marine drugs Review

Polycyclic Guanidine Alkaloids from Poecilosclerida Marine Sponges Estelle Sfecci 1 , Thierry Lacour 2 , Philippe Amade 1 and Mohamed Mehiri 1, * 1 2

*

Nice Institute of Chemistry, Marine Natural Product Team, University Nice Sophia Antipolis, Parc Valrose, 28 avenue de Valrose, 06108 Nice Cedex 02, France; [email protected] (E.S.); [email protected] (P.A.) Biopreserv, 4 traverse Dupont, 06130 Grasse, France; [email protected] Correspondence: [email protected]; Tel.: +33-492-076-154

Academic Editor: Kirsten Benkendorff Received: 2 February 2016; Accepted: 1 April 2016; Published: 9 April 2016

Abstract: Sessile marine sponges provide an abundance of unique and diversified scaffolds. In particular, marine guanidine alkaloids display a very wide range of biological applications. A large number of cyclic guanidine alkaloids, including crambines, crambescins, crambescidins, batzelladines or netamins have been isolated from Poecilosclerida marine sponges. In this review, we will explore the chemodiversity of tri- and pentacyclic guanidine alkaloids. NMR and MS data tools will also be provided, and an overview of the wide range of bioactivities of crambescidins and batzelladines derivatives will be given. Keywords: marine sponges; analytical tools; bioactivity

Poecilosclerida;

alkaloids;

crambescidins;

batzelladines;

1. Introduction The most primitive benthic marine organisms are also among the most chemodiversified producers of secondary metabolites (SM). These compounds are used for predation and competition for space, as well as for communication, and protection against potential surrounding aggressors. Due to the high water dilution, the produced metabolites exhibit several potent biological activities [1]. Several reviews dealing with bioactive marine natural products, in particular, alkaloids have been published in the last few decades [2–19]. Of the many different marine species that have been researched, sponges are likely to be the most studied sources of marine natural products due to the large amount of structurally diverse SM scaffolds they produce. Even so, the last few years have seen a slight decline in the number of newly described metabolites [17,18]. In this review, we focused on the chemodiversity and biological activities of batzelladine- and crambescidin-like guanidine alkaloids isolated from Poecilosclerida marine sponges. These polycyclic guanidine alkaloids are extremely versatile SM [20]. Since their original isolation in 1989, several revisions have been made and many aspects remain to be studied. However, what is clear is that they seem to be specific to Poecilosclerida marine sponges. Over 53 derivatives have been isolated and their original structures, based on chemical degradation studies and extensive NMR and MS studies, have been revised since the development of their total synthesis. The structural and stereochemical complexity of this class of natural products have inspired the development of a number of new synthetic methodologies [21–34], which in turn has led to several total syntheses [31,33,35–50] beyond the scope of this review. Finally, these unique and fascinating structures are coupled with a wide range of biological activities due to the typical shape of their tricyclic skeleton. However, little is known about their exact mechanism of action.

Mar. Drugs 2016, 14, 77; doi:10.3390/md14040077

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2. StructuralDiversity Diversity 2. Structural From 1989 to 2015, isolated. 2015, 53 TGA TGA (triazaacenaphthylene (triazaacenaphthylene guanidine alkaloids) have been isolated. Natural TGA reported to date are listed in Tables 1 and 2. reported to date are listed in Tables 1 and 2. Ptilomycalin A (1), (1), isolated isolatedfrom fromthe thesponges spongesPtilocaulis Ptilocaulis spiculifer and Hemimycale is Ptilomycalin A spiculifer and Hemimycale sp. sp. [51],[51], is the the parent member a group relatedmetabolites. metabolites.This Thisincludes includescrambescidins crambescidins[52–55] [52–55] and and their parent member of aofgroup ofofrelated their derivatives (6) [52,56], crambidine (7) [52], (7) neofolitispates (8–10) [57], crambescidin derivatives (isocrambescidine (isocrambescidine (6) [52,56], crambidine [52], neofolitispates (8–10) [57], acid (14) [58], crambescidic acid (15) [59], ptilomycalin D (17) [60], monanchocidins (18–22) [61,62], and crambescidin acid (14) [58], crambescidic acid (15) [59], ptilomycalin D (17) [60], monanchocidins monanchomycalins (23–25) [63,64]), which are found in several sponges crambe, Neofolitispa (18–22) [61,62], and monanchomycalins (23–25) [63,64]), which are found(Crambe in several sponges (Crambe dianchora, Monanchora arbuscula, Monanchora ungiculata, Monanchora dianchora, and Monanchora pulchra), crambe, Neofolitispa dianchora, Monanchora arbuscula, Monanchora ungiculata, Monanchora dianchora, and as well as, for a subset, in the Caledonian Fromia monilis and Fromia Celerinamonilis heffernani Monanchora pulchra), as well as, New for a subset, in thestarfishes New Caledonian starfishes and (Table 1) [65]. Additional guanidine derivatives have been isolated, such as the batzelladines Celerina heffernani (Table 1) [65]. Additional guanidine derivatives have been isolated, such as the A–E (26–30) from the Bahamanian sponge Batzella sp. Batzella (whichsp. has since has been revised Crambe batzelladines A–E (26–30) from the Bahamanian sponge (which since been to revised to crambe) [66], batzelladines F–I (31–34) from the Jamaican spongesponge BatzellaBatzella sp. [67], J (51) Crambe crambe) [66], batzelladines F–I (31–34) from the Jamaican sp.batzelladine [67], batzelladine from Caribbean spongesponge Monanchora unguifera [59], and[59], theirand derivatives (clathriadic acid (41) [68], J (51)the from the Caribbean Monanchora unguifera their derivatives (clathriadic acid merobatzelladines (42,43) [69],(42,43) and batzellamide A (50) [70]) A from Clathria calla, (41) [68], merobatzelladines [69], and batzellamide (50)Monanchora [70]) fromunguifera, Monanchora unguifera, and Monanchora (Table 2). Clathria calla, andarbuscula Monanchora arbuscula (Table 2). TGA are only found in Poecilosclerida To date, TGA are only found in Poecilosclerida marine marine sponges. sponges. To date, they they have have been been only only isolated isolated from (Crambe, Monanchora), Mycalidae (Arenochalina, Mycale),Mycale), Phoriospongidae (Batzella, from the theCrambidae Crambidae (Crambe, Monanchora), Mycalidae (Arenochalina, Phoriospongidae Hemimycale), and Microcionidae (Clathria) (Clathria) families [71]. Sponges produce can TGA be found in (Batzella, Hemimycale), and Microcionidae families [71]. that Sponges that TGA produce can be warm betweenbetween oceans and seas. A seas. largeAmajority were sampled in the found waters, in warmwithout waters, distinction without distinction oceans and large majority were sampled Caribbean Sea (Figure 1). 1). in the Caribbean Sea (Figure

Figure 1.1.Geographical Geographical repartition of TGA new(triazaacenaphthylene TGA (triazaacenaphthylene alkaloids) Figure repartition of new guanidineguanidine alkaloids) discovered © d-maps.com [72]. Used with permission. discovered from 1989 to 2015. Graphic © from 1989 to 2015. Graphic d-maps.com [72]. Used with permission.

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Table 1. Reviewed crambescidin-like GA (guanidine alkaloids) from 1989 to 2015. Metabolite

Species

Sampling Site

Discovery Year

Guanidine Moiety

Biological Activity

Synthesis Described

Ref.

ptilomycalin A (1)

Hemimycale sp. Ptilocaulis spiculifer

Red sea

1989

1

Av, Am, At

Yes

[42,51,73]

crambescidin 800 (2)

Crambe crambe

Palma de Mallorca, Mediterranean sea

1991

1

Av, Am, At

Yes

[54–56,73,74]

Ca2+

crambescidin 816 (3)

Crambe crambe

Palma de Mallorca, Mediterranean sea

1991

1

Av, At, antagonist

No

[52,55,56,75]

crambescidin 830 (4)

Crambe crambe

Palma de Mallorca, Mediterranean sea

1991

1

n.t.

No

[55]

crambescidin 844 (5)

Crambe crambe

Palma de Mallorca, Mediterranean sea

1991

1

Av

No

[55,56]

13,14,15-isocrambescidine 800 (6)

Crambe crambe

Banyuls, Mediterranean sea

1993

1

Not active

Yes

[36,42,56]

crambidine (7)

Crambe crambe

Banyuls, Mediterranean sea

1993

1

n.t.

Yes

[45,49,52]

neofolitispate 1 (8)

Neofolitispa dianchora

Andaman Islands, Indian Ocean

1999

1

Av

No

[57] [57]

neofolitispate 2 (9)

Neofolitispa dianchora

Andaman Islands, Indian Ocean

1999

1

Av

Yes

neofolitispate 3 (10)

Neofolitispa dianchora

Andaman Islands, Indian Ocean

1999

1

Av

No

[57]

crambescidin 359 (11)

Monanchora ungiculata

Belize, North Atlantic Ocean

2000

1

n.t.

Yes

[33,41,48,53]

crambescidin 431 (12)

Monanchora ungiculata

Belize, North Atlantic Ocean

2000

1

n.t.

No

[53]

crambescidin 826 (13)

Monanchora sp.

Palau, Pacific Ocean

2003

1

Av

No

[54]

crambescidin acid (14)

Monanchora ungiculata

Maldive Islands, Indian Ocean

2004

1

At

No

[58]

crambescidic acid (15)

Monanchora unguifera Monanchora dianchora

Panama, Caribbean side, Atlantic Ocean

2005

1

n.t.

No

[59]

16β-hydroxycrambescidin 359 (16)

Monanchora unguifera

Jamaica, North Atlantic Ocean

2007

1

Am

No

[73]

ptilomycalin D (17)

Monanchora dianchora

Madagascar, Indian Ocean

2007

1

n.t.

No

[60]

monanchocidin A (18)

Monanchora pulchra

Urup Island, North Pacific Ocean

2010

1

At

No

[61]

monanchocidin B (19)

Monanchora pulchra

Urup Island, North Pacific Ocean

2011

1

At

No

[62]

monanchocidin C (20)

Monanchora pulchra

Urup Island, North Pacific Ocean

2011

1

At

No

[62]

monanchocidin D (21)

Monanchora pulchra

Urup Island, North Pacific Ocean

2011

1

At

No

[62]

monanchocidin E (22)

Monanchora pulchra

Urup Island, North Pacific Ocean

2011

1

At

No

[62]

monanchomycalin A (23)

Monanchora pulchra

Urup Island, North Pacific Ocean

2012

1

At

No

[63]

monanchomycalin B (24)

Monanchora pulchra

Urup Island, North Pacific Ocean

2012

1

n.t.

No

[63]

monanchomycalin C (25)

Monanchora pulchra

Urup Island, North Pacific Ocean

2013

1

n.t.

No

[64]

Am, antimicrobial activity; Av, antiviral activity; At, antitumoral activity; and n.t., not tested.

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Table 2. Reviewed batzelladine-like GA from 1989 to 2015. Metabolites

Species

Sampling Site

Discovery Year

Guanidine Moiety

Biological Activities

Synthesis Described

Ref.

batzelladine A (26)

Batzella sp.

Bahamas, North Atlantic Ocean

1996

3

Am, Av

Yes

[32,46,66]

batzelladine B (27)

Batzella sp.

Bahamas, North Atlantic Ocean

1996

3

Av

No

[66]

batzelladine C (28)

Batzella sp.

Bahamas, North Atlantic Ocean

1996

2

Av, Am, At

No

[66,73]

batzelladine D (29)

Batzella sp.

Bahamas, North Atlantic Ocean

1996

2

Av, Am

Yes

[37,40,46,47,66]

batzelladine E (30)

Batzella sp.

Bahamas, North Atlantic Ocean

1996

2

n.t.

Yes

[35,66] [30,39,42,67]

batzelladine F (31)

Batzella sp.

Jamaica, North Atlantic Ocean

1997

2

Am

Yes

batzelladine G (32)

Batzella sp.

Jamaica, North Atlantic Ocean

1997

2

Av

No

[67]

batzelladine H (33)

Batzella sp.

Jamaica, North Atlantic Ocean

1997

2

Av

No

[67]

batzelladine I (34)

Batzella sp.

Jamaica, North Atlantic Ocean

1997

2

Av

No

[67]

dehydrobatzelladine C (35)

Monanchora arbuscula

Belize, North Atlantic Ocean

2000

2

Av, Am, At

Yes

[43,53,73] [59]

batzelladine J (36)

Monanchora unguifera

Panama, North Atlantic Ocean

2005

3

n.t.

No

batzelladine K (37)

Monanchora unguifera

Jamaica, North Atlantic Ocean

2007

1

n.t.

No

[73]

batzelladine L (38)

Monanchora unguifera

Jamaica, North Atlantic Ocean

2007

2

Av, Am, At

No

[73]

batzelladine M (39)

Monanchora unguifera

Jamaica, North Atlantic Ocean

2007

2

Av, Am, At

No

[73]

batzelladine N (40)

Monanchora unguifera

Jamaica, North Atlantic Ocean

2007

2

Av, At

No

[73]

clathriadic acid (41)

Clathria calla

Martinique, North Atlantic Ocean

2009

1

Am

No

[68]

merobatzelladine A (42)

Monanchora sp.

Amami-Oshima Island, North Pacific Ocean

2009

1

Am

No

[50,69]

merobatzelladine B (43)

Monanchora sp.

Amami-Oshima Island, North Pacific Ocean

2009

1

Am

Yes

[69]

norbatzelladine A (44)

Monanchora arbuscula

Guadeloupe Island, North Atlantic Ocean

2009

3

Am, At

No

[68]

norbatzelladine L (45)

Clathria calla

Martinique, North Atlantic Ocean

2009

2

Am, At

No

[68]

dinorbatzelladine A (46)

Monanchora arbuscula

Guadeloupe island, North Atlantic Ocean

2009

3

Am, At

No

[68]

dinorbatzelladine B (47)

Monanchora arbuscula

Guadeloupe island, North Atlantic Ocean

2009

3

n.t.

No

[68] [68]

dinordehydrobatzelladine B (48)

Monanchora arbuscula

Guadeloupe island, North Atlantic Ocean

2009

3

Am, At

No

dihomodehydrobatzelladine C (49)

Monanchora arbuscula

Guadeloupe island, North Atlantic Ocean

2009

2

Am, At

No

[68]

batzellamide A (50)

Monanchora arbuscula

Rio de Janeiro state, South Atlantic Ocean

2015

2

n.t.

No

[70]

hemibatzelladine J (51)

Monanchora arbuscula

Rio de Janeiro state, South Atlantic Ocean

2015

2

n.t.

No

[70]

∆19 -hemibatzelladine J (52)

Monanchora arbuscula

Rio de Janeiro state, South Atlantic Ocean

2015

2

n.t.

No

[70]

∆200 -hemibatzelladine J (53)

Monanchora arbuscula

Rio de Janeiro state, South Atlantic Ocean

2015

2

n.t.

No

[70]

Am, antimicrobial activity; Av, antiviral activity; At, antitumor activity; and n.t., not tested.

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Since 1989, the of discovered each considered as constant, SinceSince 1989, 1989, the number number of new new TGA discovered each year year is is considered as almost almost constant, the number of TGA new TGA discovered each year is considered as almost constant, although it should be noted that in some years no new TGA were described (Figure 2). although it should be noted that in some yearsyears no new were were described (Figure 2). 2). although it should be noted that in some no TGA new TGA described (Figure

Cumulative number of new TGA discovered Cumulative number of new TGA discovered FigureFigure 2. Number Number of new newofTGA TGA discovered since 1989. 1989. The number of TGA TGA discovered per year year (grey 2. Number newdiscovered TGA discovered sinceThe 1989. The number ofdiscovered TGA discovered per(grey year (grey Figure 2. of since number of per bars) and the cumulative data representing the total number of TGA discovered (black curve) are are bars)the and the cumulative data representing thenumber total number ofdiscovered TGA discovered bars) and cumulative data representing the total of TGA (black (black curve)curve) are presented from 1989 to 2015. presented fromto1989 presented from 1989 2015.to 2015.

2.1. TGA TGA Structures 2.1. Structures TGA Structures 2.1. Each TGA TGA is is structurally structurally closely related tothe theto others. Crambescidins-like GA differ differ from one one one Each TGA is structurally closely related the others. Crambescidins-like GA differ from Each closely related to others. Crambescidins-like GA from another, by the C-8 spiro ring, the presence or absence of a hydroxyl group at C-13 or the nature of of another, C-8ring, spirothe ring, the presence or absence of a hydroxyl C-13 or the another, by the by C-8the spiro presence or absence of a hydroxyl group atgroup C-13 oratthe nature of nature the the side chain terminus at C-14. the side chain terminus side chain terminus at C-14. at C-14. The structures of22 22related related crambescidin-like GAare are summarized inFigure Figure The structures of 22 related crambescidin-like GA are summarized in Figure 3. The structures of crambescidin-like GA summarized in 3.3. Other derivatives such as 13,14,15-isocrambescidin 800 (6), crambidin (7) or or or derivatives as 13,14,15-isocrambescidin crambidin (7) OtherOther derivatives such such as 13,14,15-isocrambescidin 800 800 (6), (6), crambidin (7) 16β-hydroxycrambescidin 359 (16) have also been isolated (Figure 4). 16β-hydroxycrambescidin 359have (16) also havebeen alsoisolated been isolated (Figure 4). 16β-hydroxycrambescidin 359 (16) (Figure 4).

A

A

R1 5

O H N

5

8 10

H H R=

R= O

H 2N

O

OHH

OH O NH2

N O OHN

N

O ON H N 815 13 10

19

N H H O

N

O

R1 19

15 O 13

O R

n

HR 2O

n

R

R2

NH2

R=

OH

O

H 2N

monanchocidin A (18): 1 = H, = Et, monanchocidin A R(18): R1R=2 H, R2 n= =13 Et, n =13 1 = H, = H, monanchocidin D (21): R2n= =13 H, n =13 monanchocidin D R(21): R1R=2 H, monanchocidin E (22):E R(22): 1 = H, = Et, monanchocidin R1R=2 H, R2 n= =12 Et, n =12

NH2 N NH2

R=N

NH2 NH2

O

monanchomycalin A (23): monanchomycalin A (23): R 2 = H, n =14 R1 = Et, R1 = Et, R2 = H, n =14 monanchomycalin B (24):B (24): monanchomycalin R1 = H, = H, R1R=2 H, R2n= =14 H, n =14

FigureFigure 3. Cont. 3. Cont. Figure 3. Cont.

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B R3 R3 3

3 O 19 OH N N 15 O 19 O8 H N N 8 10 N 13 15 R2 10 13 N R1 H R2 R1 H

crambescidin 359 (11): R1 = R2 = R3 = H crambescidin 359 (11): =H crambescidin 431 (12):R1R=1 =R2R=3 =R3H, R2 = COOEt crambescidin 431 (12): R 1 = R 3 = H, R2 R=2COOEt crambescidin acid (14): R1 = R3 = H, = COOH crambescidin acid (14): R1 = R3 = H, R2 = COOH R2 =

O

R2 =

nR4 nR4

O O O

neofolitispate 1 (8): R1 = R3 = H, R4 = COOMe, n = 15 neofolitispate 3 = H, R4 = COOMe, n = 15 3 = H, R4 = COOMe, n = 14 neofolitispate1 2(8): (9):R1R=1 =RR

= 1R=3 R = 3H, R4 R = 4COOMe, n =n14 neofolitispate R1 R = H, = COOMe, = 13 neofolitispate2 3(9): (10): 1 = R3 = H, R4 = COOMe, n = 13 neofolitispate 3 (10): R crambescidic acid (15): R1 = R3 = H, R4 = COOH, n = 14

R2 = = R2

H

O

H m OH

O O O

OH

mO

NH2 OH

N

N

O

1 = R3 = H, R4 = COOH, n = 14 crambescidic (15):RR 1 = R3 = H, R4 = Me, n = 14 ptilomycalinacid D (17): ptilomycalin D (17): R1 = R3 = H, R4 = Me, n = 14 R

NH2

R R4 = R =

OH

ON

4

H 2N 2 monanchocidin B (19): monanchocidin (19): R1 = R3 = H, m B = 13 R1monanchocidin = R3 = H, m = 13C (20): monanchocidin (20): = 14 R1 = R3 = H, m C

O ptilomycalin A (1): ptilomycalin R1 = R3 = R =AH,(1): n = 14 Rcrambescidin 1 = R3 = R = H, 800 n = (2): 14 crambescidin (2): n = 14 R1 = R3 = H, R800 = OH, Rcrambescidin 1 = R3 = H, R = 816 OH,(3): n = 14 R 1 = R = OH, R 3 = H, crambescidin 816 (3): n = 14 Rcrambescidin 1 = R = OH, R3830 = H,(4): n = 14 R1 = R = OH, 830 R3 =(4): H, n = 15 crambescidin Rcrambescidin 1 = R = OH, R3844 = H,(5): n = 15 R1 = R = OH, 844 R3 =(5): H, n = 16 crambescidin Rmonanchomycalin 1 = R = OH, R3 = H, C n =(25): 16 monanchomycalin R1 = R = H, R3 = Et,Cn(25): = 14

H N

O

O R4 = R4 =

R1 = R3 = H, m = 14

N

N O

NH2 NH2 NH 2 NH2

N

NH2 NH NH2 2 NH2

crambescidin 826 (13): crambescidin (13): = 16 R1 = R3 = H, n826 O

R1 = R3 = H, n = 16

R1 = R = H, R3 = Et, n = 14

Figure 3. Related (A) C-8 cycloheptanic spiro ring and (B) C-8 cyclopentanic spiro ring

Figure 3. Related (A) C-8 cycloheptanic spiro ring and (B) C-8 cyclopentanic spiro ring crambescidin-like Figure 3. Related GA. (A) C-8 cycloheptanic spiro ring and (B) C-8 cyclopentanic spiro ring crambescidin-like GA. crambescidin-like GA. OH N

OH N H H

N

OH

O

OH(S)

N O N H

N H

N

O 14

O O

(S)

O N

NH2 NH2 NH2 NH2

OH N H

14

O

19 OH ( R)

OH N

N NN

43

N 43 14

O O

O

OH ( S) OH

O

N

H

O

19 OH ( R)

( S)

ON

14

O

Crambidine (7)

13,14,15-isocrambescidin 800 (6)

Crambidine (7)

13,14,15-isocrambescidin 800 (6) 3

O 8

3

O 8

N

H O N 15

N 10 H 10 N

H 13 O N N

19

15 13

H

19

OH

OH

H H 16β-hydroxycrambescidin 359 (16)

16β-hydroxycrambescidin 359 (16) GA. Figure 4. Non-related crambescidin-like Figure 4. Non-related crambescidin-like GA.

Figure 4. Non-related crambescidin-like GA.

NH2 NH2 NH2 NH2

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Compared to crambescidin-like GA, batzelladines-like batzelladines-like GA GA present present more more structural structural variations. variations. Compared to crambescidin-like GA, Structurally, all of the batzelladines share a decahydroor octahydro-5,6,8b-triazaacenaphthalene Structurally, all of to thecrambescidin-like batzelladines share decahydro- or octahydro-5,6,8b-triazaacenaphthalene Compared GA,a batzelladines-like GA present more structural variations. core with different of oxidation. Batzelladines A–I (26–34) oxidation.share Batzelladines A–I all possess at least one tricyclic Structurally, all degrees of the batzelladines a decahydroor octahydro-5,6,8b-triazaacenaphthalene guanidine core that contains either a syn or anti stereo relationship of the angular hydrogens guanidine core that contains a syn or Batzelladines anti stereo relationship of all thepossess angular that core with different degreeseither of oxidation. A–I (26–34) athydrogens least that one flank tricyclic the pyrrolidine nitrogen [76]. To this, tricyclic guanidine core are connected, through an ester linkage, flank the pyrrolidine nitrogen [76]. To this, core are connected, through an esterthat guanidine core that contains either a syntricyclic or anti guanidine stereo relationship of the angular hydrogens and additional guanidine fragments ofTo varying complexity. Batzelladines F (31), FG(31), (32), Lan (38) linkage, and additional guanidine fragments oftricyclic varying complexity. Batzelladines Gand (32), and flank the pyrrolidine nitrogen [76]. this, guanidine core are connected, through ester all possess an additional tricyclic hydroxy-guanidine fragment, while the simplest members of the L (38) all possess an additional tricyclic hydroxy-guanidine fragment, while the simplest members linkage, and additional guanidine fragments of varying complexity. Batzelladines F (31), G (32),ofand family, batzelladines C additional (28), D (29), and Eand (30), a common 4-guanidino-butyl unit. The more theLfamily, C (28), Dtricyclic (29), E possess (30), possess a common 4-guanidino-butyl unit. The of (38) allbatzelladines possess an hydroxy-guanidine fragment, while the simplest members complex batzelladines, A (26) and B (27), are attached to an analogue of crambescin A (54) (Figure 5).The more complex batzelladines, A (26) and B (27), are attached to an analogue of crambescin A (54) the family, batzelladines C (28), D (29), and E (30), possess a common 4-guanidino-butyl unit. Batzelladines F (31) and J (36) are composed of two 5,6,6a-triaza-acenaphthalene cores linked via an (Figure Batzelladines F (31) and J (36) of two 5,6,6a-triaza-acenaphthalene more5). complex batzelladines, A (26) andare B composed (27), are attached to an analogue of crambescincores A (54) aliphatic linked viachain. an chain.F (31) and J (36) are composed of two 5,6,6a-triaza-acenaphthalene cores (Figure 5).aliphatic Batzelladines The structures of several linked via an aliphatic chain.members of the batzelladines have been revised since their original isolation. The originally proposed structures were based on chemical degradation studies, The originally structures were The structures of proposed several members of the batzelladines have been revised since theirNMR original spectroscopy comparison the data previously reportedstudies, polycyclic analysis (1D and 2D), and isolation. The originally proposed structures wereofbased on to chemical degradation NMR guanidine such as ptilomycalin A (1). Since the original isolation work, the structures of batzelladines such analysis as ptilomycalin A (1). the original isolation work, the structures of spectroscopy (1D and 2D), andSince comparison of the data to previously reported polycyclic A (26), D (29),A Esuch (30), as and F (31) haveand allAF been tobeen their current structures afterstructures theirstructures partial or of batzelladines (26), D (29), E (30), (31)revised have revised to their current after guanidine ptilomycalin (1). Since all the original isolation work, the total synthesis As[27–30,35,39]. a consequence ofathese reassignments, the relative stereochemistry of their partial or[27–30,35,39]. total synthesis consequence of these the relative batzelladines A (26), D (29), E (30), and F As (31) have all been revised toreassignments, their current structures after batzelladines G (32), H (33), and I (34) has been reexamined [30]. stereochemistry of total batzelladines (32), H (33), and has been reexamined [30]. their partial or synthesisG[27–30,35,39]. As Ia (34) consequence of these reassignments, the relative of 22 related batzelladine-like GA are summarized in The current structures related batzelladine-like GAhas arebeen summarized in Figure Figure 6. stereochemistry of batzelladines G (32), H (33), and I (34) reexamined [30]. 6. batzelladine-like GA have been isolated such as batzelladine C (28), K (37), and (30); Other batzelladine-like GA have been isolated such as batzelladine C (28), K (37), and The current structures of 22 related batzelladine-like GA are summarized in Figure 6. EE (30); C (35); clathriadic acid (41); and A 7). dehydrobatzelladine and batzellamide batzellamide A (50) (50) (Figure (Figure 7). K (37), and E (30); Other batzelladine-like GA have been isolated such as batzelladine C (28), dehydrobatzelladine C (35); clathriadic acid (41); and batzellamide A (50) (Figure 7). NH

O

O

O

O

8

HN

NHNH 2

NH

NH

N

NH2

8

NH HN

N

crambescin A (54) crambescin A (54) NH

A

Figure 5. 5. Crambescin Figure Crambescin A A (54). (54). Figure 5. Crambescin A (54).

A

R1 R2

NH O H R2 = R2 =

HN

O

N

O H N

O

NH HN

N

3H

N

NH2

batzelladine A (26): H, n = 8, m =A8(26): R1 =batzelladine NH

m (44): =8 R1 = H, n = 8, A norbatzelladine H, n = 8, m = 7 A (44): R1 =norbatzelladine = 7(46): R1 = H, n = 8, m A dinorbatzelladine H, n = 8, m = 6 A (46): R1 =dinorbatzelladine R1 = H, n = 8, m = 6

H

H

2

NHNH 2 3H

O

n O R1 O HN H R2 NN m n O N H RN N H N N R = R2 = H

m

R N

NN H N

H H batzelladine F (31): CH3, R = H,Fn(31): = 7, m = 6 R1 =batzelladine

R =(32): H, n = 7, m = 6 R1 = CH3, G batzelladine G (32): CH3, R = OH, n = 7, m = 8 R1 =batzelladine = OH, n = 7, m = 8 R1 = CH3, R batzelladine L (38): CH3, R = H,Ln(38): = 7, m = 8 R1 =batzelladine n = 7, m = 8 R1 = CH3, R = LH,(45): norbatzelladine CH3, R = H, n =L7,(45): m=7 R1 =norbatzelladine R1 = CH3, R = H, n = 7, m = 7 Figure 6. Cont.

Figure 6. Cont. Figure 6. Cont.

NH R2 =

N H R2 =

NHNH 2 N

NH2

H batzelladine D (29): batzelladine R1 = H, m = 7, n =D3(29):

R1 = H, m = 7, n = 3

Mar. Drugs 2016, 14, 77 Mar. Drugs 2016, 14, 77

8 of 24 8 of 24

B R1 R2

O

H N

n O N

6

R2 =

H N

R2 =

N H

N

N

NH

N

O

H

O

H

NH2

N 3H

H N

N

H

batzelladine M (39): R1 = H, n = 6

batzelladine J (36): R1 = H, n = 6

batzelladine N (40): R1 = CH3, n = 7

C O R1

H N

O R2

N

N H

n NH

R1 =

OH N

N

OH N

R1 =

6

H

N

R1 =

6

N

N H

H

H

batzelladine I (34): R2 = CH3, n = 6

batzelladine H (33): R2 = CH3, n = 6

O H

NH

D

N H

R1 =

NH2

O

N NH

dinordehydrobatzelladine B (48): R2 = CH3, n = 6

E NH

H

H N R

N H

N N H

n

H 2N

,n=5

merobatzelladine A (42): R = merobatzelladine B (43): R = Et, n = 3

H N NH

O

NH H O

O

H

H N

n O N

3

H N

O

dinorbatzelladine B (47): n = 6

H N

O

NH

N H

hemibatzelladine J (51): R = Δ19-hemibatzelladine J (52): R = Δ20-hemibatzelladine J (53): R =

N H

N H

batzelladine B (27): n = 8

F H 2N

NH2

6

HN

Dihomodehydrobatzelladine C (49): R2 = C5H11, n = 8

3N H

R OH

OH

OH

Figure Figure6.6.Related Relatedbatzelladine-like batzelladine-likeGA GAwith withdifferent differentright-handed right-handedtricycles. tricycles.

5

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Mar. Drugs 2016, 14, 77 O

H N

H 2N

9 of 24 H

NH

Mar. Drugs 2016, 14, 77

N

O

H

NH

N

N N H

H 2N

N

H

N

N

H N

batzelladine E (30) O

NH

N H

H

N

N

5

5

H

batzelladine C (28)

batzelladine E (30)

batzelladine K (37) H H

clathriadic H acid (41)

4

N

N N H

O

O

N H

H N

5

N

O 7

O dehydrobatzelladine C (35)

N

Figure 7. Unrelated batzelladine-like GA. N OH

Figure 7. Unrelated batzelladine-like GA. H

4

N

O

N H

N H

N

O

N

batzellamide A (50) N

5

N

95of 24

N

H

H N

NHN

N H OH

N

N

dehydrobatzelladine C (35) O H 2N

N

HO N

H N

O

NH

N H

H

O

H N

H 2N

N

5

H

H N

H

H

O

NH

N H

batzelladine C (28) O

H 2N

O

H N

H 2N

N

O

N H

O N H

H

H N

O 7

N

N

O

In summary, the structurally unique tricyclic guanidinium ring system batzelladine Kthe (37) structurally clathriadic acid (41) batzellamide A ring (50) In(hydro-5,6,6atriazaacenapthalene) summary, guanidinium that definesunique this class oftricyclic natural products can be found in over 53system different alkaloids. While each Figure ofthat these natural products share structural the (hydro-5,6,6atriazaacenapthalene) this class of this natural products canmotif, be found in 7.defines Unrelated batzelladine-like GA. common substituents around the While tricycliceach coreof ofthese these natural molecules leads to share a significant structuralstructural diversity, motif, over 53 different alkaloids. products this common In relate summary, unique tricyclic ringmolecules system which to a wide-range of structurally biological For instance, number of these the substituents around thethe tricyclic core ofproperties. these molecules leadsa large toguanidinium a significant structural diversity, including batzelladine F (31) and ptilomycalin A (1)class feature esters that tethercan thebe tricyclic to a53 (hydro-5,6,6atriazaacenapthalene) that defines this of natural products found core in over which relate to a wide-range of biological properties. For instance, a large number of these molecules diverse array of different groups, including othershare tricyclic other different alkaloids. Whilefunctional each of these natural products thisguanidine common subunits. structuralThe motif, the including batzelladinediversity F (31) and ptilomycalin A alkaloids (1) feature esters that tether the tricyclic core to a area of structural withincore thisoffamily is both C1 and the C8 alkyldiversity, chains, substituents around the tricyclic these of molecules leads to the a significant structural diverse array of different groups, including other tricyclic guanidine The other which vary in offunctional length, units of unsaturation, and oxidation. Remote oxidation of the alkyl which relate to terms a wide-range of biological properties. For instance, a large number ofsubunits. these molecules area of structural diversity within this family of alkaloids is both the C1 and the C8 alkyl branches batzelladine is characteristic theptilomycalin crambescidin alkaloids, including ptilomycalin A (1) including F (31)ofand A (1) feature esters that tether the tricyclic coreand tochains, a crambescidin 359different (11), which feature two spirocyclic hemiaminals as well as the tricyclic guanidine whichdiverse vary in terms of length, units ofgroups, unsaturation, and oxidation. Remote oxidation ofother the alkyl array of functional including other tricyclic guanidine subunits. The framework. In addition to structural GA crambescidins-like GA branches isofcharacteristic of the crambescidin alkaloids, including ptilomycalin A (1) crambescidin area structural diversity within thisdiversity, family ofbatzelladines-like alkaloids is both the and C1 and the C8and alkyl chains, alkaloids different stereochemical configurations ofoxidation. theastricyclic core. oxidation Both the transand which varyfeature in terms of length, units ofhemiaminals unsaturation, andwell of the alkyl 359 (11), which feature two spirocyclic as the Remote tricyclic guanidine framework. cis-configurations of the pyrrolidine subunit have been reported in this class of natural A products. branches is characteristic of the crambescidin alkaloids, including ptilomycalin (1) In addition to structural diversity, batzelladines-like GA and crambescidins-like GA alkaloidsand feature Batzelladine F359 (31) highlights this stereochemical diversity as it contains distinct guanidine tricyclic crambescidin (11), which feature two hemiaminals welltransas two theand tricyclic different stereochemical configurations of spirocyclic the tricyclic core. Bothasthe cis-configurations guanidine subunits, withtoeach featuring one of the pyrrolidine configurations. The stereochemical framework. In addition structural diversity, batzelladines-like GA and crambescidins-like GA of thediversity pyrrolidine subunit havetobeen reported inofthis class of natural products. Batzelladine F (31) is generally limited the configuration the pyrrolidine unit, as all of alkaloids in this alkaloids feature different stereochemical configurations of the tricyclic core. the Both the transand highlights this stereochemical diversity as itthe contains twoC6) distinct tricyclic guanidine subunits, class feature a trans between C4 (and/or proton alkyl with cis-configurations of relationship the pyrrolidine subunit have been reported in and this the classC1of(and/or naturalC8) products. each Batzelladine featuring of the pyrrolidine configurations. The stereochemical diversity is chain, with one the exception of merobatzelladines A (42) and B (43). Both natural products feature agenerally cis F (31) highlights this stereochemical diversity as it contains two distinct tricyclic relationship between the C6 proton and the C8 alkyl chain. limited to the configuration of the pyrrolidine as all of configurations. the alkaloids in class feature a guanidine subunits, with each featuring one of unit, the pyrrolidine Thethis stereochemical

trans diversity relationship between the C4 (and/or C6) proton the C1 unit, (and/or alkyl chain, is generally limited to the configuration of theand pyrrolidine as allC8) of the alkaloids inwith this the 2.2. TGA Classification class feature a trans relationship between C4 (and/or C6) proton and thefeature C1 (and/or alkyl exception of merobatzelladines A (42) and the B (43). Both natural products a cisC8) relationship Different alkaloids classifications made, and,Both as such, Santos et al. (2015) have chain, with theguanidine exception of merobatzelladines (42)beand B (43). natural products feature a cis between the C6 proton and the C8 alkyl chain. Acan

described four GA chemotypes [70].and Thethe first constituted of a monocyclic pyrimidinamine relationship between the C6 proton C8class alkylischain. skeleton, for example, crambescin C1 (55) or the bicyclic cyclopentapyrimidinamine skeleton, such 2.2. TGA Classification as crambine A (56) (Figure 8). The second one is a tricyclic triazaacenaphthylene skeleton, which 2.2. TGA Classification Different guanidine alkaloids classifications can beand made, and, one as such, Santos et al. (2015) have only contains one guanidine moiety like crambescidins, the third possess the same skeleton Different guanidine alkaloids classifications can be made, and, as such, Santos et al. (2015) have described chemotypes first guanidine class is constituted of abemonocyclic pyrimidinamine as forfour classGA 2, but contains, at [70]. least, The one more moiety, as can seen in the case of most described four GA chemotypes [70]. The first class is constituted of a monocyclic pyrimidinamine batzelladines. The fourth one is aC1 tricyclic cyclopentaquinazolinamine skeleton like netamine M (57) such skeleton, for example, crambescin (55) or the bicyclic cyclopentapyrimidinamine skeleton, skeleton, for example, crambescin C1 (55) or the bicyclic cyclopentapyrimidinamine skeleton, such or ptilocaulin (58). as crambine A (56) (Figure 8). 8). The triazaacenaphthylene skeleton, which as crambine A (56) (Figure Thesecond secondone one isis aa tricyclic tricyclic triazaacenaphthylene skeleton, which only contains one guanidine moiety like crambescidins, and the third one possess the same skeleton only contains one guanidine moiety like crambescidins, the same skeleton A B C and the third one possess D as forasclass 2, but contains, at at least, more guanidine moiety, as can be seen in the case of most NH for class 2, but contains, least,one one NH2 2 more guanidine moiety, as can be seen in the case of most NH2 NH batzelladines. TheThe fourth is is a tricyclic skeleton netamine M (57) batzelladines. one a tricyclic cyclopentaquinazolinamine skeleton likelike netamine M (57) N N cyclopentaquinazolinamine HN fourth N one H C HO H 10 21 C HN N HN NH or ptilocaulin 8 17 or ptilocaulin (58).(58). O

A

NH2

O

NH52

N H

O

NH

HN N crambescin C1 (55) HO

B

O

H N

NH2

NH2

D

NH

N N crambine A (56) C10H21

C8H17

C NH

2 netamine M (57)

HN

N

NH

ptilocaulin (58) HN

NH

Figure 8. (A) Crambescin C1 (55); (B) crambine A (56); (C) netamine M (57); and (D) ptilocaulin (58). O

NH2

O 5

N H

O

O

H N

NH2

NH

crambescin C1 (55)

NH

crambine A (56)

netamine M (57)

ptilocaulin (58)

Figure 8. (A) Crambescin C1 (55); (B) crambine A (56); (C) netamine M (57); and (D) ptilocaulin (58).

Figure 8. (A) Crambescin C1 (55); (B) crambine A (56); (C) netamine M (57); and (D) ptilocaulin (58).

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10of of24 24 10 of 10 24 10 of 24

Another classification can be made with the same first, second and fourth classes, and a Another classification can be made with the same first, second and fourth classes, an modified third class describing pentacyclic triazaacenaphthylene skeletons crambescidins (1–25) Another classification can bebe made with thethe same second and fourth classes, and Another Another classification classification can be can made with made the with same first, samefirst, second first, second and like fourth and fourth classes, classes, and alike andacrambescidins a modified third class describing pentacyclic triazaacenaphthylene skeletons (1– Another classification can be made with the same first, second and fourth classes, and a modified (Table 3). modified class describing triazaacenaphthylene skeletons like crambescidins (1–25) modified modified thirdthird class third describing class describing pentacyclic pentacyclic triazaacenaphthylene triazaacenaphthylene skeletons skeletons like crambescidins like crambescidins (1–25) (1–25) (Table 3). pentacyclic third class describing pentacyclic triazaacenaphthylene skeletons crambescidins (Table 3). Without taking into account any genus revision made, somelike observations may(1–25) be outlined. (Table 3).3). (Table (Table 3). Without taking into account any genus revision made, some observations may be outlin Without taking into account any genus revision made, some observations may be outlined. According to the data Monanchora is the most studied genus (Tables 1 and Some species Without taking into account any genus revision made, some may bebe outlined. Without Without taking taking intoreported, account into account any genus any genus revision revision made, made, some observations some observations may2). be may outlined. outlined. According to the data reported, Monanchora is theobservations most studied genus (Tables 1 and 2). Some spe According to the data reported, Monanchora is the most studied genus (Tables 1 and 2). Some species seem to produce both the crambescidins and batzelladines classes as is illustrated with Monanchora According thethe data reported, Monanchora is the most studied genus (Tables 1 and 2). Some species According According to thetodata to reported, data reported, Monanchora Monanchora is the most is the studied most studied genus (Tables genus (Tables 1 and 2). 1 and Some 2). species Some species seem to produce both the crambescidins and batzelladines classes as is illustrated with Monanch seem totoproduce both the crambescidins and batzelladines classes is illustrated with Monanchora unguifera, which produces 16β-hydroxycrambescidin (16),classes crambescidic (15) and batzelladines seem produce both thethe crambescidins and batzelladines classes as isacid illustrated with Monanchora seem toseem produce to produce both the both crambescidins crambescidins batzelladines and batzelladines classes as isas illustrated as is illustrated Monanchora with Monanchora unguifera, whichand produces 16β-hydroxycrambescidin (16),with crambescidic acid (15) and batzelladi unguifera, which produces 16β-hydroxycrambescidin (16), crambescidic acid (15) and batzelladines J–L J–L (36–38) (Tables 1 and 2). Other genera seem to produce only one TGA family. For example, to unguifera, which produces 16β-hydroxycrambescidin (16), crambescidic acid (15) and batzelladines unguifera, unguifera, which which produces produces 16β-hydroxycrambescidin 16β-hydroxycrambescidin crambescidic (16), crambescidic (15) acid and (15) batzelladines and batzelladines J–L (36–38) (Tables 1 and 2). (16), Other genera seemacid to produce only one TGA family. For example date, Batzella sp. was only shown to produce batzelladines A–I (26–34). (36–38) (Tables 1 and 2). Other genera seem to produce only one TGA family. For example, to date, J–L (36–38) (Tables and 2).2). Other seem to to produce only one TGA family. For example, J–L (36–38) J–L (36–38) (Tables (Tables 1 and1date, 2). 1 and Other genera Other genera seem toseem produce produce only one only TGA one family. TGA family. For (26–34). example, For example, to to to Batzella sp.genera was only shown to produce batzelladines A–I sp. only shown toshown produce batzelladines A–I (26–34). Interestingly, a was chemotaxonomic study suggested that the biogenetically related guanidine date, Batzella sp. was only shown to produce batzelladines A–I (26–34). date,Batzella Batzella date, Batzella sp.was was sp. only shown only to produce to produce batzelladines batzelladines A–I (26–34). A–I (26–34). Interestingly, a chemotaxonomic study suggested that the biogenetically related guanid alkaloids isolatedafrom Crambe crambe,study Monanchora arbuscula, Ptilocaulis spiculifer, andrelated Hemimycale sp., Interestingly, aachemotaxonomic study suggested the biogenetically guanidine Interestingly, study suggested that thethe biogenetically related guanidine Interestingly, Interestingly, chemotaxonomic achemotaxonomic chemotaxonomic suggested study suggested thatthat the that biogenetically biogenetically related related guanidine guanidine alkaloids isolated from Crambe crambe, Monanchora arbuscula, Ptilocaulis spiculifer, and Hemimycale Mar. Drugs 2016, 77from 10 10 of 24 Mar. Drugs Mar. 2016, Drugs 14, 2016, 77 14,14, 77 10 of 24 of 24 should eventually be united in a single genus, preferentially Crambe [53]. alkaloids isolated Crambe crambe, Monanchora arbuscula, Ptilocaulis spiculifer, and Hemimycale alkaloids isolated Crambe crambe, Monanchora arbuscula, Ptilocaulis spiculifer, and Hemimycale sp., alkaloids alkaloids isolated isolated fromfrom Crambe from Crambe crambe, crambe, Monanchora Monanchora arbuscula, arbuscula, Ptilocaulis Ptilocaulis spiculifer, spiculifer, and Hemimycale and Hemimycale sp., sp., should eventually be united in a single genus, preferentially Crambe [53]. sp., should eventually beunited united single genus, preferentially Crambe [53]. should eventually bebe united inin ainsingle genus, preferentially Crambe should should eventually eventually be united in a single aagenus, single genus, preferentially preferentially Crambe Crambe [53]. [53]. [53]. Another classification can bebemade the classes, Another Another classification classification can be can made with made the same thesame first, samefirst, second first,second second and and fourth andfourth fourth classes, classes, and and a anda a Tablewith 3.with GA classes. Table 3. GA classes. modified class describing pentacyclic triazaacenaphthylene skeletons like crambescidins (1–25) modified modified thirdthird class third describing class describing pentacyclic pentacyclic triazaacenaphthylene triazaacenaphthylene skeletons skeletons like crambescidins like crambescidins (1–25) (1–25) Table 3.3.classes. GA classes. GA classes. 3.Table GA 3. GA classes.3 Class 1 ClassTable 2 Table Class Class 4 Ref. (Table 3).3). (Table (Table 3). No No Class 1 Class 2 Class 3 Class 4 Ref. NH No Class 2 2genus Class 3 Class 4 Ref. No Class 11account Class Class 3 Class 4 Ref. NoWithout No Class 1Class 1account Class 2Class 2 revision Class 3 Class 3 Class 4 Class Ref. 4 Ref. taking into any made, some observations may be outlined. Without Without taking taking into account into anyClass genus anygenus revision revision made, made, some observations some observations may be may outlined. be outlined. H NH H N N H NHreported, 2 reported, According thethe data Monanchora is the most studied genus (Tables 1 2). and Some species According According to thetodata to reported, data Monanchora most is the studied most studied genus (Tables genus (Tables 1 and 1 and Some species Some species N N H N is the N Monanchora NH HN NH2). NH NH2). NH2 H N HN H H NH HN N Nclasses N Nclasses N N classes H H H to produce both the and batzelladines is is illustrated Monanchora seemseem toseem produce produce bothHN the both the and Nbatzelladines and batzelladines asN is as illustrated as illustrated with Monanchora with Monanchora H NH NH NH N 1 to 2 crambescidins 2 crambescidins 2 crambescidins NHNwith NHNH [70] NH HN HN N 1N NNN N NHN [70] N crambescidic H H H unguifera, which produces 16β-hydroxycrambescidin (15) and batzelladines unguifera, unguifera, which which produces produces 16β-hydroxycrambescidin 16β-hydroxycrambescidin (16), (16), crambescidic acid acid (15) acid and (15) batzelladines and batzelladines N crambescidic N (16), N NHN N N [70] 1 11 1 HN HN [70][70] [70] N N N orproduce more guanidine moiety J–L (36–38) (Tables and 2).2). Other genera seem to to produce one family. For example, J–L (36–38) J–L (36–38) (Tables (Tables 1 and1 2). 1 and Other genera Other genera seem+1 toseem produce only only one only TGA one family. TGA family. For For example, to to to H example, +1 orTGA more guanidine moiety H +1 or more Batzella sp.sp. was only shown to to produce A–I (26–34). date,date, Batzella date, Batzella sp. was only was shown only shown to produce produce batzelladines batzelladines A–Iguanidine (26–34). A–I (26–34). +1 oror more moiety +1 orbatzelladines more +1 guanidine more guanidine moiety moiety H H H Acanthella guanidine moiety Acanthella Interestingly, a achemotaxonomic thethebiogenetically related guanidine Interestingly, Interestingly, a chemotaxonomic chemotaxonomic studystudy suggested studysuggested suggested that that the that biogenetically biogenetically related related guanidine guanidine Clathria Clathria Arenochalina Acanthella Acanthella Acanthella Acanthella Arenochalina alkaloids isolated from Crambe crambe, Monanchora arbuscula, Ptilocaulis spiculifer, and Hemimycale alkaloids alkaloids isolated isolated from Crambe from Crambe crambe, crambe, Monanchora Monanchora arbuscula, arbuscula, Ptilocaulis Ptilocaulis spiculifer, spiculifer, and Hemimycale and Hemimycale sp., sp., sp., Crambe Batzella Clathria Clathria Clathria Clathria Crambe Batzella Batzella Arenochalina Arenochalina Arenochalina Arenochalina Batzella Crambe Batzella should eventually be united in a single genus, preferentially Crambe [53]. should should eventually eventually be united be united in a single in a genus, single genus, preferentially preferentially Crambe Crambe [53]. [53]. Batzella Hemimycale Crambe Crambe Batzella Crambe Batzella Crambe Batzella Batzella Hemimycale Crambe Biemna Sponges * Batzella Crambe Hemimycale Batzella Batzella Batzella Batzella Biemna Sponges * Monanchora Monanchora Sponges * Pseudaxinella Biemna Batzella Hemimycale Crambe Batzella Hemimycale Hemimycale Crambe Crambe Monanchora Monanchora Pseudaxinella Batzella Clathria Monanchora Monanchora Biemna Sponges * (Ptilocaulis) Biemna Biemna Sponges Sponges * * Pseudaxinella Neofolitispa GA classes. TableTable 3.Table GA3.classes. 3. GA classes. Clathria Clathria Monanchora Monanchora Pseudaxinella Monanchora Monanchora Monanchora Pseudaxinella Pseudaxinella (Ptilocaulis) Neofolitispa Neofolitispa (Ptilocaulis) Monanchora Monanchora Clathria Clathria Clathria Monanchora Monanchora Ptilocaulis Ptilocaulis Neofolitispa (Ptilocaulis) Neofolitispa (Ptilocaulis) Class 1 Neofolitispa Class 22 Class 33 Class 4Ref. No No No(Ptilocaulis) Class 1Class 1Class 2Class Class 3Class Class 4Class 4 Ref. Ref. Ptilocaulis Ptilocaulis Ptilocaulis Monanchora Monanchora Monanchora Ptilocaulis Ptilocaulis Ptilocaulis Ptilocaulis NHNH NH NH Ptilocaulis Ptilocaulis Ptilocaulis H H H HO O 1 2 21 1 2

2 2

H H H H NHNH 2 2 N N N 2 NH 2 NH NN N N N NH 2 H H H HN N NH HNHN N HN N NH NH N 2 2 N N N 2 N N N N N N HN N 2 HN HN NHN N N N N N

N N NN NN H H ON H H O O n N N O N N N N N N N n n N n N

NH O O H N NNH HN NH HNHN HN NHNHNH NH H H H H NH HN H - [70] [70] - [70] n N NH HN HN HN NHNH H H H

N N

O NO N N N

oror more +1 or+1 more +1 guanidine more guanidine moiety 1 or 3 moiety n =nguanidine 1=or 3 moiety

Clathria Clathria Clathria

3 3 n = 1 nor=n31= or 1 or

Crambe Crambe Hemimycale Hemimycale Monanchora Crambe Crambe Crambe Batzella Batzella Batzella Batzella Monanchora Neofolitispa Hemimycale Hemimycale Hemimycale Clathria Monanchora Monanchora Monanchora Ptilocaulis Pseudaxinella Neofolitispa Monanchora

Batzella Batzella Crambe Batzella Crambe Batzella Batzella Crambe Batzella Crambe Batzella Batzella Sponges * Crambe Clathria Hemimycale Crambe Hemimycale Hemimycale Crambe Crambe Pseudaxinella Batzella Batzella Batzella Crambe Sponges Sponges Sponges * * * * Clathria Sponges Monanchora Batzella Batzella Batzella (Ptilocaulis) Sponges *Monanchora Monanchora Pseudaxinella Monanchora Pseudaxinella Pseudaxinella Pseudaxinella Crambe Crambe Crambe

Monanchora Clathria Sponges * (Ptilocaulis) Monanchora Monanchora Clathria Clathria Sponges Sponges * (Ptilocaulis) * (Ptilocaulis) Monanchora Neofolitispa Neofolitispa Neofolitispa (Ptilocaulis) Pseudaxinella Pseudaxinella Pseudaxinella (Ptilocaulis) Ptilocaulis Neofolitispa Monanchora Neofolitispa Neofolitispa Monanchora Monanchora Ptilocaulis Ptilocaulis * Ptilocaulis Sponges without any genus revision made. (Ptilocaulis) (Ptilocaulis) (Ptilocaulis) Ptilocaulis Ptilocaulis Ptilocaulis NH

NHNH

H H H H n = 1 or

3

-

H H

N

-

H

H H Acanthella HAcanthella Acanthella Acanthella Acanthella Acanthella Arenochalina Arenochalina Arenochalina Arenochalina Arenochalina Acanthella Acanthella Acanthella Batzella Crambe Arenochalina Batzella Batzella Batzella Batzella Biemna Arenochalina Arenochalina Arenochalina Hemimycale Batzella Biemna Biemna Biemna - - - Biemna Clathria Batzella Batzella Batzella Monanchora Biemna Monanchora Clathria Clathria Clathria Clathria Biemna - - Clathria Biemna Biemna Neofolitispa Ptilocaulis Monanchora Monanchora Monanchora

Monanchora Clathria Clathria Clathria Ptilocaulis Ptilocaulis Ptilocaulis Ptilocaulis Ptilocaulis Monanchora Monanchora Monanchora * Sponges without any genus revision made. NHNH NH Ptilocaulis Ptilocaulis Ptilocaulis H OHwithout H O O O O any genus * Sponges revision made. O H

- -

-

Monanchora Ptilocaulis

NN N N N

2 N * Sponges any genus revision * Sponges without any genus any revision genus revision made.made. made. HN HN Nwithout NN Nwithout NAnalysis NH HN NHNH 2.3. Analytical Tools for2 TGA2* Sponges Structural H H H n n n N N 2.3. Analytical Tools for TGA Structural Analysis N N N HN N 2 2 HN HN - 2 2.3. Analytical N N for TGA Structural Analysis N Tools TGA structural determinations have been accomplished based on extensive NMR (1D and 2D) 2.3. Analytical Tools for TGA Structural Analysis 2.3. Analytical 2.3. Analytical Tools for Tools TGA for Structural TGA Structural Analysis Analysis TGA structural determinations have been accomplished based on extensive NMR (1D and 2D) TGA structural determinations based on extensive NMR (1D and and MS analyses, and chemical degradation. nor=n31=been or 3 accomplished n = 1have 1 or 3 H H H and MS analyses, and chemical degradation. TGA structural determinations have been accomplished based on extensive NMR (1D and 2D) TGAThe structural TGA structural determinations determinations have been have accomplished been accomplished based on based extensive on extensive NMR (1D NMR and (1D 2D) and and MS is analyses, and chemical following section a guideline for the degradation. structure determination of crambescidinor2D) The following section is a guideline for the structure determination of crambescidinor and MS analyses, and chemical degradation. andbatzelladine-like MSand analyses, MS analyses, andGA chemical and chemical degradation. Acanthella Acanthella The following section is afragments guidelineviafor structure determination derivatives bydegradation. their characteristic thethe useAcanthella of NMR and MS analyses. of crambescidinbatzelladine-like GA derivatives byaguideline their characteristic fragments via the use ofofcrambescidinNMR and MS oror section is a for the structure determination of The The following Thefollowing following section section is a guideline is guideline for the for structure the structure determination determination of crambescidincrambescidinCrambe Arenochalina Crambe Crambe Arenochalina Arenochalina batzelladine-like GA derivatives by their characteristic fragments via or the use of NMR and Batzella Batzella Batzella analyses. batzelladine-like GA derivatives by fragments viavia the use ofofNMR batzelladine-like batzelladine-like GA derivatives GA derivatives by their bytheir characteristic theircharacteristic characteristic fragments fragments via the use the of use NMR and NMRand MS andMS MS 2.3.1. NMR Spectroscopy Hemimycale Batzella Batzella Hemimycale Hemimycale Batzella Batzella Batzella Batzella analyses. Crambe Crambe Crambe analyses. analyses. analyses. Monanchora Clathria Biemna Sponges * * - Monanchora Monanchora Clathria Clathria Biemna Biemna Sponges Sponges * TGA NMR spectra have a high content of information. Due to the relative signal richness, the Pseudaxinella Pseudaxinella Pseudaxinella Neofolitispa Monanchora Clathria Neofolitispa Neofolitispa Monanchora Monanchora Clathria Clathria 1 H–1 H COSY experiment is appropriate in helping to find whether one or another TGA class is present (Ptilocaulis) (Ptilocaulis) (Ptilocaulis) Ptilocaulis Monanchora Ptilocaulis Ptilocaulis Monanchora Monanchora Ptilocaulis Ptilocaulis Ptilocaulis

* Sponges without any genus revision * Sponges * Sponges without without any genus any revision genus revision made.made. made.

2.3. Analytical forfor TGA Structural Analysis 2.3. Analytical 2.3. Analytical ToolsTools for Tools TGA Structural TGA Structural Analysis Analysis structural determinations been accomplished onon extensive (1D and 2D) TGATGA structural TGA structural determinations determinations havehave been have accomplished been accomplished basedbased on based extensive extensive NMRNMR (1D NMR and (1D 2D) and 2D)

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TGA NMR spectra have a high content of of information. Due to to thethe relative signal richness, thethe TGA NMR spectra have a high content information. Due relative signal richness, 1H–1H COSY experiment is appropriate in helping to find whether one or another TGA class is 1H–1H COSY experiment is appropriate in helping to find whether one or another TGA class is present byby analyzing NMR spectra between 0.80.8 and 5 ppm. Nonetheless, several characteristic by analyzing the NMR the spectra between 0.8 and 5 ppm. Nonetheless, several characteristic signals from present analyzing the NMR spectra between and 5 ppm. Nonetheless, several characteristic 1 1 signals from different atoms listed below (Figure 9) should be found in the H NMR spectra (Table 4). 4). 1 different atoms listed below (Figure 9) should be found in the H NMR spectra (Table 4). signals from different atoms listed below (Figure 9) should be found in the H NMR spectra (Table

AA 1

4 5

BB

1 2 34 5

2

O3 H H O O NO N N N a a N d N d c b

b

c

d

c

c

d

N N

b ab a

N NN N H H

Figure 9. Current Current numbering scheme for:for: (A)(A) C-8C-8 cycloheptanic spiro ring crambescidin-like GA; andand Figure 9. numbering scheme for: (A) C-8 cycloheptanic spiro ring crambescidin-like GA; and Figure 9. Current numbering scheme cycloheptanic spiro ring crambescidin-like GA; (B) batzelladine-like GA. (B) (B) batzelladine-like GA.GA. batzelladine-like Table 4. Characteristic Characteristic TGA signals. Table 4. Characteristic TGA signals. Table 4. TGA signals.

Atom Number Crambescidin-Like GA Signals GA Signals Atom Number Crambescidin-Like GA SignalsBatzelladine-Like Batzelladine-Like GA Signals Atom Number Crambescidin-Like GA Signals Batzelladine-Like GA Signals HaH *a * dddd from 2.8 to 2.5 ppm m from 2.8 to 2.5 ppm from 2.8 to 2.5 ppm m from 2.8 to 2.5 ppm Hba ** dd from 2.8 toto2.5 m 2.8 toto 2.53.9 ppm H mm from 4.64.6 3.9ppm ppm mfrom from 4.6 ppm H b * from to 3.9 ppm m from 4.6 to 3.9 ppm Hb * m from 4.6 to 3.9 ppm m from 4.6 to 3.9 ppm Hc H *c* dt dt toward 4.3 ppm m toward 4.3 ppm toward 4.3 ppm m toward 4.3 ppm Hc * dt toward 4.3 ppm m toward 4.3 ppm H **d * d from 3.5to to2.9 2.9 ppm ddfrom from 3.5 to 2.9 ppm HddH d from 3.5 ppm dd 3.5 to3.5 2.9to ppm d from 3.5 to 2.9 ppm dd from 2.9 ppm HH4H bond m toward 5.5ppm ppm Nosignal signal etH double bond 22 m 5.5 No 4* 4*et* 5**5double etH5H * double bond 2 toward m toward 5.5 ppm No signal *:*:for a,a,b, and attributions, above; d, doublet; dd,dd, doublet of of doublets; dt, dt, doublet of of b, c, c, d, d, 5 5attributions, seesee above; d, doublet; dd, doublet of doublets; dt, doublet of triplets; *:for for a, b, c, 44d,and 4 and 5 attributions, see above; d, doublet; doublet doublets; doublet m, multiplet. triplets; m, multiplet. triplets; m, multiplet.

Crambescidin Case: Ptilomycalin A (1) (1) Crambescidin Case: Ptilomycalin A (1) Crambescidin Case: Ptilomycalin A AsAs anan example, wewe choose ptilomycalin A (1), (1), which is part part ofthe thethe pentacyclic TGA class. example, choose ptilomycalin A (1), which is part of pentacyclic TGA class. As an example, we choose ptilomycalin A which is of pentacyclic TGA class. First of all, the H 1 signal (triplet) and the H4 and H5 signals of the double bond are very First of all, the H 1 signal (triplet) and the H 4 and H 5 signals of the double bond very First of all, the H1 signal (triplet) and the H4 and H5 signals of the double bond areare very characteristic. There are also clear correlations from H 1 to H5, and finally, the NMR chemical shifts of characteristic. There also clear correlations from to5H 5, and finally, NMR chemical shifts characteristic. There areare also clear correlations from H1 H to1 H , and finally, thethe NMR chemical shifts of of HaH ,, H H b, Hc, and Hd are also very characteristic within the crambescidin family (Figure 10) (Table 4). a , H b, H c, and H d are also very characteristic within the crambescidin family (Figure 10) (Table 4). H H and H are also very characteristic within the crambescidin family (Figure 10) (Table 4). a b, c, d

AA

Figure 10. Cont.

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B

12 of 24

12 of 24 2

1

3

OH N

4

B

5 2

1

4 5

OH N

14

O

O

NH2 NH2

N ptilomycalin A (1)

O

c

b

NH2 NH2

N

O

c

b

d

N

a

O

N

d

N

a 3

O

N

14

O O 1H-1H COSY

Figure 10. (A) Ptilomycalin A (1) spectrum in CD3OD (personal data); and (B) (1) NMR Figure 10. (A) Ptilomycalin A (1) 1 H-1 H ptilomycalin COSY NMR A spectrum in CD3 OD (personal data); and (B) labeled ptilomycalin A (1). labeled ptilomycalin A (1). Figure 10. (A) Ptilomycalin A (1) 1H-1H COSY NMR spectrum in CD3OD (personal data); and (B) labeled ptilomycalin A (1).

Batzelladine Case: Batzelladine F (31) Batzelladine Case: Batzelladine F (31) Batzelladine Case: Batzelladine F (31) In general, all the NMR signals reported in Table 4 are more shielded in batzelladines than in In general, all the NMR signals reported inspectra Table 4are aremore morecomplex shieldedand in are batzelladines than since the crambescidins. Moreover, the NMR often different In general, all the NMR signals reported in Table 4 are more shielded in batzelladines than in in crambescidins. Moreover, the NMR spectra are more complex and are often different since the guanidinium corethe can be once or more dehydrogenated. crambescidins. Moreover, NMR spectra are more complex and are often different since the guanidinium core can be once or more dehydrogenated. Within tricyclic TGA class 2, we used the example of batzelladine F (31). guanidinium core can the be once or more dehydrogenated. Within the tricyclic TGA class 2, we used example ofFbatzelladine batzelladine F (31).A spectra is the absence of the The major difference between batzelladine and ptilomycalin Within the tricyclic TGA class 2, we usedthe the example of F (31). The major difference between batzelladine F and ptilomycalin A spectra is the absence of the for the protons H4 and H5, and corresponding correlation. On the other hand, two The signals major difference between batzelladine andthe ptilomycalin A spectra is the absence of the signals for the protons Hare and Hcharacteristic , 5and correlation. the other two 11). signals for the protons 4 and , andthe the corresponding corresponding correlation. On On the other two correlations very within batzelladines: Ha with H b, and H chand, withhand, H d (Figure 4H 5H correlations are very characteristic withinbatzelladines: batzelladines: H b, and Hc with Hd (Figure 11). 11). correlations are very characteristic within Ha awith withHH Hc with Hd (Figure b , and

A

B

A

B

H

H

H

N N H

N

5

H

O O

N H

NH d N

H c

N

b

N

N5 H

batzelladine F (31)

a

O

8

H

H d

O

c

N

b

N

N H

a

8

batzelladine F (31)

Figure 11. (A) Batzelladine F (31) 1H-1H COSY NMR spectrum in CD3OD (adapted from Patil et al.

Figure 11. (A) Batzelladine F (31) 1 H-1 H COSY NMR spectrum in CD3 OD (adapted from Patil et al. [67]); Figure 11.batzelladine (A) Batzelladine [67]); and (B) labeled F (31). F (31) 1H-1H COSY NMR spectrum in CD3OD (adapted from Patil et al. and (B) labeled batzelladine F (31). [67]); and (B) labeled batzelladine F (31). 2.3.2. Mass Spectrometry

2.3.2. Mass Spectrometry 2.3.2. Mass Spectrometry

Several TGA were detected by positive electrospray mass spectrometry ionization studies.

+ mass Usually, TGA authors notifydetected the TGA quasi-molecular ion [M + H] with the exception of batzelladines M Several were by positive by electrospray spectrometry ionizationionization studies. Several TGA were detected positive electrospray mass spectrometry studies. 2+ [73]. On the other hand, + (39) and N (40), which were detected through their dicharged ion [M + 2H] + Usually, authors notifyauthors the TGA quasi-molecular ion [M + H]ion with of batzelladines M Usually, notify the TGA quasi-molecular [M the + H]exception with the exception of batzelladines M 2+ [73]. On2+the other hand, (39) and N (40), which were through theirthrough dicharged [M + 2H] (39) and N (40),detected which were detected theirion dicharged ion [M + 2H] [73]. On the other hand, both quasi-molecular and discharged ions were observed for batzelladine L (38) and monanchomycalin C (25). Mass spectrometry data for TGA are summarized in Table 5.

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Table 5. TGA Mass Spectrometry (MS) data. Metabolites

m/z ([M + H]+ Unless Specified) and ∆ppm Found

Ref.

ptilomycalin A (1)

977.7915 (1.0 mmu) for the bis(trifluoroacetyl) derivative

[51]

crambescidin 800 (2)

801.6205 (1.3 mmu)

[55]

crambescidin 816 (3)

817.6151 (1.6 mmu)

[55]

crambescidin 830 (4)

831.6300 (2.3 mmu)

[55]

crambescidin 844 (5)

845.6471 (0.9 mmu)

[55]

13, 14, 15 -isocrambescidine 800 (6)

927.6521 (1.3 mmu) for the acetylated compound

[52]

crambidine (7)

967.6415 (6.8 mmu) for the acetylated compound

[52]

neofolitispate 1 (8)

686 (no HRMS data)

[57] [57]

neofolitispate 2 (9)

672 (no HRMS data)

neofolitispate 3 (10)

658 (no HRMS data)

[57]

crambescidin 359 (11)

359.2567 (0.6 mmu)

[53]

crambescidin 431 (12)

431.2780 (0.4 mmu)

[53]

crambescidin 826 (13)

827.6389 (1.5 mmu)

[54]

crambescidin acid (14)

404.2541 (2.2 mmu)

[58]

crambescidic acid (15)

658.4781 (1.4 mmu)

[59]

16β-hydroxycrambescidin 359 (16)

376.2617 (1.7 mmu)

[73] [60]

ptilomycalin D (17)

627.4994 *

monanchocidin (A) (18)

859.6267 (3.0 mmu)

[61]

monanchocidin B (19)

831.5978 (3.4 mmu)

[62] [62]

monanchocidin C (20)

845.6150 (4.0 mmu)

monanchocidin D (21)

831.5920 (3.4 mmu)

[62]

monanchocidin E (22)

845.6120 (1.0 mmu)

[62]

monanchomycalin A (23)

813.6574 (0.2 mmu)

[63]

monanchomycalin B (24)

785.6259 (0.4 mmu)

[63]

monanchomycalin C (25)

813.6578 (0.3 mmu) and [M + 2H]2+ 407.3336 (0.7 mmu)

[64]

batzelladine A (26)

768.5839 (2.4 mmu)

[66]

batzelladine B (27)

738.5356 (3.8 mmu)

[66]

batzelladine C (28)

489.3903 (1.4 mmu)

[66]

batzelladine D (29)

463.3740 **

[66]

batzelladine E (30)

487.3728 (3.2 mmu)

[66]

batzelladine F (31)

624.5096 (0.6 mmu)

[67]

batzelladine G (32)

668,5353 (1.3 mmu)

[67]

batzelladine H (33)

609.4488 (0.4 mmu)

batzelladine I (34)

[67] [67]

dehydrobatzelladine C (35)

487.3711 (4.9 mmu)

[53]

batzelladine J (36)

750.5361 (3.3 mmu)

[59]

batzelladine K (37)

250.2322 (3.9 mmu)

[73]

batzelladine L (38)

653.5458 (2.4 mmu) and [M + 2H]2+ 327.2798 (1.8 mmu)

[73]

batzelladine M (39) batzelladine N (40) clathriadic acid (41)

[M +

2H]2+

298.2399 (1.0 mmu)

[M +

2H]2+

312.2546 (1.0 mmu)

318.2173 (1.0 mmu)

[73] [73] [68]

merobatzelladine A (42)

360.3444 (6.6 mmu)

[69]

merobatzelladine B (43)

306.2909 (7.0 mmu)

[69]

norbatzelladine A (44)

754.5705 (0.7 mmu)

[68]

norbatzelladine L (45)

639.5327 (0.3 mmu)

[68]

dinorbatzelladine A (46)

740.5547 (0.9 mmu)

[68]

dinorbatzelladine B (47)

710.5074 (1.2 mmu)

[68]

dinordehydrobatzelladine B (48)

708.4919 (1.0 mmu)

[68]

dihomodehydrobatzelladine C (49)

515.4064 (1.3 mmu)

[68]

batzellamide A (50)

541.3878 (1.2 mmu)

[70]

hemibatzelladine J (51)

449.3238 (0.2 mmu)

[70]

∆19 -hemibatzelladine J (52)

447.3092 (0.8 mmu)

∆200 -hemibatzelladine J (53)

* Calculated m/z value: 626.4975; reported m/z value: 627.4994; ** not specified.

[70] [70]

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Tandem mass spectrometry experiments were also performed to confirm a hypothesis or * Calculated m/z(MS²) value: 626.4975; reported m/z value: 627.4994; ** not specified. * Calculated m/z value: 626.4975; reported m/z value: 627.4994; ** not specified. provide additional information concerning the TGA side chains, as reported in Table 6. Tandem mass spectrometry (MS²) experiments were also performed to confirm a hypothesis or Tandem mass spectrometry (MS²) experiments were also performed to confirm a hypothesis or provide additional information concerning the TGA side chains, as reported in Table 6. provide additional information concerning the TGA side 2chains, as reported in Table 6.

Table 6. Characteristic MS TGA signals.

Table 6. Characteristic MS22 TGA signals. Table 6. Characteristic MS TGA signals. m/z Fragment m/z Fragment Loss Fragment m/z Fragment m/z Fragment Loss Fragment m/z Fragment

358 (or 359) 358 (or 359) 358 (or 359)

m/z Fragment Loss

322 or 336 or 350

336 or 350 322 or 336322 or or 350

114

114 114

113

113 113

Ref. Ref. Ref. [53–55,59] [53–55,59] [53–55,59] Batzelladine core + n = 6, 7 or 8 carbon side chain [53,66–68,73] Batzelladinecore core++nn == 6, 6, 77 or chain Batzelladine or88carbon carbonside side chain [53,66–68,73] [53,66–68,73] NH NH [53,59,66] N NH2 [53,59,66] [53,59,66] N NH2 H H Fragment

Crambescidin core Crambescidin core Crambescidin core

OH OH O O

101 101

101

N N

NH2 NH2

OH OH

[61,62] [61,62] [61,62]

H 2N H 2N

Intense 18 Intense 18 Intense 18 Intense 48 Intense 48 Intense 48

17 47

17 17 47 47

Carboxylic acid Carboxylic acid

-

Carboxylic acid

-

3. Biological Activities

3. Biological Activities 3. Biological Activities

TGA exhibited a wide range of biological activities with mainly antiviral, antimicrobial TGA exhibited a wide range of biological activities with mainly antiviral, antimicrobial

antibacterial, anti-yeast, and antiparasitic), and antitumor properties. TGA(including exhibitedantifungal, a wide range of biological activities with mainly antiviral, antimicrobial (including (including antifungal, antibacterial, anti-yeast, and antiparasitic), and antitumor properties. antifungal, antibacterial, anti-yeast, and antiparasitic), and antitumor properties.

3.1.

3.1. Antiviral Activities 3.1. Antiviral Activities Several TGA derivatives were evaluated for their antiviral activities against different viruses Antiviral Activities Several TGA derivatives were evaluated for their antiviral activities against different viruses such as Human immunodeficiency virus (HIV-1), Herpes simplex virus (HSV-1), and Human hepatitis such as Human immunodeficiency virus (HIV-1), Herpes simplex virus (HSV-1), and Human hepatitis Several TGA derivatives were evaluated antiviral activities against different viruses B virus (HBV). The reported data for 17 TGAfor aretheir summarized in Table 7. B virus (HBV). The reported data for 17 TGA are summarized in Table 7.

such as Human immunodeficiency virus (HIV-1), Herpes simplex virus (HSV-1), and Human hepatitis B virus Table 7. TGA antiviral activities. Table 7. TGA antiviralin activities. (HBV). The reported data for 17 TGA are summarized Table 7. HIV-1 HIV-1 Human Envelope-Mediated gp120 Binding Human Envelope-Mediated Binding Table 7. TGA antiviralgp120 activities. PBMC Fusion to CD4 PBMC Fusion to CD4 ptilomycalin A (1) 0.011 n.t. n.t. ptilomycalin A (1) 0.011 n.t. n.t. crambescidin 800 (2) 0.04 1–3 n.t. HIV-1 crambescidin 800 (2) 0.04 1–3 n.t. EC50 (µM Unless Specified) crambescidin 816 (3) n.t. n.t. n.t. crambescidin 816 (3) n.t. n.t. n.t. Human gp120 n.t. Binding crambescidin 844 (5) n.t. Envelope-Mediated n.t. crambescidin 844 (5) n.t. n.t. n.t. Fusion to n.t. CD4 13,14,15-isocrambescidin 800 (6)PBMC n.t. n.t. 13,14,15-isocrambescidin 800 (6) n.t. n.t. n.t. neofolitispate n.t. ptilomycalin A (1) 11 (8) 0.011n.t. n.t.n.t. n.t. neofolitispate (8) n.t. n.t. n.t. neofolitispate 2 (9) n.t. n.t. n.t. neofolitispate (9) n.t. n.t. n.t. crambescidin 800 (2) 32(10) 0.04 n.t. 1–3n.t. n.t. neofolitispate n.t. neofolitispate 3 (10) n.t. n.t. n.t. crambescidin 826 (13) n.t. 1–3 n.t. crambescidin 816 (3)826 (13) n.t. n.t. n.t.1–3 n.t. crambescidin n.t. batzelladine A (26) n.t. n.t. 29 batzelladine (26) n.t. n.t. 29 crambescidin 844 (5)A n.t. n.t. n.t.n.t. n.t. batzelladine B (27) 31 batzelladine B (27) n.t. n.t. 31 batzelladine800 C (28) 7.7 n.t. n.t. 13,14,15-isocrambescidin (6) n.t. n.t. n.t. batzelladine C (28) 7.7 n.t. n.t. batzelladine D (29) n.t. n.t. 72 batzelladine 72 neofolitispate 1 (8) D (29) n.t. n.t. n.t.n.t. n.t. dehydrobatzelladine C (35) 5.5 n.t. n.t. dehydrobatzelladine C (35) 5.5 n.t. n.t. batzelladine n.t. neofolitispate 2 (9) L (38) n.t. 1.6 n.t.n.t. n.t. batzelladine L (38) 1.6 n.t. n.t. batzelladine M (39) 7.7 n.t. n.t. neofolitispate 3 (10)M (39) n.t. 7.7 n.t.n.t. n.t. batzelladine n.t. batzelladine N (40) 2.4 n.t. n.t. batzelladine N (40) 2.4 n.t. n.t. EC50 (µM Unless Specified) EC50 (µM Unless Specified)

HSV-1 HSV-1

HBV HBV

Ref. Ref.

0.25 * n.t. [51] 0.25 * n.t. [51] 1.25 µg/well aa n.t. [54,55,73] 1.25 µg/well a n.t. [54,55,73] HBV HSV-1 Ref. 1.25 µg/well n.t. [55] 1.25 µg/well a n.t. [55] 1.25 µg/well aa n.t. [55] 1.25 µg/well n.t. [55] NA n.t. [56] NA n.t. [56] n.t. 0.25 * n.t. [51] n.t. n.t. 7.4 ** [57] a n.t. 7.4 ** [57] 1.25 n.t. [54,55,73] n.t. µg/well n.t. a n.t. µg/welln.t. [54] 1.25 n.t. [55] n.t. n.t. [54] n.t. n.t. [66] a n.t.µg/welln.t. [66] 1.25 n.t. [55] n.t. n.t. [66] n.t. n.t. [66] n.t. NA n.t. [73] n.t. [56] n.t. n.t. [73] n.t. n.t. [66] n.t. n.t. n.t. [66] n.t. n.t. [73] n.t. n.t. 7.4 [73] [57] ** n.t. n.t. n.t. [73] n.t. n.t. [73] n.t. n.t. [73] n.t. n.t. n.t. [73] n.t. n.t. [73] n.t. n.t. [73]

crambescidin 826 (13)immunodeficiency n.t. 1–3 Peripheral Bloodn.t. n.t. HIV, Human virus; PBMC, Mononuclear cells;n.t. gp, glycoprotein; HIV, Human immunodeficiency virus; PBMC, Peripheral Blood Mononuclear cells; gp, glycoprotein; batzelladine A (26)simplex virus;n.t. n.t. 29 tested, NA, not active; n.t. * converted n.t. HSV, Herpes HBV, Human hepatitis B virus; n.t., not HSV, Herpes simplex virus; HBV, Human hepatitis B virus; n.t., not tested, NA, not active; * converted from µM to µg/mL; ** calculated from compound (9) molecular31 weight; a Diffuse cytotoxicity at n.t. 1.25 batzelladine B (27) n.t. n.t. n.t. from µM to µg/mL; ** calculated from compound (9) molecular weight; a Diffuse cytotoxicity at 1.25 µg/well. µg/well. batzelladine C (28) 7.7 n.t. n.t. n.t. n.t.

[54]

[66] [66] [73]

batzelladine D (29)

n.t.

n.t.

72

n.t.

n.t.

[66]

dehydrobatzelladine C (35)

5.5

n.t.

n.t.

n.t.

n.t.

[73]

batzelladine L (38)

1.6

n.t.

n.t.

n.t.

n.t.

[73]

batzelladine M (39)

7.7

n.t.

n.t.

n.t.

n.t.

[73]

batzelladine N (40)

2.4

n.t.

n.t.

n.t.

n.t.

[73]

HIV, Human immunodeficiency virus; PBMC, Peripheral Blood Mononuclear cells; gp, glycoprotein; HSV, Herpes simplex virus; HBV, Human hepatitis B virus; n.t., not tested, NA, not active; * converted from µM to µg/mL; ** calculated from compound (9) molecular weight; a Diffuse cytotoxicity at 1.25 µg/well.

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In general, crambescidin-like GA seem to be more efficient against HIV compared to batzelladine-like GA (half maximal effective concentration (EC50 ) around 1 mM [66,73]) with EC50 activities below 0.05 µM [51,73]. The stereochemistry of the molecule has a great influence on the antiviral activity. For example, 13,14,15-isocrambescidin (6) is not active against HSV-1 compared to crambescidins [56]. Ptilomycalin A (1) shows very potent anti-HIV-1 and anti-HSV-1 activities at a concentration of 0.011 and 0.25 µM, respectively [51], which makes it the best antiviral candidate. Surprisingly, neofolitispates (8–10) are the only crambescidin-like GA derivatives that have been tested on HBV and exhibited an anti-HBV activity [57]. Unfortunately, few details have been reported. On the other hand, batzelladines A–E (26–30) were shown to block the interaction between the surface of the HIV envelope glycoprotein gp120 and the extracellular domains of human CD4 receptor protein [77]. This binding is vital to the replication of the virus as it controls its entry into the human cells, since without access to the biochemical environment within the cell the virus is unable to replicate. As a consequence, batzelladines have a therapeutic interest in the treatment of HIV [76]. To date, batzelladine-like GA have not been tested against HSV or HBV viruses. 3.2. Antimicrobial Activities TGA derivatives were tested against several bacteria (Mycobacterium tuberculosis, Staphylococcus aureus, Pseudomonas aeruginosa, and Mycobacterium intracellulare), yeast (Candida albicans), fungi (Cryptococcus neoformans and Aspergillus fumigatus), and parasites (Plasmodium falciparum, Tripanosoma cruzi, Leishmania infatum, and Trypanosoma brucei brucei). Table 8 reports all the antimicrobial activity results for 19 TGA tested. Crambescidin 800 (2) and ptilomycalin A (1) exhibited potent activity against most bacteria, yeast, fungi, and parasites [68,73]. Curiously, they are poorly active on Mycobacterium intracellulare and are considered inactive on Mycobacterium tuberculosis (M. tuberculosis) [73]. Furthermore, 16β-hydroxycrambescidin (16), the only crambescidin-like GA bearing a hydroxyl group on its pentacycle, was not active against all the strains tested [73]. In some cases, Batzelladine-like GA present similar activities compared to crambescidin-like GA. Batzelladines C (28) and L (38) are often the more potent molecules [73]. Nevertheless, batzelladine M (39) is the less active TGA class 2 and surprisingly, the same authors showed batzelladine N (40) to be nine times more efficient compared to batzelladine M (39) against M. tuberculosis (minimum inhibitory concentration (MIC) 3.18 and 28.5 µg¨ mL´1 , respectively), despite their chemical structures being closely related [73]. 3.3. Antitumoral Activities Over 20 TGA were tested for their cytotoxicity against several cancer cell lines such as prostate, ovary, breast, melanoma leukemia, pancreas, colon, and cervix (Table 9).

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Table 8. TGA antimicrobial activities. Table 8. TGA antimicrobial activities.

n.t. n.t. n.t. n.t. n.t.

0.10 0.10 NA n.t. 0.40 n.t. n.t. 0.6 0.55 8.0 n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

1.25 1.25 NA n.t. 5.0 n.t. n.t. 20 2.5 NA n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

0.12 0.11 3.8 n.t. 0.09 n.t. n.t. 0.073 0.073 0.21 n.t. n.t.

n.t. n.t. n.t. n.t. n.t.

0.11 0.13 NA n.t. 0.11 n.t. n.t. 0.13 0.10 0.27 n.t. n.t. 0.48 0.97 n.t. n.t. n.t. n.t. n.t.

FcB1

0.08 * n.t. NA 0.2* n.t. n.t. n.t. n.t. 0.2 * n.t. n.t. 1.4 *

0.2 * 0.3 * 1.7 * 0.6 * 2.3 *

T. brucei brucei

a

0.15 0.15 NA n.t. 0.90 n.t. n.t. 1.0 0.40 6.0 n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

W2 Clone

T. cruzi

n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

D6 Clone

L. donovani

10 15 NA n.t. 0.9 n.t. n.t. 1.0 0.25 3.50 n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

Parasites P. falciparum L. infatum

>128 46.5 >128 n.t. 34.7 n.t. n.t. 37.7 1.68 28.5 3.18 n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

A. fumigatus (AC)

1.0 0.95 NA n.t. 10 n.t. n.t. NA. 3.50 NA n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

C. neoformans

M. intracellulare

0.30 0.35 NA n.t. 0.30 n.t. n.t. 0.70 0.40 5.0 n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

Fungi

C. albicans

M. tuberculosis

0.25 0.20 NA n.t. 0.20 n.t. n.t. 0.40 0.35 3.0 n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

V. anguillarum

P. aeruginosa

ptilomycalin A (1) crambescidin 800 (2) 16β-hydroxycrambescidin 800 (16) batzelladine A (26) batzelladine C (28) batzelladine D (29) batzelladine F (31) dehydrobatzelladine C (35) batzelladine L (38) batzelladine M (39) batzelladine N (40) clathriadic acid (41) merobatzelladine A (42) merobatzelladine B (43) norbatzelladine A (44) norbatzelladine L (45) dinorbatzelladine A (46) dinordehydrobatzelladine B (48) dihomodehydrobatzelladine C (49)

MRSA

IC50 (Values are Expressed in µg/mL Unless Specified)

Yeast

S. aureus

Bacteria

n.t. n.t. n.t. n.t. n.t. 0.9 * 2.5 * n.t. 1.3 * n.t. n.t. n.t. n.t. n.t. n.t. 1.3 * n.t. n.t. n.t.

5.9 6.80 n.t. n.t. 5.5 n.t. n.t. 5.70 1.90 8.50 n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t.

n.t. n.t. n.t. n.t. n.t. 29 * 3.1 * n.t. 1.3 * n.t. n.t. n.t. n.t. n.t. n.t. 4.4 * n.t. n.t. n.t.

n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. n.t. 0.24 0.24 n.t. n.t. n.t. n.t. n.t.

Ref.

[68,73] [73] [73] [68] [73] [70] [70] [73] [68,73] [73] [73] [68] [69] [69] [68] [68,70] [68] [68] [68]

S. aureus, Staphyloccocus MRSA,Methicilline Methicilline resistant Staphyloccocus P. aeruginosa, Pseudomonas M. tuberculosis, Mycobacterium S. aureus, Staphyloccocus aureus; aureus; MRSA, resistant Staphyloccocus aureus;aureus; P. aeruginosa, Pseudomonas aeruginosa;aeruginosa; M. tuberculosis, Mycobacterium tuberculosis; M.tuberculosis; intracellulare,M. Mycobacterium intracellulare; V. angillarum, Vibrio angillarum; C.Vibrio albicans, Candida albicans; A. fumigatus, Aspergillus P. falciparum, Plasmodium falciparum; L. infatum, Leishmania intracellulare, Mycobacterium intracellulare; V. angillarum, angillarum; C. albicans, Candida albicans;fumigatus; A. fumigatus, Aspergillus fumigatus; P. falciparum, Plasmodium infatum; L. donovani, Leishmania donovani; T. cruzi, Trypanosoma cruzi; T. brucei brucei, Trypanosoma brucei brucei; AC, active concentration; NA, not active according to the authors; n.t., not falciparum; L. infatum, Leishmania infatum; L. donovani, Leishmania donovani; T. cruzi, Trypanosoma cruzi; T. brucei brucei, Trypanosoma brucei brucei; AC, active concentration; tested; * converted from µM to µg/mL; a, 9–10 mm/50 µg. NA, not active according to the authors; n.t., not tested; * converted from µM to µg/mL; a, 9–10 mm/50 µg.

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Table 9. TGA antitumor activities (values are expressed in µg/mL unless specified). Prostate Ovary

Breast

Melanoma

Lung

DU-145 IGROV SK-BR3 MDA-MB-231 SK-MEL-28 NSCL A549 ptilomycalin A (1)

crambescidin 800 (2)

crambescidin 816 (3)

monanchocidin A (18)

monanchocidin B (19)

monanchocidin C (20)

monanchocidin D (21)

monanchocidin E (22)

monanchomycalin A (23)

monanchomycalin B (24)

Leukemia

Pancreas

Colon

L-562

HL-60

THP-1

PANCL

HT29

Cervix

HCT-16 LOVO LOVO-DOX

GI50

0.05

0.04

0.07

n.t.

0.03

0.08

0.04

n.t.

n.t.

0.04

0.03

n.t.

0.05

0.05

0.04

TGI

1.22

1.74

0.54

n.t.

0.11

1.23

1.33

n.t.

n.t.

0.99

0.19

n.t.

2.14

2.04

0.22

LC50

5.21

n.t.

n.t.

n.t.

0.98

9.79

9.72

n.t.

n.t.

0.98

5.37

n.t.

9.79

8.48

3.21

GI50

0.19

0.05

0.16

n.t.

0.04

0.11

0.02

n.t.

n.t.

0.04

0.04

n.t.

0.08

0.08

0.05

TGI

1.38

2.50

0.56

n.t.

0.11

1.36

0.06

n.t.

n.t.

1.53

0.23

n.t.

2.29

2.02

0.21

LC50

7.01

n.t.

n.t.

n.t.

1.70

9.68

6.73

n.t.

n.t.

8.66

5.75

n.t.

8.97

8.50

1.58

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

IC50 0.17 *

IC50 0.09 *

IC50 0.69 *

IC50 0.55 *

IC50 0.10 *

IC50 0.11 *

IC50 4.4 *

IC50 0.24

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

Ref.

HeLa

IC50 10.1 *

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

n.t.

[73]

[73]

[52]

[61]

[62]

[62]

[62]

[62]

[63]

[63]

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Table 9. Cont. Prostate Ovary

Breast

Melanoma

Lung

DU-145 IGROV SK-BR3 MDA-MB-231 SK-MEL-28 NSCL A549 batzelladine C (28)

dehydrobatzelladine C (35)

batzelladine L (38)

batzelladine M (39)

batzelladine N (40)

clathriadic acid (41)

norbatzelladine A (44)

norbatzelladine L (45)

dinorbatzelladine A (46)

dinordehydro-batzelladine B (48)

dihomodehydro-batzelladine C (49)

Leukemia

Pancreas

Colon

L-562

HL-60

THP-1

PANCL

HT29

HCT-16

LOVO

Cervix LOVO-DOX

GI50

0.68

0.81

0.66

n.t.

1.45

1.40

0.62

n.t.

n.t.

0.55

0.65

n.t.

2.06

2.25

0.70

TGI

2.27

3.43

2.89

n.t.

3.67

3.42

3.01

n.t.

n.t.

2.03

2.16

n.t.

4.37

4.72

2.22

LC50

0.69

n.t.

n.t.

n.t.

9.24

8.31

n.t.

n.t.

n.t.

7.14

6.70

n.t.

9.29

0.99

6.50

GI50

0.46

0.73

0.23

n.t.

0.89

1.19

0.48

n.t.

n.t.

0.43

0.48

n.t.

1.60

2.07

0.48

TGI

1.91

4.17

1.14

n.t.

3.48

3.24

2.42

n.t.

n.t.

1.83

1.77

n.t.

3.68

4.48

1.52

LC50

7.15

n.t.

n.t.

n.t.

n.t.

8.81

n.t.

n.t.

n.t.

8.66

7.50

n.t.

8.47

9.69

5.45

GI50

0.44

0.52

0.23

n.t.

0.88

1.30

n.t.

n.t.

n.t.

0.34

4.96

n.t.

1.09

n.t.

0.38

TGI

1.39

1.74

0.56

n.t.

2.18

9.99

n.t.

n.t.

n.t.

1.33

n.t.

n.t.

2.41

n.t.

1.16

LC50

3.78

5.01

2.10

n.t.

4.95

n.t.

n.t.

n.t.

n.t.

4.38

n.t.

n.t.

5.36

n.t.

3.58

GI50

1.77

2.28

1.12

n.t.

1.18

3.80

n.t.

n.t.

n.t.

1.22

3.56

n.t.

1.99

n.t.

1.64

TGI

3.44

5.08

2.51

n.t.

4.66

n.t.

0.00

n.t.

n.t.

3.58

n.t.

n.t.

3.56

n.t.

3.05

LC50

6.66

n.t.

5.59

n.t.

n.t.

n.t.

0.00

n.t.

n.t.

n.t.

n.t.

n.t.

6.37

n.t.

5.68

GI50

1.39

1.78

1.12

n.t.

1.47

1.94

0.66

n.t.

n.t.

1.37

1.31

n.t.

1.96

4.42

0.59

TGI

3.12

4.97

3.84

n.t.

3.41

4.29

3.27

n.t.

n.t.

3.50

3.11

n.t.

4.16

n.t.

1.80

LC50

7.04

n.t.

n.t.

n.t.

7.97

9.47

n.t.

n.t.

n.t.

8.97

7.35

n.t.

8.85

n.t.

5.13

GI50

n.t.

n.t.

n.t.

13.5

n.t.

>30

n.t.

n.t.

n.t.

n.t.

>30

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

>30

n.t.

>30

n.t.

n.t.

n.t.

n.t.

>30

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

>30

n.t.

>30

n.t.

n.t.

n.t.

n.t.

>30

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

3.8

n.t.

2.1

n.t.

n.t.

n.t.

n.t.

1.6

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

6.4

n.t.

4.6

n.t.

n.t.

n.t.

n.t.

3.2

n.t.

TC50 4.7 µM

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

11.4

n.t.

8.6

n.t.

n.t.

n.t.

n.t.

5.7

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

0.7

n.t.

1.1

n.t.

n.t.

n.t.

n.t.

1.9

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

1.9

n.t.

2.1

n.t.

n.t.

n.t.

n.t.

4.2

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

4.8

n.t.

4.2

n.t.

n.t.

n.t.

n.t.

7.6

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

3.0

n.t.

1.9

n.t.

n.t.

n.t.

n.t.

1.9

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

3.8

n.t.

4.2

n.t.

n.t.

n.t.

n.t.

4.2

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

5.4

n.t.

7.6

n.t.

n.t.

n.t.

n.t.

7.6

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

n.t.

n.t.

7.9

n.t.

n.t.

n.t.

n.t.

6.2

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

n.t.

n.t.

>14

n.t.

n.t.

n.t.

n.t.

> 14

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

n.t.

n.t.

>14

n.t.

n.t.

n.t.

n.t.

> 14

n.t.

n.t.

n.t.

n.t.

GI50

n.t.

n.t.

n.t.

6.1

n.t.

>30

n.t.

n.t.

n.t.

n.t.

>30

n.t.

n.t.

n.t.

n.t.

TGI

n.t.

n.t.

n.t.

9.8

n.t.

>30

n.t.

n.t.

n.t.

n.t.

>30

n.t.

n.t.

n.t.

n.t.

LC50

n.t.

n.t.

n.t.

15.6

n.t.

>30

n.t.

n.t.

n.t.

n.t.

>30

n.t.

n.t.

n.t.

n.t.

n.t., not tested; * calculated value from µM to µg/mL.

Ref.

HeLa [73]

[73]

[73]

[73]

[73]

[68]

[68]

[68]

[68]

[68]

[68]

Mar. Drugs 2016, 14, 77

19 of 24

Ptilomycalin A (1) is once again the most active TGA tested as its half maximal growth inhibition values (GI50 ) are always below 0.1 µg/mL on all the cell lines tested [73]. Crambescidin 800 (2) shows similar activities [73]. Compared to TGA class 3, TGA class 2 is less active, although batzelladine C (28) and L (38) and dehydrobatzelladine C (35), in general, exhibited a GI50 below 1 µg/mL [73]. Finally, crambescidin 816 (3) was shown to inhibit cell migration by altering the cytoskeleton dynamics and induced cell death by apoptosis [75,78]. In summary, both TGA class 2 and 3 have been tested against viruses, microbes, and several cancer cell lines. The wide-ranging biological activity of this class of natural products can be in part attributed to the cationic nature of the guanidinium functional group that can participate in a large number of non-covalent molecular interactions [77]. In general, TGA from class 3 exhibited better activities compared to TGA from class 2 [73]. Within TGA class 3, ptilomycalin A (1) and crambescidin 800 (2) showed similar activities in all assays, suggesting that the hydroxyl group of the right-handed portion in crambescidin 800 (2) did not affect the bioactivity. Nevertheless, 16β-hydroxycrambescidin 359 (16) did not show any significant antimicrobial activity, suggesting that the hydroxyl group, located on the pentacycle at C-16, diminished the activity [73]. Further studies are needed to confirm this hypothesis. This could be assessed by evaluating the inhibitory activities of crambescidins 816 (3), 830 (4) and 844 (5), as they carry the same hydroxyl moiety as crambescidin 800 (2) and another hydroxyl located in the pentacycle at C-13. In parallel, several batzelladines have been reported to disrupt protein–protein interactions. Elucidation of the mechanism by which protein–protein interactions are modulated by these molecules is of great interest, since protein–protein associations are important in all the aspects of cell biochemistry. Moreover, small molecules that influence protein–protein association would be new biological tools and potential therapeutic agents. In particular, batzelladines or their derivatives may prove to be applicable for AIDS treatment. Batzelladines A–E (26–30) block interaction between the surface of the HIV envelope glycoprotein gp120 and the extracellular domains of human CD4 receptor protein [66]. A subset of batzelladines exhibited also potential immunosuppressive activity as they induce dissociation of the complex between the protein kinase p56lck and CD4 [67]. Synthetic derivatives of batzelladines were reported to disrupt Nef–p53, Nef–actin, and Nef–p56lck interactions [77]. Bewley et al. tested a series of 28 synthetic batzelladine-like GA analogues on HIV-1 cell fusion assay, to find structure-activity relationships [76]. According to this study, the greater the rigidity of the molecule, the less biologically active it is. Moreover, they have shown that the most active compounds tested were compounds which contain two tricyclic guanidine moieties connected by an alkyl ester linkage including eight heavy atoms, such as batzelladines F (31) and G (32). Batzelladines biological properties could be dramatically affected by the ester side chains. For example, batzelladine A (26) inhibits the binding of HIV glycoprotein gp120 to CD4 receptors, whereas batzelladine D (29) has no known biological activity [77]. Finally, several derivatives that do not feature an ester side chain may still exhibit interesting biological properties such as the antibacterial and antimalarial activities of merobatzelladines A (42) and B (43) [69]. 4. Conclusions Several batzelladine- and crambescidin-like guanidine alkaloids have been isolated from Poecilosclerida marine sponges. Their biosynthesis, or the biosynthesis of their precursors, may involve symbiotic microorganisms [79]. This class of natural products is structurally unique as all the derivatives are constituted by a tricyclic guanidinium ring system, to which are appended different substituents. This significant structural diversity has led to wide-ranging biological properties with mainly antiviral, antimicrobial (including antifungal, antibacterial, anti-yeast, and antiparasitic), and antitumor activities. In addition to the biomimetic strategy, a number of groups completed the total synthesis of several of these alkaloids by developing new synthetic methodologies. Although there are many efficient and stereoselective synthetic routes towards this class of natural products, there is not yet one method that would allow entry into all of the cores of this family. Nonetheless, a number of these

Mar. Drugs 2016, 14, 77

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syntheses have enabled the establishment of their relative and absolute stereochemical configurations. In conclusion, several of these alkaloids and their synthetic analogs were prepared on a large enough scale to allow further biological testing, including few structure-activity relationship studies. Ongoing studies may provide us with further clues regarding this class of Marine Natural Products. Acknowledgments: We thank J. Pattinson and D. Coaten for their kind reading of this manuscript. E. Sfecci is the recipient of a thesis grant from the “Conseil Régional Provence Alpes Côte d’azur”. M. Mehiri’s research is supported by the French program ENVI-Med “MEDIBIO”, the ANR/Investissements d’Avenir program via the OCEANOMICs project (grant #ANR-11-BTBR-0008), and the H2020 European program via the EMBRIC project. Author Contributions: All the authors wrote, read, and approved the final version of the manuscript. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations The following abbreviations are used in this manuscript: A.m. Antimicrobial activity A.v. Antiviral activity A.t. Antitumor activity COSY Correlation Spectroscopy EC50 half maximal Effective Concentration GA Guanidine Alkaloids GI50 half maximal Growth Inhibition gp120 glycoprotein 120 HBV Human hepatitis B virus HIV-1 Human Immunodeficiency Virus 1 HSV-1 Herpes simplex Virus 1 IC50 half maximal Inhibitory Concentration LC50 half maximal Lethal Concentration MIC Minimum Inhibitory Concentration MS Mass Spectrometry NMR Nuclear Magnetic Resonance n.t. Not tested PBMC Peripheral Blood Mononuclear Cells SM Secondary Metabolites TC50 half maximal Toxic Concentration TGA Triazaacenaphthylene Guanidine Alkaloids TGI Total Growth Inhibition concentration References 1. 2.

3. 4. 5. 6.

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32. 33. 34. 35. 36. 37. 38.

39. 40. 41. 42. 43. 44.

45. 46.

47.

48. 49.

50. 51. 52.

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Polycyclic Guanidine Alkaloids from Poecilosclerida Marine Sponges.

Sessile marine sponges provide an abundance of unique and diversified scaffolds. In particular, marine guanidine alkaloids display a very wide range o...
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