MARINE

PHARMACOLOGY

Marine pharmacology in 1998: Marine Compounds with Antibacterial, Anticoagulant, Antifungal, Anti
inflammatory, Anthelmintic, Antiplatelet, Antiprotozoal, and Antiviral Activities; with actions on the Cardiovascular,
Endocrine, Immune, and Nervous Systems; and other Miscellaneous Mechanisms of Action.
A le ja n d ro M.S. M ayer12 a nd Virginia K. B. Lehmann3
INTRODUCTION
D uring 1998 research on the pharm acology of
m arine chem icals included in this review involved
investigators from 22 countries, nam ely Australia,
Belgium, Bolivia, Brazil, Canada, China, France,
Germany, India, Italy, Japan, the Netherlands,
Norway, N ew Zealand, Philippines, Russia,
Slovenia, Spain, Sw itzerland, U nited Kingdom,
U ruguay and the U nited States. This review at
tempts to classify 59 peer-reviewed articles on the
basis o f the reported p reclinical pharm acological
properties o f m arine chem icals derived from a
diverse group o f m arine animals, algae, fungi and
bacteria. Thirty m arine chem icals had antibacterial,
anticoagulant, antifungal, a ntih elm in th ic, a nti
platelet, antiprotozoal or antiviral activities. An
additional seventeen m arine com pounds were
shown to have significant effects on the cardiovas
cular, im m une or nervous system. Finally, tw enty
m arine com pounds were reported to act on a
variety o f m olecular targets that could potentially
contribute to various pharm acological classes.
Thus, during 1998, m arine organisms provided a
variety o f novel chem ical leads for the potential
developm ent o f new therapeutic agents for the
treatm ent o f m ultiple disease categories.
The purpose o f this b rief article was to review studies
w ith bioactive m arine natural products published
exclusively during 1998 and to classify them into m ajor
pharm acological categories w ith the exception o f marine
chem icals w ith a ntitum or and cyto to xic properties that
were recently reviewed (37). O n ly those articles report
ing on the bio activity and/or pharm acology o f marine
chem icals whose structures have been determ ined were
included in the present review. Schmitz's chem ical
classification (56) was used to assign each marine
com pound to a m ajor chem ical class: polyketides,
terpenes, nitrogen-containing com pounds or polysaccha
rides. The publications reporting on antibacterial,
anticoagulant, antifungal, a ntih elm in th ic, antiplatelet,
antiprotozoal or antiviral properties o f marine chem icals
have been tabulated in Table 1. The articles reporting on
m arine com pounds affecting the cardiovascular, im m une
or nervous system are grouped in Table 2. Finally marine
com pounds targeting a num ber o f d istinct ce llu la r and
m olecular targets and mechanisms are presented in Table

62

3. Due to space lim itations, publications on the pharm a

cological activity o f m arine extracts or as yet structurally
uncharacterized m arine com pounds have been excluded
from this article.
Table 1 includes reports on preclinical research on the
antibacterial, anticoagulant, antifungal, a ntihelm inthic,
antiplatelet, antiprotozoal or antiviral activities o f 30
m arine com pounds isolated from four m ajor groups of
organisms. It is notew orthy to highlight the fact that
m arine sponges yielded ten com pounds, w h ile tw enty
other marine chem icals were derived from corals, snails,
mussels, crinoids, cucum bers and tunicates, fungi,
m arine algae and cyanobacteria. The m arine natural
products listed in Table 1 represent all four chem ical
classes, nam ely polyketides (fatty acids, macrolides),
terpenes (diterpenes, sesterterpenes, sesquiterpenes,
sterols), nitrogen-containing com pounds (indoles,
proteins, depsipeptides, peptides, amides, pyrrols) and
polysaccharides. A lthough p reclinical pharm acological
studies allow ed classifying the m arine com pounds listed
in Table 1 into a particular drug class, i.e. antibacterial,
anticoagulant, antifungal, a ntih elm in th ic, antiplatelet,
antiprotozoal or antiviral, it should be noted that no
detailed m echanism o f action studies were reported for
most o f these m arine com pounds w ith o nly a few
exceptions. Hal sulfate and Suvanine inhibited the serine
proteases throm bin and trypsin and are thus potentially
novel anticoagulants (28); M ycalolide-B inhibited
platelet aggregation by interfering w ith actin polym e riza
tion (58), and D idem naketal inhibited the HIV-1 protease
by an unusual mechanism, and m ight become part o f a
novel class o f HIV-1 protease inhibitors (1 6). Further
more, C yanovirin-N (40) as w ell as A d ocia virin (44)
bound w ith high affinity to the H IV viral surface enve
lope glycoprotein 120 w h ile a sulfoquinovosyldiacylglycerol (45) from a red alga inhibited HIV-reverse
transcriptase type 1. A lthough all the pharm acological
studies w ith the marine com pounds listed in Table 1
were o f a p reclinical nature (both in vitro and/or in vivo),
D olastin 10 advanced to c lin ic a l anticancer trials during
1 99 8 (3 7 , 64).
Table 2 includes reports on preclinical research on 1 7
m arine chem icals affecting the cardiovascular, im m une
or nervous system. In contrast to Table 1, in addition to in
vitro and/or in vivo p re clinical pharm acological studies,
1 6 o f these 1 7 m arine com pounds were characterized
extensively at the m olecular level. Interestingly, several
m arine chem icals, though belonging to d ifferent chenii-

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PHARMACOLOGY

Table 1: Marine pharmacology in 1998: Marine Compounds with Antibacterial, Anticoagulant, Antifungal,
Antihelminthic, Antiplatelet, Antiprotozoal, and Antiviral Activities.
Drug Class
Antibacterial

Compound

Organism

Chemistry

MMOA0

Countryv

Ref

F lexibilide /

Coralb

D iterp.k

Undet.'1

AUS,JPN,

PHL, USA

Si nulariol ide
Antibacterial

Hexadecenoid acid

Synthet.3

Fatty acid'

Undet.'1

USA

Antibacterial

Indolequinones

Snail3

Indole"1

Undet.'1

JPN

19

Antibacterial

Lectin

Mussel3

Protein31

Undet.'1

NRW

62

Hal sulfate/

Sponge3'

SesterT

Ser.prot.

UK,JPN,

28

In hib .h

USA

Undet.'1

BRZ,UK

42

C H N ,U S A

Anticoagulant

Suvanine
Anticoagulant

C hondroitin

C ucum ber3

Polysac.3

Antifungal

Polylactones

Fungus

Polyketide

Lipodepsipeptide

Undet.'1

Depsip31
Depsip31

Undet.'1

USA

10

Antifungal

Lobanes

Coralb

D iterp.k

Undet.'1

GER,NTH

14

Antifungal

Dolastatin 10

Tunicatef

Peptide31

Undet.'1

USA

48

Antifungal

Spongistatin

Sponge3'

M acrolide'

Undet.'1

USA

47

Antifungal

Lipodepsipeptide

Fungus

Depsip31

Undet.'1

USA

54

Antifungal

Acanthosterols

Sponge3'

Sterolsk

Undet.'1

JPN,NTH

61

A n tih e lm in tic

Tetrahydrofuran

Algah

Fatty acid'

Undet.'1

AUS

A n tih e lm in tic

C hondriam ide C

Alga'

Indole31

Undet.'1

URG

12

Antiplatelet

M ycalolide-B

Sponge3'

M acrolide'

A ctin pol

JPN

58

A ntim alarial

Rapuanoate

Sponge3'

Terpenek

Undet.'1

BOL,ITA,FRA

11

Antim alarial

Bistramides

Tunicatef

Am ides31

Undet.'1

FRA

20

Antim alarial

Kalihinol A

Sponge3'

D iterp.k

Undet.'1

JPN

39

Antiplasm odial

O ro id in

Sponge3'

CL

Undet.'1

G ER,SW Z

30

A ntiviral

Didem naketal

Tunicatef

Com plex

H IV prot.

USA

16

polyketide

Inhib.5

A ntiviral

Frondosin

Sponge3'

A ntiviral

Sulfated polysacchride

A ntiviral

G ym nochrom e D

Sponge3'

i_
i_

C yclolithistide A

Antifungal

Sesquit.k

Undet.'1

USA

22

Algah

Polysac.3

Undet.'1

JPN

24

C rin oid 3

Com plex

Undet.'1

JPN

32

polyketide
A ntiviral

C yanovirin-N

Bacterium'

Protein31

H IV b in d.1

USA

40

A ntiviral

A dociavirin

Sponge3'

Protein31

H IV b in d.1

USA

44

Antiviral

Sulfoquinovosyl

Alga'

Fatty acid'

H IV R T 3

JPN

45

diacylglycerol
(a) synthet.: synthetic; Organism: Kingdom Anim alia: (b) coral (Phylum Cnidaria), (c) snail and mussel (Phylum M ollusca),
(d) sponge (Phylum Porifera), (e) crinoid and cucum ber (Phylum Echinodermata); (f) tunicate (Phylum Chordata); Kingdom
Fungi: (g) fungus; Kingdom Plantae: (h) alga (Phylum Phaeophyta), (i) alga (Phylum Rodophyta); Kingdom M onera : (j)
bacterium (Phylum Cyanobacteria); Chemistry: (k)Terpenes: diterp: diterpenes, sester: sesterterpene, sesquit: sesquiterpene;
(I) Polyketides;(m) N itro g e n -co n ta in in g com pounds: depsi: depsipeptide; (n) Polysac: polysaccharide; (o) M M O A :
m olecular mechanism o f action; (p) undet.: undeterm ined m echanism o f action;(q) ser.prot. inhib.: serine protease
in h ib itio n ; (r) polym : polym erization; (s) H IV prot. Inhib.: H IV protease in h ib itio n ; (t)H IV bind.: H IV gp 120 binding; (u)
H IV RT.: H IV reverse transcriptase b inding ; (v)Country: AUS: Australia; BOL: Bolivia, BRZ: Brazil, C H N : China, FRA:
France, CER: Germany, ITA: Italy, JPN: Japan, NTH: Netherlands, NRW: Norway, PHL: Philippines, URG: Uruguay,
SWZ: Sw itzerland, UK: U nited Kingdom; (w) Ref: references.
THE PHARMACOLOGIST VOLUME 42

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Table 2: Marine pharmacology in 1998: Marine Compounds affecting the Cardiovascular, Immune and Nervous
Systems
Drug Class

Compound

Organism

Chemistry

MMOA"

Countryy

Refz

Cardiovascular

Sapogenins

Seastarb

SteroP and

Ca2+ influx

RUS

21

saponink
Cardiovascular

Zooxanthellatoxin-B

D inoflag.h

M acrolide 1

Ca2+ influx

JPN

41

Cardiovascular

B-90063

Bacterium'

Pyridine31

Endot. in h ib .0

JPN

59

A ntihistam ine

Verongamine

Synthet.3

Im idazole31

Histam. antag.p

USA

Fatty acid

Eicos. in h ib .q

JPN

25

analogs
A n ti-in flam m ato ry

Decatetraenoic

Alga1

acids

m etab.1

A nti-inflam m atory

Pseudopterosins

Corah

D iterp.k

Eicos. in h ib .q

USA

36

A n ti-in flam m ato ry

Prenyl

Synthet.3

Terpene

Eicosa in h ib .q

SPA, ITA

60

Hydroquinones

T N F -a in h ib /

Immunosuppressant

Palau'amine

Sponged

G uanidine31

Undet.5

USA

29

Immunosuppressant

Rateamine A

Sponged

M acrolide 1

IF-2 in h ib /

USA

51

Nervous System
Nervous System

C onotoxin
Ciguatoxin

Snail6
D inoflag.h

Peptide31
C om plex
polyketide

Serot. rec. inact.3

Na+ chan. inact.v

USA
AUS

15
23

Nervous System

Anthopleurins

Tunicate'

Peptide31

Na+ chan. inact.v

USA

27

Nervous System

Saxitoxin

DinoflagT

G uanidine31

Na+ chan, in a c t/

USA

46

Tetrodotoxin

Fishg

Xestospongin D

Sponged

Q u in o l.31

N O synth. in h ib ."

IN D ,U SA

50

Sponged

Pyridine31

Acetylch. in h ib /

FRA,SFOV

55

Nervous System

Araguspongin C
A u to no m ic Nervous
System

A lkylp yrid in iu m
polym er

(a) synthetcsynthetic; Organism: Kingdom A nim alia: (b) seastar (Phylum Echinodermata), (c) coral (Phylum Cnidaria),
(d) sponge (Phylum Porifera), (e) snail (Phylum M ollusca, (f) tunicate and (g) fish (Phylum Chordata); Kingdom Protista:
(h) dinoflagellate; Kingdom Plantae, (i) alga (Phylum C hlorophyta); Kingdom M onera : (j) bacterium (Phylum Bacteria);
Chemistry: (k)Terpenes: diterp: diterpenes; (1) Polyketides: fattyacid metab.: fatty acid metabolites ;(m) N itrogen-containing
com pounds: quinol.: q u in o lizid in e ; (n) MMOA: m olecular mechanism o f action; (o) endot. inhib.: endothelin converting
enzyme inh ibito r; (p) histam. antag.: histamine receptor antagonist; (q) eicos. inhib.: eicosanoid in h ib itio n ; (r)T N F -a
in h ib .:T N F -a in h ib itio n ; (s) undet: undeterm ined; (t) IF-2 inhib: interleukin-2 in h ib itio n ; (u) serot. rec. inact. : serotonin
receptor inactivation; (v) Na+chan. inact.: Na+ channel inactivation; (w) N O synth. Inhib.: nitric oxide synthase inhibition;
(x) acetylch. inhib.: acetylcholinesterase in h ib itio n ; (y) Country: AUS: Australia, FRA: France, IN D : India, ITA: Italy,
JAPN: Japan, RUS: Russia, SPA: Spain, SFOV: Slovenia; (z) Ref: references.

64

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Table 3: Marine pharmacology in 1998: Marine Compounds with Miscellaneous Mechanisms o f Action
Compound

Organism

Chemistry

MMOA1

Country33

Ref

Bistheonel lide
Sw inholide

Sponge3

M a cro lid e 1

A ctin d epol.m

JPN

52

AFP-2

Fishb

Protein'

Antifreeze

CAN

34

M icrocystin

Bacterium'

Peptide'

Apoptosis

USA

38

G ym no din ium A3

D in o fla g /

PolysacT

Apoptosis

JPN

57

M apacalcine

Sponge3

Protein'

Ca2+ chan, bind."

FRA

63

Carboxym ethyln ico tin ic acid

Sponge3

Pyridine'

Cyst. prot. in h ib .0

JPN

35

M isakinolide

Sponge3

M acrolide'

Liver fenestra'5

BEL,USA

Rhopaloic acid

Sponge3

Sester.h

Gastrul. in h ib .q

JPN

65

Adociasulfate-2

Sponge3

Triterp.,h

Kinesin in h ib /

USA

53

Ralytoxin

Corald

C om plex Polyketide

MAP kin. activ.5

USA

33

Jaspisin

U rchin3

Tyr.'

M etallop. in h ib /

JPN

26

Norzoantham ine

Corald

A lkaloid'

Osteop. in h ib .u

JPN

31

O kadaic acid

Sponge3

C om plex Polyketide

PI kin. a c tiv /

USA

Dragm acidins

Sponge3

Indole'

Phosph. in h ib ."

AUS

Clavosines A-C

Sponge3

Am ide'

Phosph. in h ib ."

USA,NZ, CAN

18

C acospongionolide

Sponge3

Sester.h

PLA in h ib /

ITA,SPA

13

Petrosaspongiolides

Sponge3

Sester.h

PLA in h ib /

ITA,FRA SPA

49

Cyclotheonam ides

Sponge3

Peptides'

Ser. prot. in h ib /

JPN

43

Pulchellalactam

Fungus3

Am ide'

Tyr. p h o s p .in h ib /

USA

Organism: K ingdom A n im a lia : (a) sponge (Phylum Porifera), (b) fish (Phylum Chordata), (c) sea urchin (Phylum
Echinodermata), (d) coral (Phylum Cnidaria); Kingdom Fungi: (e) fungus; Kingdom M onera: (f) bacterium (Phylum
Cyanobacteria); Kingdom Protista: (g) dinoflagel late; Chemistry: (h) Terpenes: triterp: triterpene, sester: sesterterpene; (i)
Polyketides;(j) N itro ge n -co nta inin g compounds: tyr. tyrosine-based m etabolite; (k) Polysac: p olysaccharide; (I) M M O A :
m olecular m echanism o f action; (m) actin depol: actin depolim erizing; (n) Ca2+ chan, bind.: Ca2+ channel binding; (o)
cyst. prot. inhib.: cysteine protease in h ib itio n ; (p) liver fenestra: liver fenestra form ation; (q) gastrul. inhib.: gastrulation
in h ib itio n ; (r) kinesin inh ib.: kinesin in h ib itio n ; (s) M AP kin. A ct iv.: M AP kinase activation; (t) m etallop. Inhib.:
m etalloprotease in h ib itio n ; (u) osteop. inhib.: osteoporosis in h ib itio n ; (v) PI kin. activ.: phosphatidylinositol 3'-kinase
activation; (w) phosph. inhib.: phosphatase in h ib itio n ; (x) PLA inhib.: phospholipase A in h ib itio n ; (y) ser. prot. inhib.:
serine protease in h ib itio n ; (z) tyr. phosp. inhib.: tyrosine phosphatase in h ib itio n ; (aa) Country: AUS: Australia, BEL:
Belgium, CAN: Canada, FRA: France, ITA: Italy, JAPN: Japan, SPA: Spain, NZ: N ew Zealand; (bb) Ref.: References.
THE PHARMACOLOGIST VOLUME 42 NUMBER 2 2000

65

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cal classes and m arine Phyla, shared s im ila r pharm aco

logical properties. Thus in h ib itio n o f Ca2+ influ x was
affected by both the sapogenins, sterols derived from a
seastar that showed stim ulatory action on the isolated
m olluscan heart (21), and zooanthellatoxin-B , a m ac
rolide derived from a dinoflagellate that caused a
concentration-dependent contraction o f rabbit isolated
aorta (41 ). Sim ilarly, eicosanoid in h ib itio n was observed
in M C/9 mouse mast cells w ith hexa- and octadecatetraenoic acids, fatty acid m etabolites isolated from
edible m arine algae (25), in mouse peritoneal m acroph
ages w ith the pseudopterosins, diterpenes derived from
soft corals (36); and in human neutrophils and mouse
macrophages w ith prenyl hydroquinones analogs of
sponge terpenes (60). Finally, sodium channel inactiva
tion was observed in rat parasym pathetic neurons w ith
ciguatoxin, a com plex polyketide derived from benthic
dinoflagellates (23); in m urine neuroblastom a and rat
tum or cell lines expressing cardiac and neuronal sodium
channel isoforms w ith the anthopleurins, peptides
isolated from a sea anemone (27); and in skeletal muscle
sodium channel a-su bu nit expressed in Xenopus oocytes
w ith ciguatoxin and tetrodotoxin, m arine guanidines
produced by dinoflagellates and fish (46).
Table 3 lists 20 m arine com pounds w hich have been
particula rly w ell investigated at the m olecular level.
Although for all these m arine chem icals, a particular
m echanism o f action has been identified, they have not
been proposed for preclinical studies in a particular
pharm acological drug class at this tim e. Interestingly, as
was the case w ith the chem icals included in Table 1,
tw elve o f these m arine com pounds were isolated from
sponges (Phylum Porifera), and though most were
nitrogen-containing com pounds (i.e. proteins, peptides,
pyridines, tyrosine-based m etabolites, alkaloids, indoles
and amides), terpenes, polyketides and polysaccharides
are also represented. N otew orthy are the variety of
m olecular targets that have been identified and studied
during 1998, w hich suggests that some o f these m arine
chem icals m ight affect one or more pharm acological
class, e.g. pulchellalactam , a tyrosine phosphatase
inhibitor.
In conclusion, this brief overview clearly documents
that research into the p reclinical pharm acological
potential o f m arine chem icals was an extrem ely active
scientific enterprise during 1998, invo lvin g colla bo ra
tions between natural product chemists and pharm acolo
gists from 22 foreign countries and the U nited States. W e
thus concur w ith conclusions o f the author o f a recent
review on marine pharm acology that " ... p ha rm aco log i
c a l research in vo lvin g m arine organisms is in trin s ic a lly
slow er a nd has disadvantages com pared w ith a program
based on synthesis, b u t the n um ber a nd q u a lity o f the
leads generated m ore than ju s tify research on m arine
p h a rm a co lo g y..." (17).
66

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Acknowledgments
This paper was funded in part by a grant to A.M .S.M .
from the N ational Sea Grant College Program, N ational
O ceanic and Atm ospheric A dm inistration, U.S. D epart
m ent o f Commerce, under grant num ber NA66RG 0477,
project R/MP 73 through the C alifornia Sea Grant
College System, w hich is gratefully acknowledged. The
view s expressed herein are those o f the authors and do
not necessarily reflect the view s o f N O A A or any o f its
sub-agencies. The U.S. Governm ent is authorized to
reproduce and distribute for governmental purposes.

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