) or glicomacrolide (GL), and macrolide glycoside (MG) of Lyngbya sp. have also been screened as anticancer activities (Table 1). (Teruya et al. 2009a; Costa et al. 2012). Cyclic peptides are ring structures formed by linking one end of a peptide chain for formation of an amide bond between amino and carboxyl termini of two compounds, as well as, other chemically stable bonds such as, with lactone, ether, thioether, disulfide, etc., are formed during the cyclization (Joo 2012). Cyanobacterial cyclic peptides have been documented to have anticancer activity (Moore 1996; Costa et al. 2012). Indeed, cyclic peptides, alotamides, antanapeptins, apratoxins, aurilides, dolastatins, largamides, lyngbyabellins, obyanamides and a few more are found in most cyanobacteria. For example from Lyngbya sp., dolastatin 10, a peptide isolated with anticancer activity has entered into phase I clinical trials for cancer drug development. Similarly, desmethoxy-majusculamide C (DMMC), a peptide isolated from L. majuscula also has been included in preclinical trials. Peptides can be isolated from cyanobacteria or can be prepared synthetically (Joo 2012). For example, the drug soblidotin is a synthetic analogue of dolastatin 10, and drugs cematodin and tasidotin are synthetic analogues of dolastatin 15; these 3 drugs are in phase III clinical trials as anticancer agents (Newman and Cragg 2004; Bhatnagar and Kim 2010). Other subclasses of cyanobacterial peptides, CDO, LD, LP and PP with addition(s) of several groups of polypeptide chains too have anticancer properties (Costa et al. 2012). For example from L. majuscula, wewakazole, a CDO was isolated with an anticancer activity (Nogle and Gerwick 2003). Isolated from cyanobacteria fatty acid amides, isomalyngamides and malyngamides have anticancer

L. bouillonii

Species

5. Dolastatin 13 (CD) MF: C46H63N7O12 Avg. mass: 906.0321 Da ChemSpider ID: 10279681

3. Apratoxin E (CD) MF: C43H65N5O7S MW: 796.0705 (g/mol) PubChem ID: 24897176

1. Alotamide (CD) MF: C32H49N3O5S Avg. mass: 587.813599 Da ChemSpider ID: 27024257

Chemical structure and other details

Table 1 Anticancerous cyano-compounds of the cyanobacterium Lyngbya

6. E-dehydroapratoxin A (CD) MF: C45H67N5O7S MW: 822.10778 (g/mol) PubChem ID: 44585957

4. Apratoxin F (CD) MF: C44H69N5O8S MW: 828.11236 (g/mol) PubChem ID: 70696073

2. Apratoxin A (CD) MF: C45H69N5O8S MW: 840.12306 (g/mol) PubChem ID: 6326668

Tidgewell et al. (2010)

Costa et al. (2012) Matthew et al. (2008)

Soria-Mercado et al. (2009)

References


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Species

Table 1 continued

123

9. Lyngbyapeptin A (LP) MF: C37H55N5O6S Ave. mass: 697.92749 Da ChemSpider ID: 10478301

7. Lyngbyabellin B (CD) MF: C28H40Cl2N4O7S2 MW: 679.6758 (g/mol) PubChem ID: 44558912


10. Lyngbyapeptin B (LP) MF: C38H51N5O7S Avg. mass: 721.905823 Da ChemSpider ID: 10479163

8. Lyngbyabellin J (CD) MF: C37H51Cl2N3O12S MW: 864.84974 (g/mol) PubChem ID: 46939789 Luesch et al. (2000)

Klein et al. (1999) Luesch et al. (2000)

References


Species

Table 1 continued

13. 2-Epi-Lyngbyaloside (GL) MF: C31H49BrO10 MW: 661.61876 (g/mol) PubChem ID: 46939688

11. Lyngbyapeptin D (LP) MF: C36H53N5O6S Avg. mass: 683.900879 Da ChemSpider ID: 27025083


14. 18E-Lyngbyaloside C (GL) MF: C30H49BrO10 MW: 649.60806 (g/mol) PubChem ID: 46939689

12. Lyngbyaloside (GL) MF: C31H49BrO10 MW: 661.61876 (g/mol) PubChem ID: 49865665 Luesch et al. (2000)

Luesch et al. (2000)

References


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123

L. confervoides

Species

Table 1 continued

1. Obyanamide (CD) MF: C30H41N5O6S MW: 599.74144 (g/mol) PubChem ID: 636989

15. 18Z-Lyngbyaloside C (GL) MF: C30H49BrO10 MW: 649.60806 (g/mol) PubChem ID: 46939690


2. Grassystatin A (LD) MF: C58H95N9O1 MW: 1174.4256 (g/mol) PubChem ID: 44255320

16. 27-deoxylyngbyabellin A (CD) MF: C29H40Cl2N4O6S2 Avg. mass: 675.687073 Da ChemSpider ID: 25050782

Williams et al. (2002)


References


Species

Table 1 continued

5. Grassystatin B (LD) MF: C59H97N9O16 MW: 1188.45218 (g/mol) PubChem ID: 44253976

3. Grassypeptolide C (CD) MF: C56H79N9O10S2 MW: 1102.41076 (g/mol) PubChem ID: 50907342


6. Grassystatin C (LD) MF: C50H82N8O12 Avg. mass: 987.232483 Da ChemSpider ID: 24632269

4. Grassystatin A (LD) MF: C58H95N9O16 Avg. mass: 1174.425659 Da ChemSpider ID: 24631671

Matthew et al. (2008, 2009a)

Kwan et al. (2009)

References


123

Species

Table 1 continued

123 9. Largamide C (CD) MF: C47H63N7O13 MW: 934.04222 (g/mol) PubChem ID: 44246699

7. Largamide A (CD) MF: C41H59N7O12 MW: 841.94686 (g/mol) PubChem ID: 51360487


10. Lissoclinamide 7 (CD) MF: C38H45N7O5S2 MW: 743.9378 (g/mol) PubChem ID: 390558

8. Largamide B (CD) MF: C46H61N7O13 MW: 920.01564 (g/mol) PubChem ID: 51360488 Matthew et al. (2009a)

Matthew et al. (2009a)

References


Species

Table 1 continued

13. Lyngbyastatin 6 (CD) MF: C54H69N8NaO18S Avg. mass: 1173.223145 Da ChemSpider ID: 27023114

11. Lyngbyastatin 4 (CD) MF: C53H68N8O18S MW: 1137.21482 (g/mol) PubChem ID: 16104920


14. Pompanopeptin A (CD) MF: C46H73BrN10O12S Avg. mass: 1070.1 Da ChemSpider ID: 27023335

12. Lyngbyastatin 5 (CD) MF: C53H68N8O15 Avg. mass: 1057.151611 Da PubChem ID: 44246696 Matthew et al. (2008)

Matthew et al. (2007)

References


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123

L. majuscula

Species

Table 1 continued

1. Antanapeptin A (CD) MF: C41H60N4O8 Avg. mass: 736.937073 Da ChemSpider ID: 9942494

15. Tiglicamides A (CD) MF: C45H59N7O13 Avg. mass: 905.989075 Da ChemSpider ID: 27024665


2. Antanapeptin B (CD) MF: C41H62N4O8 Avg. mass: 738.953003 Da ChemSpider ID: 9051639

16. Tiglicamides B (CD) MF: C44H57N7O12 Avg. mass: 875.963 Da ChemSpider ID: 27024666 Nogle and Gerwick (2002)

Matthew et al. (2009b)

References


Species

Table 1 continued

5. Antanapeptin C (CD) MF: C41H64N4O8 Avg. mass: 740.968872 Da ChemSpider ID: 9051646

3. Antillatoxin A (LP) MW: 503.674 (g/mol) MF: C28H45N3O5 PubChem ID: 10051827


6. Aplysiatoxin (LP) MF: C32H47BrO10 MW: 671.61358 (g/mol) PubChem ID: 40465

4. Antillatoxin B (LP) MF: C33H47N3O5 Avg. mass: 565.743408 Da ChemSpider ID: 8160989 Montaser et al. (2011) Mynderse et al. (1977)

Cao et al. (2010) Nogle et al. (2001)

References


123

Species

Table 1 continued

123 9. Aurilide B (CD) MF: C44H75N5O10 MW: 834.0938 (g/mol) PubChem ID: 15939634

7. Apratoxin A (CD) MF:C45H69N5O8S MW:840.12306 (g/mol) PubChem ID: 6326668


10. Aurilide C (CD) MF: C43H73N5O10 Avg. mass: 820.1 Da ChEBI ID: 354961

8. Apratoxin D (CD) MF:C48H75N5O8S Avg. mass: 882.203 Da ChemSpider ID: 24707726 McPhail et al. (2007)

Luesch et al. (2001) Gutie´rrez et al. (2008)

References


Species

Table 1 continued

13. Caylobolide A (MA) MF: C42H80O11 MW: 761.078 (g/mol) PubChem ID: 49866296

11. Carmabin A (LP) MF: C40H57N5O6 MW: 703.91048 (g/mol) PubChem ID: 16757536


14. Cocosamide A (CD) MF: C42H57N5O7 Avg. mass: 743.931274 Da ChemSpider ID: 26344046

12. Carmabin B (LP) MF: C40H59N5O7 MW: 721.92576 (g/mol) PubChem ID: 44566391 Luesch et al. (2000, 2001) MacMillan and Molinski (2002)

Han et al. (2006)

References


123

Species

Table 1 continued

123 17. Curacin A (LP) MF: C23H35NOS MW: 373.5951 (g/mol) PubChem ID: 5281967

15. Cocosamide B (CD) MF: C42H55N5O7 Avg. mass: 741.915405 Da ChemSpider ID: 26343717


18. Debromoaplysiatoxin (LP) MF: C32H48O10 MW: 592.71752 (g/mol) PubChem ID: 2967

16. Cocosamides B (LP) MF: C42H55N5O7 MW: 741.9154 PubChem ID: 52952543 Catassi et al. (2006)

Gunasekera et al. (2011)

References


Species

Table 1 continued

21. Dragonamide (LP) MF: C36H57N5O5 MW: 639.86828 (g/mol) PubChem ID: 44559994

19. Dolastatin 16 (CD) MF: C47H70N6O10 Avg. mass: 879.09290 Da ChEBI ID: 67337


22. Hantupeptin A (CD) MF: C41H60N4O8 MW: 736.9371 (g/mol) PubChem ID: 25210138

20. Dragomabin (LP) MF: C37H51N5O6 MW: 661.83074 (g/mol) PubChem ID: 16737469 Jimeńez and Scheuer (2001) Tripathi et al. (2009a)

Montaser et al. (2011)

References


123

Species

Table 1 continued

123 25. Hectochlorin (CD) MF: C27H34Cl2N2O9S2 MW: 665.60286 (g/mol) PubChem ID: 636718

23. Hantupeptin B (CD) MF: C41H62N4O8 Avg. mass:738.953003 Da ChemSpider ID: 27024581


26. Hermitamides A (LP) MF: C23H37NO2 MW: 359.54538 (g/mol) PubChem ID: 10473646

24. Hantupeptin C (CD) MF: C41H64N4O8 Avg. mass: 740.968872 Da ChemSpider ID: 27024582 Ramaswamy et al. (2007)

Tripathi et al. (2009b)

References


Species

Table 1 continued

29. Iejimalide A (MA) MF: C40H58N2O7 MW: 678.89772 (g/mol) PubChem ID: 6443363

27. Hermitamides B (LP) MF: C25H38N2O2 MW: 398.58142 (g/mol) PubChem ID: 10386173


30. Isomalyngamide A (FAAA) MF: C29H45ClN2O6 MW: 553.1304 (g/mol) PubChem ID: 10626553

28. Homodolastatin 16 (CD) MF: C48H72N6O10 Avg. mass: 893.119507 Da ChemSpider ID: 10258245

Chang et al. (2011)

Davies-Coleman et al. (2003)

References


123

Species

Table 1 continued

123 33. Jamaicamide B (PP) MW: 489.04668 (g/mol) MF: C27H37ClN2O4 PubChem ID: 49787032

31. Isomalyngamide A1 (FAAA) MF: C28H43ClN2O6 MW: 539.10382 (g/mol) PubChem ID: 54578266


34. Jamaicamide C (PP) MF: C27H39ClN2O4 MW: 491.06256 (g/mol) PubChem ID: 49787033

32. Jamaicamide A (PP) MF: C27H36BrClN2O4 MW: 567.94274 (g/mol) PubChem ID: 49787031 Edwards et al. (2004)

Edwards et al. (2004)

References


Species

Table 1 continued

37. Lagunamide A (CD) MF: C45H71N5O10 MW: 842.07274 (g/mol) PubChem ID: 50901239

35. Kalkitoxin V (LP) MF: C24H36O9 MW: 468.53724 (g/mol) PubChem ID: 44584060


38. Lagunamide B (CD) MF: C45H69N5O10 MW: 840.05686 (g/mol) PubChem ID: 50901240

36. Kulokekahilide-2 (DP) MF: C44H67N5O10 Avg. mass: 826.030273 Da ChemSpider ID: 27025932 Luesch et al. (2000) Tripathi et al. (2011)

LePage et al. (2005) White et al. (2004)

References


123

Species

Table 1 continued

123

41. Lyngbyabellin B (CD) MF: C51H82N8O1 MW: 679.6758 (g/mol) PubChem ID:483840

39. Lagunamide C (CD) MF: C46H73N5O10 MW: Not available ChemSpider ID: 28289216


42. Lyngbyastatin 1 (CD) MF: C28H40Cl2N4O7S MW: 999.24318 (g/mol) PubChem ID: 154163

40. Lyngbyabellin A (CD) MF: C29H40Cl2N4O7S2 MW: 691.6865 (g/mol) PubChem ID: 10032587 Luesch et al. (2000)


References


Species

Table 1 continued

45. Malyngolide (FAA) MF: C16H30O3 MW: 270.4076 (g/mol) PubChem ID: 155655

43. Majusculamide C (CD) MF: C50H80N8O12 MW: 985.2166 (g/mol) PubChem ID: 21628817


46. Malyngamide B (FAA) MF: C28H45ClN2O6 MW: 541.1197 (g/mol) PubChem ID: 44246695

44. Malyngamide 3 (FAA) MF: C28H47ClN2O7 Avg. mass: 559.13501 Da ChemSpider ID: 26346930

Gross et al. (2010)

Pettit et al. (2008) Gunasekera et al. (2011)

References


123

Species

Table 1 continued

123 49. Malyngamide U (FAA) MF: C23H39NO5 MW: 409.55946 (g/mol) PubChem ID: 637170

47. Malyngamide C (FAA) MF: C24H38ClNO5 MW: 456.01522 (g/mol) PubChem ID: 20847479


50. Nhatrangin A (PP) MF: C21H32O8 Avg. mass: 412.474 Da ChemSpider ID: 27025353

48. Malyngamide T (FAA) MF: C25H38ClNO5 MW: 468.02592 (g/mol) PubChem ID: 643677 Chlipala et al. (2010)

Gross et al. (2010)

References


Species

Table 1 continued

52. Palmyramide A (CD) MF: C36H53N3O9 MW: 671.82072 (g/mol) PubChem ID: 45380200

54. Pitipeptolide B (CD) MF: C44H67N5O9 MW: 810.03088 (g/mol) PubChem ID: 10819182

51. Nhatrangin B (PP) MF: C21H31BrO8 Avg. mass: 491.370 Da ChemSpider ID: 27025354

53. Pitipeptolide A (CD) MF: C44H65N5O9 MW: 808.015 (g/mol) PubChem ID: 11803484



Taniguchi et al. (2010)

References


123

Species

Table 1 continued

123 57. Pseudodysidenin (LP) MF: C17H23Cl6N3O2S MW: 546.16642 (g/mol) PubChem ID: 10745152

55. Pitipeptolide C (CD) MF: C44H69N5O9 MW: 812.04676 (g/mol) PubChem ID: 15479259


58. Serinolamide A (LP) MF: C23H45NO3 MW: 383.6083 (g/mol) PubChem ID: 56597771

56. Pitiprolamide (CD) MF: C49H72N6O10 Avg. mass: 905.130188 Da ChemSpider ID: 27026161 Jimeńez and Scheuer (2001)

Montaser et al. (2011)

References


Species

Table 1 continued

63. 8-Epi-malyngamide C (FAA) MF: C24H38ClNO5 Avg. mass: 456.015198 Da ChemSpider ID: 24658926

61. Somocystinamide A (LP) MF: C42H70N4O4S2 Avg. mass: 759.159607 Da ChemSpider ID: 10478837

59. Somamide A MF: C48H67N7O12S Avg. mass: 966.150 Da ChemSpider ID: 10214335


64. 8-O-acetyl-8-epi-malyngamide C (FAA) MF: C26H40ClNO6 Avg. mass: 498.05191 Da ChemSpider ID: 27025100

62. Wewakazole (CDO) MF: C59H72N12O12 MW: 1141.27618 (g/mol) PubChem ID: 21578002

60. Somamide B MF: C46H62N8O12 MW: 919.03088 (g/mol) PubChem ID: 23657292

Gross et al. (2010)

Wrasidlo et al. (2008) Singh et al. (2011)

Nogle et al. (2001)

References


123

123

L. semiplena

L. polychroa

Species

Table 1 continued

1. Cyclic depsipeptide (CD) MF: C24H36N4O6S2 MW: 540.69584(g/mol) PubChem ID: 5352062

3. Carriebowmide (CD) MF: C46H68N6O9S Avg. mass: 881.132 Da ChemSpider ID: 28285867

1. Dragonamide C (LP) MF: C33H57N5O6 MW: 619.83558 (g/mol) PubChem ID: 24878746


2. Lyngbyastatin 8 (CD) MF: C47H64N8O12 MW: 933.05746 (g/mol) PubChem ID: 71718338

2. Dragonamide D (LP) MF: C32H55N5O6 MW: 605.809 (g/mol) PubChem ID: 24878793

Li and Rein (2010) Kwan et al. (2009)



References


Species

Table 1 continued

7. Semiplenamide C (LP) MF: C20H39NO2 MW: 325.52916 (g/mol) PubChem ID: 11347939

5. Semiplenamide A (LP) MF: C23H43NO2 Avg. mass: 365.592987 Da ChemSpider ID: 8559689

3. Lyngbyastatin 9 (CD) MF: C49H68N8O12 MW: 961.11062(g/mol) PubChem ID: 50915769


8. Semiplenamide D (LP) MF: C26H49NO3 MW: 423.67216 (g/mol) PubChem ID: 11316191

6. Semiplenamide B (LP) MF: C25H45NO3 Avg. mass: 407.6297 Da ChemSpider ID: 8629501

4. Lyngbyastatin 10 (CD) MF: C49H67BrN8O12 Avg. mass:1040 Da ChemSpider ID: 27024731

Han et al. (2003)

Han et al. (2003)

Kwan et al. (2009)

References


123

Species

Table 1 continued

123 13. Wewakpeptin B (LP) MF: C52H89N7O11 Avg. mass: 988.303406 Da ChemSpider ID: 9598105

11. Semiplenamide G (LP) MF: C24H45NO4 MW: 411.6184 (g/mol) PubChem ID: 21589501

9. Semiplenamide E (LP) MF: C24H45NO3 MW: 395.619 (g/mol) PubChem ID:11463588


14. Wewakpeptin C (LP) MF: C54H81N7O11 Avg. mass: 1004.260986 Da ChemSpider ID: 9518611

12. Wewakpeptin A (LP) (LP) MF: C52H85N7O11 Avg. mass: 984.271606 Da ChemSpider ID: 9380429

10. Semiplenamide F (LP) MF: C22H43NO3 MW: 369.58172 (g/mol) PubChem ID: 10022023

Han et al. (2005)

Han et al. (2003) Han et al. (2005)

Han et al. (2003)

References


L. sordida

Species

Table 1 continued

3. Wewakazole (CDO) MF: C59H72N12O12 MW: 1141.27618 (g/mol) PubChem ID: 21578002

1. Apratoxin D (CD) MF: C48H75N5O8S MW: 882.2028 (g/mol) PubChem ID: 24896935

15. Wewakpeptin D (DP) MF: C54H85N7O11 Avg. mass: 1008.29303 Da ChemSpider ID: 9609508


2. Malyngamide 2(FAA) MF: C25H42ClNO6 Avg. mass: 488.057098 Da ChemSpider ID: 26386326

Gutierrez et al. (2008)

Gutierrez et al. (2008) Malloy et al. (2011)

Han et al. (2005)

References


123

Lyngbya sp.

Species

Table 1 continued

123 5. Biselyngbyaside (MG) MF: C34H54O10 Avg. mass: 622.786621 Da ChemSpider ID: 29214826

3. Apratoxin C (CD) MF: C44H67N5O8S Avg. mass: 826.09768 ChEBI ID: 35216

1. Apratoxin A (CD) MF: C45H69N5O8S MW: 840.12306 (g/mol) PubChem ID: 6326668


6. Coibamide A (CD) MF: C65H110N10O16 Avg. mass: 1287.626343 Da ChemSpider ID: 27023755

4. Bisebromoamide (PE) MF:C51H72BrN7O8S MW: Not available ChemSpider ID: 27025887

2. Apratoxin B (CD) MF: C44H67N5O8S Avg. mass: 826.09768 Da ChEBI ID: 35215

Teruya et al. (2009b)

Teruya et al. (2009a)

Singh et al. (2011) Luesch et al. (2002)

References


Species

Table 1 continued

11. Dragonamide C (LP) MF: C33H57N5O6 MW: 619.83558 (g/mol) PubChem ID: 24878746

9. Dolastatin 12 (CD) MF: C50H80N8O11 Avg. mass: 969.217224 Da ChemSpider ID: 10235751

7. Curacin D (LP) MF: C22H33NOS Avg mass: 785.090881 Da PubChem ID: 21575335


12. Dragonamide D (LP) MF: C32H55N5O6 MW: 605.809 (g/mol) PubChem ID: 24878793

10. Dolastatin 15 (LP) MF: C45H68N6O9 Avg. mass: 837.056 Da ChemSpider ID: 8094620

8. Dolastatin 10 (LP) MF: C42H68N6O6S MW: 359.56852 (g/mol) ChemSpider ID: 7986684


Taori et al. (2008) Singh et al. (2011)

Dixit and Suseela (2013)

References


123

Species

Table 1 continued

123 15.Lyngbyastatin 5 (CD) MF: C53H68N8O15 Avg. mass: 1057.151611 Da ChemSpider ID: 23076610

13.Kempopeptin A (CD) MF: C50H70N8O13 MW: 991.1366 (g/mol) PubChem ID: 25112524


16.Lyngbyastatin 6 (CD) MF: C54H69N8NaO18S Avg. mass: 1173.22 Da ChemSpider ID: 27023114

14.Kempopeptin B (CD) MF: C46H73BrN8O11 MW: 994.022 (g/mol) PubChem ID: 25112655 Taori et al. (2007)

Taori et al. (2008)

References


Species

Table 1 continued

19. Pahayokolide A (CD) MF: C72H105N13O20 Avg. mass: 1472.679199 Da ChemSpider ID: 23076846

17. Lyngbyastatin 7 (CD) MF: C48H66N8O12 Avg. mass: 947.083984 Da ChemSpider ID: 23076612


20. Pahayokolide B (CD) MF: C63H90N12O18 Avg. mass: 1303.458252 Da ChemSpider ID: 23076847

18. Palauamide (CD) MF: C46H69N5O10 MW: 852.067 (g/mol) PubChem ID: 11549667 An et al. (2007)

Williams et al. (2003) Zou et al. (2005)

References


123

Species

Table 1 continued

123 23. Ulongamide B (CD) MF: C32H45N5O7S MW: 643.794 (g/mol) PubChem ID: 11093484

21. Somamide B (CD) MF: C46H62N8O12 MW: 919.03088 (g/mol) PubChem ID: 23657292


24.Ulongamide C (CD) MF: C36H45N5O7S MW: 691.8368 (g/mol) PubChem ID: 10941492

22. Ulongamide A (CD) MF: C32H45N5O6S MW: 627.7946 (g/mol) PubChem ID: 10985040



References


27. Ulongapeptin (CD) MF: C44H68N6O8 Avg. mass: 809.046082 Da ChemSpider ID: 9150045

25. Ulongamide D (CD) MF: C34H49N5O7S MW: 671.84716 (g/mol) PubChem ID: 10952495


26. Ulongamide E (CD) MF: C35H51N5O7S MW: 685.87374 (g/mol) PubChem ID: 44559889 Williams et al. (2003)


References

Avg. mass average mass, CD cyclic depsipeptide, CDO cyclic dodecapeptide, DP depsipeptide, FAA fatty acid amide, GL glicomacrolide, LD linear depsipeptide, LP lipopeptide, MA macrolactone, MG macrolide glycoside, MF molecular formula, MW molecular weight, PE peptide, PP polyketide-peptide

Species

Table 1 continued


123


activity. GLs are another class of chemical compounds isolated from cyanobacteria with anticancer activity. For example, lyngbyaloside, 2-epi-lyngbyaloside, 18e-lyngbyaloside C, 18z-lyngbyaloside C, isolated from L. bouillonii has anticancer activity (Table 1). Peptides have suitability as drugs or drugable agents; peptides are suitable alternatives to small synthetic molecules because of several advantages, notably: 1. compared to small synthetic molecules, peptides possess less toxicity and they should not accumulate in organs; 2. rapid degradation of peptides as drugs is a desirable trait due to which, peptide-drugs are effective; 3. the degraded product(s) are innocuous amino acids without toxicity (Loffet 2002); 4. peptides can work on their targets very selectively, as the interaction with target molecule(s) is very specific compared to small synthetic molecules (Hummel et al. 2006). These features of peptides contribute to their adoption as drugable agents. Peptide drugs include receptor agonists and antagonists, peptide hormones and analogues, HIV protease inhibitors, and a few more (Vlieghe et al. 2010). Thus, considering the merits of peptides as drug molecules, cyclic peptides also could be used as the better peptide-based drugs. Many chemicals of other cyanobacteria have been used with eukaryotic cytoskeleton cancer targets, such as tubulin and actin microfilaments for the cancer treatment. Furthermore, a number of cyano-peptides modulate cellular events for apoptosis in cancer cell (Simmons et al. 2005; Oftedal et al. 2010). Thus, cyanobacterial toxins are a natural source of anticancer agents in pharmacology and pharmaceutical chemistry for the drug development (Tan 2007).

Cyanobacterial bioactive molecules under clinical trials Phases of clinical trials are, phase 0 or pre-clinical, phase I, phase II and phase III that are involved in the drug-development process of a synthetic, or a semisynthetic chemical or an active natural compound. Generally, the approval of Food and Drug Administration (FDA) is mandatory for each phase. A few prominent Lyngbya-compounds such as, dolastatin 10, dolastatin 15, curacin and desmethoxymajusculamide C, etc., and their analogues are in clinical trials as potential anticancer drugs (Marks et al. 2003; Perez et al. 2005). Dolastatins are a group

123

of unique peptides that were identified too in other cyanobacteria (Luesch et al. 2001). The antineoplastic activity of dolastatins is the inhibition of microtubule assembly of proliferating cells; eventually, its analogues, dolastatin 1, 2, 3 and so on, up to dolastatin 16 from Lyngbya and other cyanobacteria have gained prominence as anticancer drugs, of which, dolastatin 10 and dolastatin 15 have been recorded with promising antineoplastic activities (Costa et al. 2012). Furthermore, phase I and II clinical trials of dolastatin 10 had been undertaken by National Cancer Institute, USA; however, its toxic effects caused a moratorium of clinical trials (Simmons et al. 2005). Alternatively, soblidotin, the synthetic analogue of dolastatin 10 with an improved pharmacological and pharmacokinetic properties without any exaggerated toxicity was promoted, which had too cleared clinical trial phases I, II and III by Aska Pharmaceuticals, Tokyo (Bhatnagar and Kim 2010). Thus, Lyngbya-compounds directly or their modified analogues are desirable chemical species, with the potentiality of passing through the drug development process as antineoplastic agents (Marks et al. 2003; Catassi et al. 2006; Ma et al. 2006; Dixit and Suseela 2013). The other Lyngbya-compound, curacin is a unique thiazolinecontaining lipopeptide that inhibits microtubule assembly in cancer cells (Blokhin et al. 1995). Its natural analogues from L. majuscula, curacin A, B, C and D (Gerwick et al. 1994; Yoo and Gerwick 1995; Ma´rquez et al. 1998) were unable to produce anticancer effectivity during in vivo animal trails; but, synthetic analogue(s) of curacin served the development of anticancer agents (Wipf et al. 2004). Updated clinical information reveals that most Lyngbya-compounds, their several synthetic analogues individually and antibody–drug conjugates (ADCs) are in the process of development as anticancer drugs (Bouchard et al. 2014; Table 2). ADCs are nearer to development as potent anticancer drugs, since those have proved as the sought after anticancer agents, simulating the classical magic bullet theory of Paul Ehrlich in the use of an antibiotic. In the simplest form, an ADC is comprised of an antibody to which, a cytotoxic agent was attached through a linker to a Lyngbya compound, for the possible use in cancer chemotherapy as a stratagem (Table 2). The list of ADCs continues to grow, bolstered by the success of the brentuximab vedotin (BV, the trade name, Adcetris, as an injection made by Settle

MMAE

MMAF

MMAF

MMAE

MMAE

Dolastatin 15

AGS-15E (AGS-15ME)a

AGS-16C3F (AGS-16M8F)a

A1-mcMMAF (PF-06263507)a

BAY 79-4620 (3ee9/MMAE)a

Brentuximab vedotin (cAC10vc or SGN-35)a

Cematodin (LU-103793); peptide

L. majuscula

MMAE

MMAE

L. majuscula

MMAE

MMAE

Lyngbya sp.

Lyngbya sp.

MMAE

MMAE

Curacin A; lipid

DCDT-2980Sa

DCDS-4501Aa

Desmethoxy-majusculamide C (DMMC); peptide

DMUC-5754A (RG-7458)a

DNIB-0600A (RG-7599)a

Dolastatin 10; peptide

Dolastatin 15; peptide

DSTP-3086S (RG-7450)a

Enfortumab vedotin (AGS22MSE and AGS-22ME)a

synthetic analogues

MMAF

Source

ABT-414 (NCT01741727)a

Chemical class

Name;

Solid tumours, Urogenital cancer

Metastatic prostate cancer

Phase I trial trials

Phase I clinical trials

Preclinical phase trials

Phase II clinical trials

Brest cancer Microtubule assembly




Preclinical phase



Preclinical phase

Phase III clinical trials








Previous status

Tubulin

Lung, platinum resistant ovarian cancer

Ovarian and pancreatic cancer

Tubulin

Follicular B cell lymphoma

Leukemias

Inhibits microtubule assembly and tubulin

Lung cancer

Microtubule assembly

Lymphoma and CD30 of tumor cell

Hodgkin

Solid tumors

Advanced solid tumors

Renal and liver cancer

Bladder cancer

Brain tumors and lung cancer

Molecular target

Under review

Under review

Withdrawn for low water solubility

Under review

Dropped due to some toxic effects

Under review

Under review

Under review

Under review

Under review

Withdrawn due to low water solubility

Under review

Withdrawn due to lack of objective response

FDA approved

Under review

Under review

Under review

Under review

Under review

Current status

Table 2 Clinical status of compounds of Lyngbya, their chemical class, molecular targets for cancer drug development

Genetics and Astellas Pharma

Seattle

Genentech, Roche

–

Multicenter Cooperative group

Cancer Institute, US

National

Seattle Genetics

Genentech, Roche

–

Genentech, Roche

Genentech, Roche

–

North Central Cancer Treatment Group

Knoll division of Abbott GMBH for treatment of breast cancer

Seattle Genetics

Seattle Genetics

Pfizer

Astellas Pharma

Seattle Genetics

AbbVie (Abbott Pharmaceutical)

Company

Newman and Cragg (2014)


Marks et al. (2003)

Perez et al. (2005)

Simmons et al. (2005)




Li et al. (2013)

Li et al. (2013)

Wipf et al. (2004)

Blokhin et al. (1995)

Marks et al. (2003)


de Arruda et al. (1995)

Anonymous (2011)

Francisco et al. (2003)




Phillips et al. (2013)

Reference


123

123

MMAE

MMAE

MMAF

MMAF

Dolastatin 10 synthetic analogues

Dolastatin 15 synthetic analogues

MMAF

MLN-0264a

PSMA-ADCa

SGN-LIV1Aa

SGN-19A (SGN-CD19A)a

Soblidotin (TZT 1027); peptidea

Tasidotin (ILX-651); peptide

Vorsetuzumab mafodotin; SGN-75a


Solid tumors, microtubule assembly, lung cancer Phase I clinical trials


Microtubule assembly and breast cancer

Renal cell cancer and CD70





Phase II trial trials

Previous status

Acute Leukemia and Hodgkin Lymphoma

Breast cancers (ER?/ HER2-; HER2 ? and triple negative

Prostate cancer

Pancreatic cancer

Brest cancer

Molecular target

Under review

Under review

Under review

Under review

Under review

Under review

Under review

Under review

Current status

Seattle Genetics

Genzyme Corporation, Cambridge

Aska Pharmaceuticals, Tokyo

Seattle Genetics

Seattle Genetics

Progenics Pharmaceuticals

Seattle Genetics

CuraGen

Company

Doronina et al. (2003)

Mita et al. (2006)


Bhatnagar and Kim (2010)



Wang et al. (2011)


Yardley et al. (2012)

Reference

Antibody–drug conjugate drug (ADC), rest others are individual chemicals; monomethylauristatin E (MMAE) is a synthetic analogue of dolastatin 10; monomethylauristatin F (MMAF) is a derivative of MMAE

a

MMAE

Source

Glembatumumab Vedotin (CDX-011)a

Chemical class

Name;

Table 2 continued



Genetics), as the first ADC drug, approved by FDA in 2011, against Hodgkin lymphoma or the systemic anaplastic large cell lymphoma (Anonymous 2011). BV was designed for the cancer target, CD30, as an adduct of brentuximab, a monoclonal antibody and the antitubulin agent, monomethyl auristatin E (the synthetic analogue of dolastatin 10, in short, vedotin), through an enzyme-cleavable dipeptide linker. The ADC was stable in body circulation in vivo, during the treatment. The release of vedotin occurs, when the linker is cleaved selectively, soon after the binding of CD30 via brentuximab with the ADC at lysosomes at cancer cells, wherein it binds to tubulin, causing the breakdown of microtubules; eventually, the G2/M (gap 2 phase and mitosis) in cell-cycle is arrested with the eventual apoptosis. The derivatives of monomethyl auristatin E (MMAE) is monomethyl auristatin F (MMAF), which is used for the development of an ADC with a particular antibody for a specific cancer. MMAE and MMAF as adducts with specific antibodies, nearly 20 anticancer drugs have been developed; each of those is a target to specific cancer types. Of 20 drugs, CDX-014, HuMax-CD74 and HuMab-TF-011-vcMMAE, etc., are in preclinical trials; while (ABT-414, AGS-15E, AGS-16C3F, A1mcMMAF, DCDT-2980S, DCDS-4501A, DMUC5754A, DNIB-0600A, DSTP-3086S, enfortumab vedotin, glembatumumab vedotin, MLN-0264 and MLN-0264, etc. are in clinical trials, developed by Seattle Genetics, Genentech, Progenics Pharmaceuticals, Astellas Pharma, CuraGen, Pfizer and Abbott Pharmaceutical, (Newman and Cragg 2014), along with license from FDA. Since, there is a commonality of the control of cancer types broadly by the inhibition of a target protein, responsible for the origin of cancer stem cells (Costa et al. 2012; Dixit and Suseela 2013), it can be envisaged that the concept of the development of ADCs, in a systematic approach, could be widely adopted with the involvement of a natural compound. The development of emulative and efficacious drugs for the diverse cancer types, individually as well as holistically, is still an elusive goal in pharmaceutics, today; and bioactive compounds of Lyngbya are used to target cancer macromolecules, tubulin or actin filaments, protein kinase, microtubule, calcium influx, serine proteases, caspase, Bcl-2 protein, voltage-gated sodium channel and cancer related secretary pathways inhibition in eukaryotic cells (Ma´rquez et al. 1998; Newman and Cragg 2004;

Perez et al. 2005; Simmons et al. 2005; Watanabe et al. 2006; Tabuchi et al. 2009; Oftedal et al. 2010; Sainis et al. 2010). Chemotherapy, radiation therapy, surgery and targeted therapy, etc., are in use for cancer treatment. The targeted therapies are designed to interfere with specific molecules, for tumor growth, the drug development cascade stems from information on molecular biology of cancer cells. Several drugs are developed for targeting particular protein receptor/enzymes, approved by FDA (Anonymous 2015). Since, traditional chemotherapies eliminate rapidly the majority of dividing body cells, the primary aim of targeted therapies is to eliminate cancer cells precisely and have potentially lesser side effects. Antineoplastic activities of Lyngbya compounds, apratoxin A to E were screened with U2OS osteosarcoma, HT29 colon adenocarcinoma and HeLa cervical carcinoma, LoVo colon cancer, H-460 lung cancer cell lines; similarly, antineoplastic activities of biselyngbyaside was screened with HeLa S3 epithelial carcinoma, SNB-78 central nervous system cancer and NCI H522 lung cancer cell lines (Costa et al. 2012). Additionally cell lines, breast cancer MDA-MB-231, melanoma LOX IMVI, leukemia HL-60 and astrocytoma SNB75, Ovarian carcinoma OVCAR-3, kidney cancer A498, lung cancer NCI-H460, colorectal cancer KM20L2 and glioblastoma SF-295 were generally used for most Lyngbya compounds (Costa et al. 2012).

Conclusion It can be suggested that the cited Lyngbya compounds could further be pursued for cancer drug development, since most of them have structural complexities and have promising anticancer activities, identified at preliminary levels. It is discernible that when the structure of a compound was available, its synthesis could be pursued for an efficacious drug with fewer side effects, as seen with the development of synthetic analogues of dolastatin 10, as soblidotin; similarly, of dolastatin 15, the synthetic analogue is tasidotin, suitable for chemical manipulation, to cite as examples of dolastatins. Moreover, soblidotin and tasidotin are in clinical trial stages. However, with the development of the ADC approach, the synthetic analogue of dolastatin 10, MMAE adduct with an antibody has

123


been approved by FDA. Obviously, structural information of individual Lyngbya compounds could lend themselves in the cancer drug development attempts, holistically.

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Anticancer compounds from plants.

Comparative genomic analyses of the cyanobacterium, Lyngbya aestuarii BL J, a powerful hydrogen producer.

Identification and characterization of anticancer compounds targeting apoptosis and autophagy from Chinese native Garcinia species.

Draft Genome Sequence of Filamentous Marine Cyanobacterium Lyngbya confervoides Strain BDU141951.

Antifungal Compounds from Piper Species.

Powerful fermentative hydrogen evolution of photosynthate in the cyanobacterium Lyngbya aestuarii BL J mediated by a bidirectional hydrogenase.

Anticancer and cancer preventive compounds from edible marine organisms.

Bisebromoamide, an extract from Lyngbya species, induces apoptosis through ERK and mTOR inhibitions in renal cancer cells.

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Effects of PAR and UV Radiation on the Structural and Functional Integrity of Phycocyanin, Phycoerythrin and Allophycocyanin Isolated from the Marine Cyanobacterium Lyngbya sp. A09DM.

Anti-Chikungunya viral activities of aplysiatoxin-related compounds from the marine cyanobacterium Trichodesmium erythraeum.

A phenotypic screening approach to identify anticancer compounds derived from marine fungi.

Ultrahigh pressure extraction of bioactive compounds from plants-A review.

Transcriptional regulation of the plastocyanin and cytochrome c553 genes from the cyanobacterium Anabaena species PCC 7937.

A stable and functional single peptide phycoerythrin (15.45 kDa) from Lyngbya sp. A09DM.

A Novel, Poly(Ethyl Ethylene Ether) Inhibitor to Trypsin from Marine Cyanobacteria, Lyngbya confervoides.

Microcolins A and B, new immunosuppressive peptides from the blue-green alga Lyngbya majuscula.

Anticancer potential of selected Fallopia Adans species.

Endophytic fungi with antitumor activities: Their occurrence and anticancer compounds.

Anticancer Natural Compounds: Molecular Mechanisms and Functions. Part I.

Structures of potent anticancer compounds bound to tubulin.

antiviral compounds.

Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression.

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