Marine pharmacology in 2003 4: Marine compounds...

gy, Part C 145 (2007) 553–581www.elsevier.com/locate/cbpc

Comparative Biochemistry and Physiolo

Marine pharmacology in 2003–4: Marine compounds with anthelminticantibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial,antiplatelet, antiprotozoal, antituberculosis, and antiviral activities;

affecting the cardiovascular, immune and nervous systems,and other miscellaneous mechanisms of action

Alejandro M.S. Mayer a,⁎, Abimael D. Rodríguez b, Roberto G.S. Berlinck c, Mark T. Hamann d

a Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University,555 31st Street, Downers Grove, Illinois 60515, USA

b Department of Chemistry, University of Puerto Rico, San Juan, Puerto Rico 00931, USAc Instituto de Quimica de Sao Carlos, Universidade de Sao Paulo, Sao Carlos, 13560-970, Brazil

d School of Pharmacy, The University of Mississippi, Faser Hall, University, Mississippi 38677, USA

Received 28 October 2006; received in revised form 29 January 2007; accepted 30 January 2007Available online 9 February 2007

Abstract

The current marine pharmacology review that covers the peer-reviewed literature during 2003 and 2004 is a sequel to the authors' 1998–2002reviews, and highlights the preclinical pharmacology of 166 marine chemicals derived from a diverse group of marine animals, algae, fungi andbacteria. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities werereported for 67 marine chemicals. Additionally 45 marine compounds were shown to have significant effects on the cardiovascular, immune andnervous system as well as possessing anti-inflammatory effects. Finally, 54 marine compounds were reported to act on a variety of moleculartargets and thus may potentially contribute to several pharmacological classes. Thus, during 2003–2004, research on the pharmacology of marinenatural products which involved investigators from Argentina, Australia, Brazil, Belgium, Canada, China, France, Germany, India, Indonesia,Israel, Italy, Japan, Mexico, Morocco, the Netherlands, New Zealand, Norway, Panama, the Philippines, Portugal, Russia, Slovenia, South Korea,Spain, Thailand, Turkey, United Kingdom, and the United States, contributed numerous chemical leads for the continued global search for noveltherapeutic agents with broad spectrum activity.© 2007 Elsevier Inc. All rights reserved.

Keywords: Drug-leads; Marine; Metabolites; Natural products; Pharmacology; Review; Toxicology

1. Introduction

The purpose of this article is to review the 2003–4 primaryliterature on pharmacological studies with marine naturalproducts using the same format as in our previous reviews ofthe marine pharmacology peer-reviewed literature (Mayer andLehmann, 2000), (Mayer and Hamann, 2002, 2004, 2005).Consistent with our previous reviews, only those articlesreporting on the bioactivity or pharmacology of 166 marine

⁎ Corresponding author. Tel.: +1 630 515 6951; fax: +1 630 971 6414.E-mail address: [email protected] (A.M.S. Mayer).

1532-0456/$ - see front matter © 2007 Elsevier Inc. All rights reserved.doi:10.1016/j.cbpc.2007.01.015

chemicals whose structures have been established are included inthe present review. As in our previous reviews, we have usedSchmitz's chemical classification (Schmitz et al., 1993) to assigneach marine compound to a major chemical class, namely,polyketides, terpenes, nitrogen-containing compounds or poly-saccharides. Those publications reporting anthelmintic antibac-terial, anticoagulant, antifungal, antimalarial, antiplatelet,antiprotozoal, antituberculosis or antiviral properties of 67marinechemicals have been tabulated in Table 1 with the correspondingstructures shown in Fig. 1. The articles reporting on 45 marinecompounds affecting the cardiovascular, immune and nervoussystems, as well as those with anti-inflammatory effects are

Table 1Marine pharmacology in 2003–4: marine compounds with anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal,antituberculosis, and antiviral activities

Drug class Compound/organisma Chemistry Pharmacologic activity MMOAb Countryc References

Anthelmintic Thiocyanatins (1–4)/sponge Polyketided Nematocidal activity toHaemonchus contortus

Undetermined AUS (Capon et al., 2004b)

Antibacterial Kalihinol Y and X (5,6)/sponge

Diterpenee B. subtilis inhibition Folate biosynthesisinhibition

PHIL, USA (Bugni et al., 2004)

Antibacterial MC21A (7)/bacterium Bromophenol Methicillin-resistantS. aureus inhibitioncomparable to vancomycin

Permeabilization ofcell membrane

JAPN (Isnansetyo et al., 2003)

Antibacterial Nagelamide A (8)/sponge Alkaloidf M. luteus, B. subtilis andE. coli inhibition

Protein phosphatase2A inhibition

AUS, JAPN (Endo et al., 2004)

Antibacterial Plicatamide (9)/tunicate Peptidef Methicillin-resistantS. aureus, L. monocytogenes,E. coli and P. aeruginosainhibition

Bind to plasmamembrane causingK+ efflux anddepolarization

USA (Tincu et al., 2003)

Antibacterial Manoalide (10)/sponge Sesterterpenee S. aureus inhibition Undetermined JAPN (Namikoshi et al., 2004)Antibacterial Melophlin C (11)/sponge Polyketided B. subtilis and S. aureus

inhibitionUndetermined CHI, INDO,

GER, NETH(Wang et al., 2003a)

Antibacterial Eudistomin X (12)/tunicate Alkaloidf S. aureus, B. subtilis andE. coli inhibition

Undetermined GER (Schupp et al., 2003)

Antibacterial Dolabellanin B2 (13)/sea hare Peptidef B. subtilis, H. influenza andV. vulnificus inhibition

Undetermined JAPN (Iijima et al., 2003)

Antibacterial Pseudopterosin X and Y(14,15)/soft coral

Diterpenee S. aureus, S. pyogenes, andE. faecalis inhibition

Undetermined CAN, USA (Ata et al., 2004)

Antibacterial Sinularia lipids (16–18)/soft coral

Polyketided B. subtilis, B. pumilus,E. coli and P. aeruginosainhibition

Undetermined RUS (Dmitrenok et al., 2003)

Antibacterial Rhodomelabromophenol (19)/alga

Bromophenold S. aureus, S. epidermidisand P. aeruginosa inhibition

Undetermined CHI (Xu et al., 2003)

Antibacterial Cribrostatin 6 (20)/sponge Alkaloidf S. pneumoniae inhibition Undetermined USA (Pettit et al., 2004)Antibacterial Purpuramine L (21)/sponge Bromotyrosine

alkaloids fS. aureus, B. subtilis andC. violaceum inhibition

Undetermined IND (Goud et al., 2003b)

Antibacterial Germacrane (22)/sponge Sesquiterpenee S. aureus and B. subtilisinhibition

Undetermined THAI (Satitpatipan et al., 2004)

Antibacterial Ptilocaulisguanidine (23)/sponge

Alkaloidf S. aureus inhibition Undetermined USA (Yang et al., 2003c)

Antibacterial Membranolides C andD (24,25)/sponge

Diterpenee S. aureus and E. coliinhibition

Undetermined USA (Ankisetty et al., 2004)

Antibacterial Arenicins 1 and 2(26,27)/polychaeta

Peptidef E. coli, L. monocytogenesand C. albicans inhibition

Undetermined RUS (Ovchinnikova et al.,2004)

Antibacterial Perinerin (28)/polychaeta

Peptidef Gram-negative, Gram-positive and fungal inhibition

Undetermined CHI (Pan et al., 2004)

Antibacterial Hippoglossoides peptide(29)/American plaice

Peptidef P. aeruginosa and S. aureusinhibition

Undetermined CAN (Patrzykat et al., 2003)

Anticoagulant Dysinosin C (30)/sponge Peptidef Factor VIIa and thrombininhibition

Two structuralmotifs contribute toprotease binding

AUS (Carroll et al., 2004)

Anticoagulant Fucosylatedchondroitin sulfate(31)/sea cucumber

Polysaccharideg Anticoagulant, bleedingand antithrombotic effectsin vivo

Acceleratedthrombin inhibition

BRA (Zancan et al., 2004)

Anticoagulant Sulfated galactans(32,33)/alga and sea urchin

Polysaccharideg Antithrombin-mediatedanticoagulant activity

Interaction holdsantithrombin inactive

BRA (Melo et al., 2004)

Antifungal Astroscleridae sterol(34)/sponge

Sterol sulfated S. cerevisiae inhibition Undetermined USA (Yang et al., 2003b)

Antifungal Dysidea arenariasterol (35)/sponge

Terpenee Fluconazole resistancereversal in C. albicans

MDR1-type effluxpump inhibition

USA (Jacob et al., 2003)

Antifungal Massadine (36)/sponge Alkaloidf Geranylgeranyltransferase Iinhibition

Undetermined JAPN, NETH (Nishimura et al., 2003)

Antifungal Naamine G (37)/sponge Alkaloidf C. herbarum inhibition Undetermined GER, NETH (Hassan et al., 2004)Antifungal Utenospongin B (38)/sponge Diterpenee C. tropicales and

F. oxysporum inhibitionUndetermined NETH, MOR,

PORT(Rifai et al., 2004)

Antifungal (2S,3R)-2-aminododecan-3-ol(39)/ascidian

Polyketided C. albicans inhibition Undetermined BRA, USA (Kossuga et al., 2004)

Antimalarial Bielschowskysin (40)/coral Diterpenee P. falciparum inhibition Undetermined PAN, USA (Marrero et al., 2004)Antimalarial Briarellins (41–43)/coral Diterpenee P. falciparum inhibition Undetermined PAN, USA (Ospina et al., 2003)

554 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

Table 1 (continued )

Drug class Compound/organisma Chemistry Pharmacologic activity MMOAb Countryc References

Antimalarial Cembradiene (44)/sea whip Diterpenee P. falciparum inhibition Undetermined PAN, USA (Wei et al., 2004)Antimalarial Dolastatin 10 (45)/sea hare Peptidef P. falciparum FCH5.C2

inhibitionMicrotubule andmitotic inhibition

USA (Fennell et al., 2003)

Antimalarial Manzamine A (46)/sponge Alkaloidf P. falciparum D6 and W2inhibition

Undetermined USA (Rao et al., 2003)

Antimalarial Trioxacarcin A and D(48,49)/bacterium

Glycosided, g P. falciparum strains NF54and K1 inhibition

Undetermined NETH, GER (Maskey et al., 2004)

Antiprotozoal Renieramycin A (50)/sponge Alkaloidf Leishmania amazonensisinhibition

Undetermined JAPN (Nakao et al., 2004a)

Antiprotozoal Euplotin C (51)/ciliate Sesquiterpenee Leishmania majorand infantum inhibition

Undetermined ITA (Savoia et al., 2004)

Antiprotozoal Defensins/mussel Peptidef T. brucei and L. majorinhibition

Undetermined BEL, FRA (Roch et al., 2004)

Antituberculosis (+)-8-hydroxymanzamine A(47)/sponge

Alkaloidf M. tuberculosis inhibition Undetermined USA (Rao et al., 2003)

Antituberculosis Homopseudopteroxazole(52)/soft coral

Diterpenee M. tuberculosis inhibition Undetermined USA (Rodríguez et al., 2003)

Antituberculosis Ingenamine G (53)/sponge Alkaloidf S. aureus, E. coli andresistant S. aureus inhibition

Undetermined BRA, GER (De Oliveira et al., 2004)

Antituberculosis 12-Deacetoscalarin19-acetate (54)/sponge

Sesterterpenee M. tuberculosis inhibition Undetermined THAI (Wonganuchitmeta et al.,2004)

Antituberculosis Oceanapiside sp. compounds(55–57)/sponge

Polyketided Mycothiol-S-conjugateamidase inhibition

Non-competitiveinhibition

USA (Nicholas et al., 2003)

Antiplatelet Xetospongin A (58)/sponge Alkaloidf Collagen-induced plateletaggregation inhibition

Undetermined PHIL, USA (Pimentel et al., 2003)

Antiplatelet Zoanthamine alkaloids(59–60)/zoanthids

Alkaloidf Agonist-induced plateletaggregation inhibition

Undetermined BRA, SPA (Villar et al., 2003)

Antiviral Crambescidin 826(61)/sponge

Alkaloidf HIV-1 envelope-mediatedfusion inhibition in vitro

Undetermined USA (Chang et al., 2003)

Antiviral Dehydrofurodendin(62)/sponge

Furanoterpenee Reverse transcriptase RNA-and DNA-directed DNApolymerase inhibition

Undetermined ISRA, FRA (Chill et al., 2004)

Antiviral Neamphamide A (63)/sponge Depsipeptide f HIV-growth inhibition Undetermined USA (Oku et al., 2004)Antiviral Dictyota diterpenes

(64,65)/algaDiterpenee Inhibition of HIV-1

replication in cell lineRNA-dependentDNA-polymeraseRT inhibition

BRA (Pereira et al., 2004)

Antiviral Petrosins (66,67)/sponge Alkaloidf HIV-growth inhibition Giant cell formationand RT inhibition

IND (Goud et al., 2003a)

a Organism, Kingdom Animalia: flounder (American plaice) and tunicates (Phylum Chordata); polychaeta (Phylum Annelida); sea urchins and cucumbers (PhylumEchinodermata), mussels and sea hares (PhylumMollusca), sponges (Phylum Porifera); corals, sea whips and zoanthids (Phylum Cnidaria); KingdomMonera: bacteria(Phylum Cyanobacteria); Kingdom Plantae: algae; Kingdom Protista: ciliates (Phylum Ciliophora).b MMOA: molecular mechanism of action.c Country: AUS: Australia; BEL: Belgium; BRA: Brazil; CAN: Canada; CHI: China; FRA: France; GER: Germany; IND: India; INDO: Indonesia; ISRA: Israel;

ITA: Italy; JAPN: Japan; MOR: Morocco; NETH: The Netherlands; NOR: Norway; PAN: Panama; PHIL: The Phillipines; PORT: Portugal; RUS: Russia; SPA: Spain;THAI: Thailand.d Polyketide.e Terpene.f Nitrogen-containing compound.g Polysaccharide.

555A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

grouped in Table 2 and the structures presented in Fig. 2. Finally54 marine compounds targeting a number of distinct cellular andmolecular targets and mechanisms are shown in Table 3 and theirstructures depicted in Fig. 3. Publications on the biological orpharmacological activity of marine extracts or as yet structurallyuncharacterized marine compounds have been excluded from thepresent review, although several promising reports were pub-lished during 2003–4: a specific inhibitor of a thyrotropinreleasing hormone-specific peptidase (Pascual et al., 2004);antimicrobial activity in sub-Arctic marine invertebrates(Lippert et al., 2003); antifilarial activity of the red alga

Botryocladia leptopoda (Lakshmi et al., 2004); antiviral effectsof a sulfated exopolysaccharide from the marine microalgaGyrodinium impudicum (Yim et al., 2004) and Sargassuumpatens (Zhu et al., 2004); a polyhydroxylated fucophloretholisolated from the marine brown alga Fucus vesiculosusshown to be bactericidal towards selected Gram-positive andGram-negative bacteria in vitro (Sandsdalen et al., 2003); andan improvement of “current cytokine-based therapies”by sulphated polysaccharides purified from the green algaCodium fragile, as well as fucoidan and carrageenan, isolatedfrom brown and red algae, respectively (Nika et al., 2003).


2. Marine compounds with anthelminthic, antibacterial,anticoagulant, antifungal, antimalarial, antiplatelet,antiprotozoal, antituberculosis, and antiviral activities

Table 1 summarizes new pharmacological findings reportedduring 2003–4 on the preclinical anthelminthic, antibacterial,anticoagulant, antifungal, antimalarial, antiplatelet, antiproto-zoal, antituberculosis, and antiviral pharmacology of the 67marine natural products shown in Fig. 1.

Fig. 1

2.1. Anthelminthic and antibacterial compounds

One study contributed to the search of novel anthelminticmarine natural products during 2003–4. The novel acycliclipids thiocyanatins (1–4), were isolated from the Australiansponge Oceanapia sp. (Capon et al., 2004b) and were shown tobe nematocidal (LD99=3.1–8.3 μg/mL) to the commerciallivestock parasite Haemonchus contortus. Although the mech-anism of action of these compounds remains undetermined, the

.

Fig. 1 (continued ).


investigators noted that both the 2°-alcohol, SCN functionalitiesand chain length influenced the nematocidal activity.

In view of the fact that resistance to current antibiotics remains asignificant challenge for pathogenic bacterial infections, during2003–4, 19 studies contributed to the search for novelantibacterialmarine natural products, an increase from 1998–2002 (Mayer andLehmann, 2000; Mayer and Hamann, 2002, 2004, 2005). Fourstudies reported on the mechanism of action of novel marineantibacterial agents (2–6; Fig. 1). Bugni et al. (2004) investigated aseries of kalihinols, diterpenes isolated from the Philippine marinesponge Acanthella cavernosa, as potential bacterial folatebiosynthesis inhibitors. The investigators reported that the

pyranyl-type kalihinols Y (5) and X (6), although potentantibacterials (MIC=1.56 μg/mL), were however less selectiveinhibitors of bacterial folate biosynthesis than the furanyl typekalihinols, with the “C-10 position important for potency”.Isnansetyo and Kamei (2003) reported that a bactericidalcompound named MC21-A (7), a 3,3′,5,5′-tetrabromo-2,2′-biphenyldiol, from the new marine bacterium Pseudoalteromonasphenolica sp. nov. MC21-A was bactericidal (MIC=1–2 μg/mL)against 10 clinical isolates of methicillin-resistant Staphylococcusaureus, and displayed comparable bioactivity to vancomycin(MIC=0.25–2 μg/mL). The mechanism of action of MC21-Ainvolved permeabilizing bacterial cell membranes, and thus “might



be a useful compound” because of a mode of action that differsfrom vancomycin. A new dimeric bromopyrrole alkaloid,nagelamide G (8) was isolated from the Okinawan marine spongeAgelas sp. (Endo et al., 2004). Nagelamide G exhibitedantibacterial activity against M. luteus, B. subtilis and E. coli, butweakly inhibited protein phosphatase 2 A (IC50=13 μM), thussuggesting that this enzyme may not be the main molecular targetresponsible for the antibacterial activity of this compound. Tincuet al. (2003) reported a new antimicrobial octapeptide plicatamide(9) from the hemocytes of the marine tunicate Styela plicata. In an

extensive and detailed mechanistic study these investigatorsdiscovered that despite its small size, the octapeptide plicatamideproved to be a potent, rapidly acting and broad spectrumantimicrobial. The fact that both wild type and methicilin-resistantS. aureus responded to plicatamide with a massive and rapidpotassium efflux is “consistent with an antimicrobial mechanismthat targets their cell membrane”.

Although additional novel marine antibacterials werereported in 2003–4, no mechanism of action studies werereported for compounds (10–29). Nevertheless, these studies



highlight the fact that novel antibiotics are present in marinebacteria, tunicates, sea hares, soft corals, algae, sponges, worms,and fish. Two papers reported on antibacterial activity incompounds isolated from marine sponges: Namikoshi et al.(2004) reported the isolation of several manoalide derivatives(10) from a Luffariella sp. sponge collected in Palau, whichwere active against S. aureus at 5–10 μg/disk. The investigatorsnoted that the presence of an “OH group at the C-25 position(hemiacetal moiety) is important for antibacterial activity.”Wang et al. (2003a) reported thirteen novel tetramic acidsisolated from the marine sponge Melophlus sarassinorum.Interestingly, only melophlin C (11) displayed “pronounced

antibacterial activity” against B. subtilis and S. aureus. Onepaper reported on new antimicrobial compounds isolatedfrom marine tunicates: Schupp et al. (2003) discovered thatthe β-carboline eudistomin X (12), isolated from the Microne-sian ascidian Eudistoma sp. was active against B. subtilis,S. aureus and E. coli. One paper reported on a new antimicrobialpeptide isolated from sea hares: Iijima et al. (2003) reported anovel 33 amino acid antimicrobial peptide dolabellanin B2 (13)from the sea hare Dolabella auricularia. One hundred percentinhibition of growth of B. subtilis, H. influenza and Vibriovulnificus was reported with 2.5–5 μg/mL dolabellanin B2.Two papers reported on new antimicrobial peptides isolated



from marine soft corals: Ata et al. (2004) reported two newditerpenes, pseudopterosin X and Y (14–15) from the soft coralPseudopterogorgia elisabethae which showed antibacterialactivity against Gram-positive bacteria Streptococcus pyogenes,S. aureus, and Enterococcus faecalis, while being inactiveagainst Gram-negative bacteria. Dmitrenok et al. (2003)reported several sphingolipids and glycolipids (16–18) fromsoft corals of the Andaman Islands (Indian Ocean). Although

the MIC were not reported, “preliminary tests for antibacterialactivity of lipids” demonstrated that these compounds inhibitedthe growth of E. coli, Pseudomonas aeruginosa, B. subtilis andB. pumilus on solid agar. One paper reported on the presence ofantibacterial compounds in marine algae: Xu et al. (2003)reported that among 5 bromophenols isolated from the marinered alga Rhodomela confervoides, the known compound bis(2,3-dibromo-4,5-dihydroxybenzyl) ether (19) showed

Table 2Marine pharmacology in 2003–4: marine compounds with anti-inflammatory activity, and affecting the cardiovascular, immune and nervous systems

Drug class Compound/organisma Chemistry Pharmacological activity MMOAb Countryc References

Anti-inflammatory Astaxanthin (68)/salmon,sea stars

Tetraterpened Inhibition of endotoxin-induced uveitis in rats

iNOS, NO, TNF-αand PGE2 inhibition

JAPN (Ohgami et al., 2003)

Anti-inflammatory Bolinaquinone (69)/sponge

Merosesquiterpened Inhibition of cytokine,iNOS and eicosanoids

sPLA2 inhibition SPA, ITA (Lucas et al., 2003b)

Anti-inflammatory Cacospongionolide B(70)/sponge

Sesterterpened Nitric oxide, PGE2 andTNF-α inhibition invitro and in vivo

Nuclear factor-κBinhibition

SPA, ITA (Posadas et al., 2003a)

Anti-inflammatory Clathriol B (71)/sponge Sterold Neutrophil superoxideinhibition

Undetermined NZEL (Keyzers et al., 2003)

Anti-inflammatory Conicamin (72)/tunicate Indole alkaloide Histamine antagonist Undetermined ITA (Aiello et al., 2003)Anti-inflammatory Cycloamphilectene 2

(73)/spongeDiterpened Nitric oxide inhibition Inhibition of NF-κB

pathwayITA, SPA (Lucas et al., 2003a)

Anti-inflammatory Plakohypaphorine D(74)/sponge

Indole alkaloide Histamine antagonist Undetermined ITA (Borrelli et al., 2004)

Anti-inflammatory Pourewic acid A andmethylpourewate B(75,76)/sponge

Diterpenesd Superoxide inhibition Undetermined NZEL (Keyzers et al., 2004)

Anti-inflammatory Cadlinolide C (77)/sponge Diterpened Superoxide inhibition Undetermined NZEL (Keyzers et al., 2004)Anti-inflammatory Petrocortyne A (78)/sponge Polyacetyleneg Macrophage

inflammatorymediator inhibition

NO and TNF-αinhibition

SKOR (Hong et al., 2003)

Anti-inflammatory Petrosaspongiolide M(79)/sponge

Sesterterpened Nitric oxide, PGE2 andTNF-α inhibition invitro and in vivo

Nuclear factor-κBinhibition

ITA, SPA (Posadas et al., 2003b)

Anti-inflammatory Petrosaspongiolides M-R(79–83)/sponge

Sesterterpenesd Macrophageinflammatory mediatorinhibition

PLA2 inhibition ITA (Monti et al., 2004)

Anti-inflammatory Pseudopterosin N(84)/sea whip

Diterpened Inhibition of mouse earinflammation

Undetermined USA (Ata et al., 2003)

Anti-inflammatory Seco-pseudopterosin E(85)/sea whip



Anti-inflammatory Elisabethadione(86)/sea whip



Anti-inflammatory Pseudopterosin R(87)/sea whip

Diterpened Microglia thromboxaneB2 inhibition

Undetermined USA (Rodríguez et al., 2004)

Cardiovascular Callipeltin A (88)/sponge Depsipeptidee Affected resting aortacontraction

Na+-ionophoreaction

ITA (Trevisi et al., 2004)

Immune system Codium fragilepolysaccharide/alga

Polysaccharide f Binding to IL-2, IL-7and INF-γ

Undetermined UK (Nika et al., 2003)

Immune system Sulfircin (89)/sponge Sesterterpened Mobilization of T cellsand dendritic cells

CCR7 chemokinereceptor binding

USA (Yang et al., 2003d)

Immune system Mucins/sea star Polysaccharide f Inhibition of neutrophiladhesion

Undetermined UK (Bavington et al., 2004)

Immune system Perybysins A–D(90–93)/fungus

Sesquiterpenesd Inhibition of humanleukemia cell adhesion

Undetermined JAPN (Yamada et al., 2004)

Immune system Phycarine/alga Polysaccharide f Stimulation ofmacrophage phagocytosis

IL-1, IL-6 andTNF-α synthesis

FRA, USA (Vetvicka et al., 2004)

Immune system Sulfated PMG (94)/alga Polysaccharide f Inhibition of HIV virusinfection of lymphocytes

Binding to CD4receptor onlymphocytes

CHI (Meiyu et al., 2003)

Immune system Sulfated PMG (94)/alga Polysaccharide f Binding to lymphocytes Interaction withCD4 receptor

CHI (Miao et al., 2004)

Nervous system PetrosaspongiolideM (79)/sponge

Sesterterpened Reduction of morphinewithdrawal in vitro

Undetermined ITA (Capasso et al., 2003)

Nervous system Aplidine(95)/tunicate Depsipeptidee Inhibition of aggregationof prion petide intoβ-sheet fibrils

Undetermined SPA,USA (Perez et al., 2003)

Nervous system Aspermytin A (96)/fungus Polyketideg Induction of neuriteoutgrowth

Undetermined JAPN (Tsukamoto et al.,2004a)

Nervous system Labuanine A (97)/sponge Pyridoacridinealkaloide

Induction of neuiteoutgrowth

Undetermined JAPN, INDO (Aoki et al., 2003)

Nervous system Linckosides C–E(98–100)/sea star

Steroidalglycosided

Induction of neuriteoutgrowth

Undetermined JAPN (Qi et al., 2004)

(continued on next page)


Table 2 (continued )

Drug class Compound/organisma Chemistry Pharmacological activity MMOAb Countryc References

Nervous system Parguerol-isoparguerol(101–102)/sea hare

Diterpened Induction of neuriteoutgrowth

Undetermined JAPN (Tsukamoto et al.,2004b)

Nervous system Sargaquinoic acid(103)/alga

Meroditerpened Induction of neuriteoutgrowth

PI-3 kinaseindependent;TrKA-MAP kinaseand adenylatecyclase-PKAdependent

JAPN (Tsang et al., 2004;Kamei et al., 2003)

Nervous system SJG-2 ganglioside(104)/sea cucumber

Ganglioside Induction of neuriteoutgrowth

Undetermined JAPN (Kaneko et al., 2003)

Nervous system Cribronic acid(105)/sponge

Amino acide Convulsant activityin mice

Binding toNMDA-typereceptor

JAPN (Sakai et al., 2003)

Nervous system Dysibetaine CPa–CPb(106,107)/sponge

Betaine Binding to ionotropicglutamate receptors

Undetermined JAPN (Sakai et al., 2004)

Nervous system Jamaicamide A(108)/cyanobacterium

Lipopeptidee Sodium channel blocking Undetermined USA (Edwards et al., 2004)

Nervous system Esmodil (109)/sponge Quaternary amine Acetylcholine mimetic Undetermined AUS (Capon et al., 2004a)Nervous system ω-conopeptide MVIIA

(110)/snailPeptidee Inhibition of refractory

pain in patients withAIDS or Cancer

Binding to N-typeCa2+ channels

USA (Staats et al., 2004)

Nervous system δ-conotoxin (111)/snail Peptidee Na+ current inhibition Undetermined IND (Sudarslal et al., 2003)Nervous system χ-conopeptide

MrIA (112)/snailPeptidee Norepinephrine

transporter inhibitionNon-competitivebinding at theantidepressantbinding site

AUS (Sharpe et al., 2003)

Nervous system Acidic oligosaccharide/alga Polysaccharidef Inhibition of amyloidbeta toxicity

Inhibition ofapoptosis andintracellular Ca2+

CHI (Hu et al., 2004)

a Organism: Kingdom Animalia: sea whip (Phylum Cnidaria); tunicate (Phylum Chordata), sea star and cucumber (Phylum Echinodermata); sea hare and snail(Phylum Mollusca); sponge (Phylum Porifera); Kingdom Fungi: fungus; Kingdom Plantae: alga; Kingdom Monera: bacterium (Phylum Cyanobacteria).b MMOA: molecular mechanism of action, NO: nitric oxide.c Country: AUS: Australia; CHI: China; FRA: France; INDO: Indonesia; ITA: Italy; JAPN: Japan; N. ZEL: New Zealand; SPA: Spain; S.KOR: South Korea; UK:

United Kingdom.d Terpene.e Nitrogen-containing compound.f Polysaccharide.g Polyketide.


antibacterial activity against S. aureus (MIC=70 μg/mL), Sta-phylococcus epidermidis and P. aeruginosa (MIC=70 μg/mL).Additional antibacterial marine natural products were isolatedfrom sponges: Pettit et al. (2004) reported the antibacterialactivity of a novel nitrogen heterocyclic compound cribrostatin6 (20) isolated from the dark-blue marine Cribochalina sp.sponge. Cribrostatin 6 showed antibacterial activity againstGram-positive bacteria, and it was most active againstS. pneumoniae (MIC=0.5 μg/mL), a leading cause of infectionand mortality worldwide. Goud et al. (2003b) reported a novelpurpuramine L (21) from the Indian marine sponge Psamma-plysilla purpurea which was active against S. aureus, B. subtilisand C. violaceum. A new nitrogenous sesquiterpene germa-crane (22) was isolated from an Axinyssa n. sp. sponge thatdemonstrated strong antimicrobial activity against S. aureusand B. subtilis (Satitpatipan and Suwanborirux, 2004). Yanget al. (2003c) isolated a new bicyclic guanidine alkaloid (23)from the marine sponge Ptilocaulis spiculifer, contributing anew member to the crambescin A class of compounds.Interestingly, 50 μg of the guanidine alkaloid was as potent as10 μg gentamicin. Two diterpenes membranolides C and D (24,

25) derived from an Antarctic cactus sponge, displayed “modestyet broad spectrum” Gram-negative antibiotic activity (Anki-setty et al., 2004). Two novel antibacterial peptides were isolatedfrom marine worms: Ovchinnikova et al. (2004) purified andcharacterized two small 21-residue peptides arenicin-1 and-2(26–27), from the coelomocytes of the marine lugworm Areni-cola marina. Both arenicins were active against Gram-positive L.monocytogenes, Gram-negative E. coli and the fungusC. albicans. Pan et al. (2004) isolated and characterized a 51-amino acid highly basic and hydrophobic peptide perinerin (28),from the marine clamworm Perinereis aibuhitensis, an organismthat is extensively used as bait in fisheries and aquaculture.Perinerin, a peptide that is constitutively present in the marineworm and whose sequence appears to be novel among all knowantimicrobial peptides, was active against Gram-negative andGram-positive bacteria as well as fungi. Patrzykat et al. (2003)reported active novel antimicrobials peptides by screening bothgenomic and mRNA transcripts from a number of differentspecies of flatfish. The most active peptide coded as NRC-13 (29)which was derived from the American plaice Hippoglossoidesplatessoides Frabricius, “rapidly (5 to 10 min) and efficiently


(95–100%)” killed antibiotic-resistant P. aeruginosa, methicillin-resistant S. aureus and C. albicans.

2.2. Anticoagulant compounds

During 2003–4 three articles reported on the anticoagulantproperties of marine natural products, an increase from ourprevious reviews (Mayer and Lehmann, 2000; Mayer andHamann, 2002, 2004, 2005). Carroll et al. (2004) reported three

Fig. 2

new peptides, dysinosins B, C (30) and D, isolated from thesponge Lamellodysidea chlorea, that inhibited the bloodcoagulation cascade serine proteases factor VIIa and thrombin.Furthermore, the study revealed that two structural motifs of thedysinosins contributed to the binding of these compounds tofactor VIIa and thrombin proteases. Zancan and Mourao (2004)extended the antithrombotic pharmacology of fucosylatedchondroitin sulfate (31), a glycosaminoglycan isolated fromthe Brazilian sea cucumber Ludwigothurea grisea. The

.



researchers noted that it was possible to dissociate theanticoagulant, bleeding and antithrombotic effect of this com-pound, i.e. the antithrombotic effect varied depending on thein vivo experimental model being used, and that it was“apparently unrelated to its effect on platelet aggregation”.Melo et al. (2004) extended the pharmacology of antico-agulant sulfated galactans (32–33) isolated from the red algaBotryocladia occidentalis and the sea urchin Echinometralucunter. The studies demonstrated that the antithrombin-activating conformational change appeared to be of minorsignificance for the sulfated galactans's anticoagulant activity,and that the antithrombin-sulfated galactan complex differedfrom the antithrombin–heparin complex, thus leading theresearchers to propose that “the paradigm of the heparin–antithrombin interaction cannot necessarily be extended to othersulfated polysaccharides”.

2.3. Antifungal compounds

Six studies during 2003–4 reported on the antifungalproperties of 6 novel marine natural products isolated frommarine sponges and ascidians, a slight decrease from 1998–2002 (Mayer and Lehmann, 2000; Mayer and Hamann, 2002,2004, 2005).

Several novel marine antifungals (34–38) were isolated frommarine sponges. Yang et al. (2003b) reported a new sterol sulfate(34) isolated from a deep-water marine sponge of the familyAstroscleridae, which exhibited antifungal activity against“supersensitive” Saccharomyces cerevisiae (MIC=15 μg/mL).As part of an ongoing project to discover potential new drugs totreat resistant opportunistic fungal infections, Jacob et al. (2003)reinvestigated the antifungal properties of a previously describedsterol (35) isolated from the marine sponge Dysidea arenaria.



Interestingly, they observed a reversal of fluconazole resistancefrom 300 to 8.5 μM when combined with 3.8 μM of theD. arenaria sterol, putatively as a result of inhibition of theMDR1-type efflux pump in multidrug-resistant C. albicans.With the purpose of finding more selective antifungal agents,Nishimura et al. (2003) focused their research efforts inidentifying inhibitors of the pathogenic fungus C. albicansgeranylgeranyltransferase (GGTase), an enzyme that sharesonly 30% amino acid sequence homology with the human

GGTase. Bioassay-guided fractionation resulted in the isola-tion of a novel alkaloid massadine (36) from the marinesponge Stylissa aff. massa, which inhibited fungal GGTase(IC50=3.9 μM). One novel imidazole alkaloid, naamineG (37) was reported from the Indonesian marine spongeLeucetta chagosensis that exhibited strong antifungal activityagainst the phytopathogenic fungus Cladosporium herbarum(Hassan et al., 2004). It remains to be determined if this com-pound will also be effective against fungi that infect mammalian



hosts. Rifai et al. (2004) reported that untenospongin B (38),isolated from the Moroccan marine sponge Hippospongiacommunis, was more potent than amphotericin B, a clinicallyused antifungal agent, againstCandida tropicalis (MIC=4–8 μg/mL) and Fusarium oxysporum (MIC=2–4 μg/mL). Furtherstudies are required to determine the toxicity of untenospongin Bin vivo as well as its molecular mechanism of action.

Kossuga et al. (2004) reported a new antifungal agentpolyketide, (2S, 3R)-2-aminododecan-3-ol (39), isolated fromthe Brazilian ascidian Clavelina oblonga, which was veryactive against C. albicans (MIC=0.7±0.05 μg/mL). Althoughthe mechanism of action of this compound remains undeter-mined its bioactivity was comparable to the clinically usedantifungal agents nystatin (MIC=1–4 μg/mL) and ketocona-zole (MIC=1–4 μg/mL).

2.4. Antimalarial, antiprotozoal, antituberculosis and antipla-telet compounds

During 2003–4, and as shown in Table 1, 16 studies werereported in the area of antimalarial, antiplatelet, antiprotozoaland antituberculosis pharmacology of structurally characterizedmarine natural products. Ten compounds (40–49; Fig. 1) wereshown to possess antimalarial activity. Moderate antimalarialactivity (IC50=10 μg/mL) against Plasmodium falciparum wasobserved with bielschowskysin (40), a new and highly oxygen-ated hexacyclic diterpene isolated from the Caribbean gorgonianoctocoralPseudopterogorgia kallos (Marrero et al., 2004), as wellas the novel diterpenes of the eunicellin class, briarellins Khydroperoxide (41), D hydroperoxide (42) and L (43), isolatedfrom the gorgonian Briareum polyanthes (IC50=9, 9 and 8 μg/mL, respectively) (Ospina et al., 2003). Wei et al. (2004) reportedmoderate cytotoxic activity against the P. falciparum W2

(chloroquine-resistant) strain by the novel cembradiene diterpe-noid (44) isolated from the Caribbean gorgonian octocoral Euni-cea sp., (IC50=23, 15 and 16 μg/mL, respectively). Fennell et al.(2003) reported the antimalarial activity of dolastatin 10 (45), apeptide microtubule inhibitor isolated from the sea hare D.auricularia which is a potent anticancer drug. Although anextensive structure–activity relationship study was described anddolastatin 10 showed potent inhibition of P. falciparum(IC50=0.1 nM) by affecting the schizont stage of intraerythrocyticdevelopment, which has the highest concentration of tubulin, theinvestigators concluded that dolastatin 10 was an “unpromisingbasis for further antimalarial evaluation” because of the lack ofmarked selectivity for parasite over mammalian cells. Rao et al.(2003) reported structure–activity relationship studies with themanzamine alkaloids as potential antimalarial agents. ManzamineA (46) was observed to be particularly active againstP. falciparum(D6 clone, IC50=4.5 ng/mL) and P. falciparum (chloroquine-resistant W2 clone, IC50=8.0 ng/mL), which compared well withartemisinin used as a control in these studies (IC50=10 and 6.3 ng/mL, respectively). As part of an ongoing screening program fornovel bioactive compounds frommarine Streptomycetes, Maskeyet al. (2004) reported that the trioxacarcins A and D (48,49)isolated from the marine Streptomyces sp. isolate B8652 BCC5149 possessed “extremely high antiplasmodial activity” againstthe parasite P. falciparum K1 and NF54 strains (IC50=1.5–1.6and 2.3–1.7 ng/mL, respectively) whichwasmuch higher than theclinically used compound chloroquine (IC50=70 and 3.7 ng/mL,respectively).

Three compounds were shown to possess antiprotozoalactivity. Nakao et al. (2004a) reported the isolation ofrenieramycin A (50) a new compound from the Japanese spongeNeopetrosia sp. that dose-dependently inhibited recombinantLeishmania amazonensis proliferation (IC50=0.2 μg/mL) while


showing cytotoxicity at “ten times higher concentration(IC50=2.2 μg/mL)”. Savoia et al. (2004) examined the activityof the sesquiterpene euplotin C (51), isolated from the marineciliate Euplotes crassus on pathogenic protozoa Leishmaniamajor and Leishmania infantum. Because a significant leishma-nicidal activity was noted against both Leishmania species(LD50=4.6–8.1 μg/mL), the authors proposed evaluation of thisnatural product as “synergistic compound(s) for currentantiprotozoon chemotherapeutics”. Roch et al. (2004) reportedthat novel non-cytotoxic variant analogues of truncateddefensins isolated from the Mediterranean mussel Mytilusgalloprovincialis were antiprotozoal. Two defensin fragments,designated D (Sequence CGGWKRKRC) and P (SequenceCGGYCGGWKRKRCTSYRCG), killed both the Africantrypanosome Trypanosoma brucei (ID50=4–12 μM), whichcauses sleeping sickness, and the causative agent of cutaneousleishmaniasis, namely L. major (ID50=12–45 μM), in a time-and concentration-dependent manner. The mechanism mayinvolve binding of the defensin fragments “to parasite mem-branes”, perhaps affecting membrane fluidity.

Seven novel compounds (47, 52–57; Fig. 1) were contributedto the search for novel antituberculosis agents. Rodríguez andRodríguez (2003) reported that a novel diterpene alkaloidhomopseudopteroxazole (52), isolated from the Caribbean seaplume P. elisabethae, inhibited growth of Mycobacteriumtuberculosis H37Rv (MIC=12.5 μg/mL). As part of a manzaminealkaloid structure–activity relationship study, Rao et al. (2003)noted that (+)-8-hydroxymanzamine A (47) was very potentagainst M. tuberculosis (H37Rv, MIC=0.91 μg/mL), comparingfavorably with rifampin (MIC=0.5 μg/mL). De Oliveira et al.(2004) reported a new alkaloid ingenamine G (53) thatdemonstrated activity against M. tuberculosis H37Rv at 8 μg/mL.A new scalarane-type bioactive sesterterpene, 12-deacetoxysca-larin 19-acetate (54), which was purified from the Thai spongeBrachiaster sp. (Wonganuchitmeta et al., 2004), inhibited growthof a nonvirulent strain ofM. tuberculosis by 50% at MIC=4 μM,comparing favorablywith kanamycin sulfate (MIC=3.5–8.5μM).As a result of a research program designed to identify marinenatural products that inhibit the mycothiol-S-conjugate amidase, amycobacterial detoxification enzyme, Nicholas et al. (2003)reported several active compounds: a mixture of 1,3 pyridiniumpolymers (55) isolated from the marine sponge Amphimedon sp.,IC50=0.1 μM; an Oceanapiside sp.-derived bromotyrosinecompound (56), IC50=3 μM; and the glycosphingolipid oceanapi-side (57), IC50=10 μM. Oceanapiside, was observed to be a“simple non-competitive inhibitor” of the mycothiol-S-conjugateamidase enzyme.

Two studies contributed to antiplatelet pharmacology ofmarine natural products during 2003–4. Pimentel et al. (2003)using a new microplate assay for Ca2+-induced platelet aggre-gation, determined that xestospongin A (58), isolated from themarine sponge Xestospongia sp., inhibited both collagen- andepinephrine-induced platelet aggregation more potently thanaspirin. Villar et al. (2003) evaluated the effects of severalzoanthamine-type alkaloids isolated from the zoanthidsZoanthus numphaeus and Zoanthus sp. on the aggregation ofhuman platelets: 11-hydroxyzoanthamine (59) demonstrated

strong inhibition of thrombin-, collagen- and arachidonic acid-induced platelet aggregation which appeared related to thehydroxyl group at C-11; in contrast, aromatization in ring Awasprobably responsible for the selectivity of zoanthenol (60)towards collagen-induced aggregation.

2.5. Antiviral compounds

As shown in Table 1 interest in the antiviral pharmacology ofmarine natural products remained high during 2003–4. Duringthis two-year period 7 novel marine compounds (61–67) (Fig. 1)were reported to possess antiviral properties against the humanimmunodeficiency (HIV) virus by targeting a number of diversemolecular targets. As a result of an effort to identify smallmolecules that disrupt protein–protein interactions involvedin HIV-1 cellular entry, a new polycyclic guanidine alkaloidcrambescidin 826 (61) was reported from the marine spongeMonanchora sp. (Chang et al., 2003). Crambescidin 826inhibited HIV-1 envelope-mediated fusion in vitro (IC50=1–3 μM), thus suggesting that this class of compounds mightultimately aid in “the rational design…of small molecule HIV-1fusion inhibitors”. Chill et al. (2004) isolated a new C22

furanoterpene designated dehydrofurodendin (62) from aMadagascan Lendenfeldia sponge, that was active againstHIV-1 reverse transcriptase-associated RNA- and DNA-directedDNA polymerase (IC50=3.2–5.6 μM). As a result of theNational Cancer Institute's HIV-inhibitory natural product leaddiscovery program, a new HIV-inhibitory depsiundecapeptideneamphamide A (63) was isolated from the Papua New Guineamarine sponge Neamphius huxleyi (Oku et al., 2004). Neam-phamide A potently inhibited the cytopathic effect of HIV-1infection in a cell-based in vitro assay (EC50=28 nM). Pereira etal. (2004) reported an extensive study on the mechanism ofaction of two diterpenes, Da-1 and AcDa-1 (64, 65), isolatedfrom the marine alga Dictyota menstrualis, that inhibited HIV-1virus replication in the PM-1 cell line in vitro. Although bothditerpenes did not affect viral attachment nor internalization ofthe virus into PM-1 cells, they inhibited the RNA-dependentDNA polymerase activity of the viral reverse transcriptaseenzyme (IC50 = 10 and 35 μM, for Da-1 and AcDa-1,respectively) in a cell-free in vitro assay. These results stronglysuggested that “inhibition of synthesis of the proviral DNA bythe diterpenes” was the probable mechanism involved in HIVreplication inhibition in PM-1 cells. Goud et al. (2003a) reportedinhibition of HIV by two bis-quinolizidine alkaloids petrosins(66, 67) isolated from the Indian marine sponge Petrosia similis.The extensive investigation determined that both petrosinsinhibited HIV-1 replication (IC50=41.3–86.8 μM), formation ofgiant cells (IC50=21.2–36.1 μM) and recombinant reversetranscriptase in vitro (IC50=10.6–14.8 μM).

3. Marine compounds with anti-inflammatory effects andaffecting the cardiovascular, immune and nervous system

Table 2 summarizes the preclinical pharmacological researchcompleted during 2003–2004 with the 45 marine chemicalsshown in Fig. 2.

Table3

Marineph

armacolog

yin

2003–4:

marinecompo

unds

with

miscellaneousmechanism

sof

actio

n

Com

pound/organism

aChemistry

Pharm

acological

activ

ityIC

50b

MMOAc

Country

dReferences

Acylsperm

idineD

and

E(113

,114

)/softcoral

Polyaminee

Vacuo

larH+-pyrop

hosphatase

inhibitio

n0.98

μMNoinhibitio

nof

F–P-and

V-typ

eH+ATPases

and

cytosolic

pyroph

osph

atase

JAPN

(Hiron

oet

al.,20

03)

Ageladine

A(115)/spon

geAlkaloide

Matrixmetalloprotease

(MMP)inhibitio

n0.33–2μg

/mL

Non-com

petitiveinhibitio

nof

MMP-2

NETH,JA

PN

(Fujita

etal.,20

03a)

Ago

sterol

C(116

)/sponge

Sterolf

Proteasom

einhibitio

n10

μg/m

LUndetermined

NETH,JA

PN

(Tsukamotoet

al.,2003)

Alkylpyridinium

/(117)/sponge

Pyridinium

oligom

ere

Poreform

ationon

neuronal

mem

branes

ND

Reversibleandirreversible

increase

[Ca2

+]i;mem

brane

prop

ertiesattenu

ated

byzinc

TUR,S

LO,U

K(M

cClelland

etal.,20

03)

Alkylpyridinium

(poly-APS

)(118)/sponge

Pyridinium

oligom

ere

StableDNA

transfectio

n0.5μg

/mL

Transient

andreversible

pore

form

ation

SLO,UK

(Tuckeret

al.,20

03)

Arenarolandisoarenarol

(119,12

0)/spong

eMerosesquiterpenef

Protein

kinasesinhibitio

n4–

7μM

Undetermined

NETH,CAN

(Yoo

etal.,2003)

Atriolum

robu

stum

nucleoside

(121)/ascidian

Aminoacid

derivede

Partialagonistat

ratbrain

A1adenosinereceptors

23±0.2μM

Binding

toA1andA3

adenosinereceptors

GER

(Kehraus

etal.,2004)

CallysponginolsulfateA

(122)/spon

gePolyk

etideg

MT1-matrixmetalloproteinase

inhibitio

n15

.0μg

/mL

Undetermined

JAPN,NETH

(Fujita

etal.,2003b)

Calyculin

A(123)/sponge

Polyk

etideg

Histone

H1kinase

phosph

orylationindu

ction

ND

Type

1ph

osph

ataseinhibitio

nJA

PN

(Tosujiet

al.,20

03)

CEL-III/sea

cucumber

Proteine

Erythrocyte

hemolysis

ND

Crystal

structuresuggests

lectin

domain3invo

lved

inpore

form

ation

JAPN

(Uchidaet

al.,20

04)

Clio

nasterol

(124)/spon

geSterolf

Com

plem

entcompo

nent

C1inhibitio

n4.1μM

Undetermined

THAI,

NETH,PORT

(Cerqueira

etal.,2003)

Cucum

arioside

A2-2

(125)/seacucumber

Triterpeneglycosidef

Increased[Ca2

+]iand

lysosomal

activ

ityin

mou

semacrophages

ND

Undetermined

RUS

(Agafonova

etal.,2003)

Cym

opol

(126

)and

avrainvilleol

(127

)/alga

Merom

onoterpene

f /polyketg

Antioxidant

4.0–

6.1μM

Undetermined

USA

(Takam

atsu

etal.,2003)

Dictyoceratida

diterpenoids

(128

–13

0)/spo

nge

Diterpenef

DNA

polymeraseBlyase

activ

ityinhibitio

n20

.6–26

μg/m

LUndetermined

USA

(Chaturvedulaet

al.,2004)

Furano-

andarom

atic

terpenoids

(131–13

3)/spo

nge

Terpenes

fCDC25

phosph

ataseinhibitio

n0.4–

4μM

Undetermined

ITA,FRA,S

PA,

TUR,U

SA

(Erdog

an-O

rhan

etal.,20

04)

Halistano

lsulfate(134)/sponge

Sterolf

P2Y

12pu

rinergic

receptor

inhibitio

n0.48

μMUndetermined

USA

(Yanget

al.,2003a)

Lam

ellarinG

andI

(135,13

6)/ascidian

Alkaloids

eFreeradicalscavenging

activ

ity2.96–3.28

mM

Undetermined

IND

(Krishnaiahet

al.,2004)


Table3(contin

ued)

Com

pound/organism

aChemistry

Pharm

acological

activ

ityIC

50b

MMOAc

Cou

ntry

dReferences

Lysophosphatid

ylcholine

(137)/spon

gePolyketideg

IncreasedCa2

+mob

ilizatio

nin

HL-60cells

ND

Undetermined

S.KOR

(Lee

etal.,2004)

(+)-Subersicacid

(138)/sponge

Meroterpene

fMAPKAPkinase

2inhibitio

n9.6–

20μM

Undetermined

CAN,INDO,

NETH,U

SA

(Williamset

al.,2004b)

MeridianinE(139)/ascidian

Alkaloids

eCellproliferationandapoptosis

inhibitio

n0.18–0.6μM

Cyclin

B,p

25,protein

kinase

AandG

inhibitio

nARG,F

RA

(Gom

pelet

al.,20

04)

Penasulfate

A(140

)/spon

geAminoacid/

polyketid

egα-glucosidase

inhibitio

n3.5μg

/LUndetermined

JAPN,N

ETH

(Nakao

etal.,2004b)

Pregnanes

1and2

(141–14

2)/coral

Steroidsf

Mito

chon

drialrespiratory

chaininhibitio

n1.1–

1.9μM

Undetermined

ITA,IN

D(Ciavatta

etal.,2004)

Psammocinia

sp.diterpenes

(143–14

7)/spo

nge

Terpenef

Hum

an15

-lipox

ygenase

inhibitio

n0.3–

0.8μM

Reductio

nof

lipoxyg

enase

non-hemeferric

center

USA

(Cichewiczet

al.,2004)

Pun

agland

ins(148

–15

2)/coral

Polyketideg

Cytotoxicity

andapoptosis

0.04–0.37

μMP53

accumulationand

ubiquitin

isop

eptid

ase

activ

ityin

vivo

andin

vitro

USA

(Verbitski

etal.,20

04)

SchulzeienesA–C

(153–15

5)/spong

eAlkaloide/

polyketid

eα-glucosidase

inhibitio

n0.048–

0.1μM

Undetermined

JAPN,N

ETH

(Takadaet

al.,2004)

Sinu

lariaandLobop

hytum

sp.steroids(156

–15

9)/

softcoral

Glycosidicsteroidf

5α-reductase

inhibitio

nND

Undetermined

IND,MEX

(Radhika

etal.,2004)

Sipho

nodictyalC(160

)/spon

geMerosesqu

iterpenee

CDK4/cyclin

D1inhibitio

n9μg

/mL

Undetermined

NZEL,S

WI,

USA

(Mukku

etal.,20

03)

Spirastrello

lideA

(161)/sponge

Polyketideg

Protein

phosph

atase2A

inhibitio

n0.001μM

Undetermined

CAN,U

SA

(Williamset

al.,2004a)

Spon

giasesquiterpenoid

(162)/spon

geMerosesqu

iterpenef

DNA

polymeraseBlyase

activ

ityinhibitio

n16

.2μg

/mL

Undetermined

USA

(Cao

etal.,2004)

Strobilin-felix

inin

(163,16

4)/spo

nge

Sesterterpene

fAntioxidant

andradical

scavenger

ND

Sup

erox

idescavenging

inhibitio

nandH2O2indu

ced

DNA

strand

scission

protectio

n

CHI,S.KOR

(Jiang

etal.,20

04)

Sulfatobastadins1and2

(165,16

6)/spong

eBromotyrosine

peptides

eInhibitio

nof

ryanod

ine

bind

ing

13–29

μMUndetermined

USA

(Masunoet

al.,2004)

hPolysaccharide.

aOrganism,Kingdom

Animalia:ascidians(Phylum

Chordata),corals(Phylum

Cnidaria),seacucumber(Phylum

Echinodermata),sponge

(Phylum

Porifera);Kingdom

Plantae:alga.

bIC

50,ND:notdeterm

ined.

cMMOA:molecular

mechanism

ofactio

n.dCountry:A

RG:A

rgentin

a;CAN:C

anada;CHI:China;F

RA:F

rance;GER:G

ermany;

IND:Ind

ia;INDO:Ind

onesia;ITA

:Italy;JAPN:Japan;M

EX:M

exico;

NETH:T

heNetherlands;N

ZEL:N

ewZealand;P

OR:

Portugal;RUS:Russia;

S.KOR:South

Korea;SLO:Slovenia;

SPA

:Spain;THAI:Thailand

;TUR:Turkey;

UK:UnitedKingd

om.

eNitrogen-containingcompound.

fTerpene.

gPolyketide.



3.1. Anti-inflammatory compounds

The anti-inflammatory pharmacology of the marine com-pounds astaxanthin, bolinaquinone, cacospongionolide B,clathriol B, conicamin, cycloamphilectene 2, elisabethadione,plakohypaphorine, pourewic acid A, methylpourewate B,cadlinolide C, petrocortyne A, petrosaspongiolides M-R,pseudopterosin N, pseudopterosin R, and seco-pseudopterosinE was reported during 2003–4, a large increase from ourprevious reports (Mayer and Lehmann, 2000; Mayer andHamann, 2002, 2004, 2005).

NH

O

N

acylaspermidine D (113)

NH

N

NNH

H2N

Br

Br

ageladine A (115) AcO

OAc OAc

H H

H

O

ag

N

N

N

n = 19-29 or 99

polyalkylpyridinium (poly-APS) (118)

O

SO

O

O

NNH

O

OMeOH

N

NN

N

NH2

unnamed nucleoside derivative (121)

HO2C

OSO

Fig. 3

Ohgami et al. (2003) reported the effect of astaxanthin (68), acarotenoid found in crustacean cells, salmon and sea stars onlipopolysaccharide-induced uveitis in rats both in vitro and invivo. The investigators observed that astaxanthin, at 100 mg/kg,suppressed development of uveitis and was as potent as 10 mg/kgprednisolone. The mechanism of action determined for astax-anthin probably involved inhibition of nitric oxide, prostaglandinE2 and TNF-α generation. Lucas et al. (2003b) described adetailed mechanistic study on the modulatory effect of bolina-quinone (69), a sesquiterpenoid isolated from a Dysidea sp.sponge, in several models of acute and chronic inflammation. The

N

N

O

NN

acylaspermidine E (114)

H

H

OH

osterol C (116)

N Cl

n = 29, 99

alkylpyridinium (117)

HO

OHH

arenarol (119)

HO

OHH

isoarenarol (120)

3Na

callysponginol sulfate A (122)

.

calyculin A (123)

MeO NH

O

NMe2

OH

OH

O

N

O

O

OMeOH

H2O3PO

OH

CNHO

H

H

H

clionasterol (124)

OO

O

O

O

O

O

OH

OH

O

O

OH

OHOH

O

OH

O

OH

O

HO

OH

OMe

OH

OH

MeOSO3cucumarioside A2-2 (125)

OH

Br

OH

cymopol (126)

Br

OH

OH

OH

OH

Br

avrainvilleol (127)

O

unnamed diterpenoid (128)

O

CO2R

unnamed nor-bisditerpenoids(129) R = H

(130) R = Me

OH

O

H

furospinosulin-1 (131)4 R1

R2

4-OH-3-tetraprenylphenylacetic acid (132) R1 = OH, R2 = CH2CO2H4-OAc-3-tetraprenyl benzoic acetate (133) R1 = OAc, R2 = CO2H

O3SO

O3SO

OSO3H

H

H

H

halistanol sulfate (134)



observation that bolinaquinone significantly inhibited cytokine,iNOS expression and eicosanoid (LTB4, PGE2) generationin vitro and in vivo in several models of inflammation throughsecretory PLA2 inhibition led the authors to propose thatbolinaquinone is a marine compound of “potential interest inthe search for new anti-inflammatory agents”. Posadas et al.(2003a) extended the cellular and molecular pharmacology of thesesterterpene cacospongionolide B (70) isolated from theMediterranean sponge Fasciospongia cavernosa, and previouslyshown to be an inhibitor of secretory phospholipase A2. In mouse

peritoneal macrophages in vitro, as well as in an in vivomodel ofinflammation, cacospongionolide B decreased nitric oxide,prostaglandin E2 and TNF-α generation as well as thecorresponding gene expression. At the molecular level, cacos-pongionolide B inhibited nuclear factor-κ-DNA binding activityand enhanced IκB-α expression. Keyzers et al. (2003) contributeda novel anti-inflammatory sterol, clathriol B (71) from the NewZealand sponge Clathria lissosclera. Clathriol B was shown tomoderately inhibit production of superoxide anion from agonist-stimulated human peripheral blood neutrophils. A novel indole

O

N

HO O

MeO

OMe

R3

135 R1 = OMe, R2 = H, R3 = OH136 R1 = H, R2 = OMe, R3 = OMe

lamellarin G (135)lamellarin I (136)

R1

R2OMe MeO

O

O

OMeOH

P

O

O

ON

compound D (137)

HO

CO2H

H

(+)-subersic acid (138)

NH

N

N

H2N

OH

Br

meridianin E (139)

N

CO2Me

O4

OSO3Na

OSO3Na

penasulfate A (140)

HH

OOAc

H

unnamed pregnane (141)

H

O

AcO

unnamed pregnane (142)

HO

CO2H

H

jaspic acid (143)

HO

OHjaspaquinol (144)

O

HO

chromarol A (145)



alkaloid histamine antagonist, conicamin (72), was isolated fromthe Mediterranean tunicate Aplidium conicum (Aiello et al.,2003). Ex vivo studies with guinea pig ileum demonstrated aconcentration-dependent reduction of histamine-induced contrac-tions, probably by a non-competitive mechanism. Lucas et al.(2003a) examined the effects of a series of 6 new cycloamphi-lectenes isolated from the Vanuatu sponge Axinella sp. on murinemacrophage and human neutrophil functions. All compoundstested reduced nitric oxide (NO) production in the submicromolarrange. Interestingly, cycloamphilectene 2 (73), which reducedNOproduction and elastase release without affecting TNF-α release,inhibited the nuclear factor-κB pathway and also exhibited in vivoactivity. One novel iododinated plakohypaphorine (74) with

antihistamine activity was isolated from the Caribbean spongePlakortis simplex (Borrelli et al., 2004). The authors noted thatthe antihistamine activity appeared to be “connected to thenumber and nature of the halogen atoms”, because replacement ofthe iodine atom by chlorine resulted in a loss of the antihistamineproperty of this compound. Three novel diterpenes, namelypourewic acid A (75), methylpourewate B (76) and cadlinolide C(77), were purified from the New Zealand sponge Chelonaply-silla violacea (Keyzers et al., 2004). The three diterpenesmoderately inhibited production of the inflammatory superoxideanion from human peripheral blood neutrophils stimulated withphorbol myristate acetate or N-formyl-methionine-leucine-phenylalanine. Hong et al. (2003) investigated the anti-

chromarol D (146)

O

HO OH

HO2C

4-hydroxy-3-tetraprenylbenzoic acid (147)

O

HO

CO2Me

OAc

OAc

OH

punaglandin 3 (149)

O

HO

CO2Me

AcO

OAc

OAc

OH

punaglandin 2 (148)

O

HO

CO2Me

OAc

OAc

OH

punaglandin 4 (150)

O

HO

OH

Z-punaglandin 4 (151)

AcO

OAc

O

HO

CO2Me

OAc

OAc

OH

punaglandin 6 (152)

N O

NH

O

OSO3Na

R

OSO3Na

NaO3SO

OH

HO

schulzeine A (153) R = Meschulzeine C (155) R = H

N O

NH

O

OSO3Na

OSO3Na

NaO3SO

OH

HO

schulzeine B (154)

OH

RO

O OH

HO HOPR-01 (156) R = OHPR-02 (157) R = H



inflammatory properties of petrocortyne A (78), a C46 poly-acetylenic alcohol isolated from the marine sponge Petrosia sp.Petrocortyne A inhibited release of both TNF-α (IC50=2.35 μM)and nitric oxide from macrophages and induced homotypicaggregation of U937 human leukemic monocytes, a process thatappears to involve phosphorylation of several intracellularsignaling molecules. The molecular pharmacology of petrosas-pongiolide M (79) was characterized by Posadas et al. (2003b),who determined that this marine sesterterpenoid inhibitedproduction of nitrite, prostaglandin E2 and TNF-α both in vitro

and in vivowhile concomitantly inhibiting NF-κB signaling. Theauthors' results suggested that petrosaspongiolide M had“potentially (a) wide therapeutic spectrum” in inflammatoryconditions. Monti et al. (2004) extended the molecular pharma-cology of the marine anti-inflammatory petrosaspongiolides M-R(79–83), bioactive sesterterpenes isolated from themarine spongePetrosaspongia nigra. The irreversible inhibition of bee-venomphospholipase A2 (PLA2) was investigated by mass spectrometryand molecular modelling approaches and demonstrated thatpetrosaspongiolides N, O, P and R shared the same inhibition

R1HOOH

OH

PR-03 (158) R1 = OH, R2 = H PR-04 (159) R1 = H, R2 = OH

R2

NaO3SO

CHO

OSO3Na

OSO3Na

siphonodictyial (160)

O

O

O

O

OHO

O O OH

HO

HO OMe

Cl

OMeHO2C

OH

spirastrellolide A (161)

O

O OH

MeO

ilimaquinone (162)

O

O

OH

O(8E,13Z,20Z)-strobillinin (163)

O

O

OH

O

(7E,13Z,20Z)-strobillinin (164)

BrHN

O

NOH

Br

OHO

BrBr

NOH

NH

OHO

Br

O

bastadin-5 (165)HNBr

NaO3SOO

N

Br

OH

OH

1-O-sulfatohemibastadin-1(166)



mechanism and covalent binding site already reported for petro-saspongiolide M. Ata et al. (2003) reported two new diterpenespseudopterosin N (84) and seco-pseudopterosin E (85) and thehydroxyquinone elisabethadione (86) from the marine gorgonianP. elisabethaewith in vivo anti-inflammatory activity. Interestinglyall three compounds inhibited edema (inflammation) in a mouseear anti-inflammatory assay more potently than “the wellcharacterized pseudopterosins A and E”. With the purpose ofcontributing to the search of novel agents to treat neuroinflamma-tion, several novel diterpene glycoside pseudopterosins and seco-

pseudopterosins from the Caribbean sea whip P. elisabethae wereevaluated in an in vitro anti-neuroinflammatory assay (Rodríguezet al., 2004). Pseudopterosin R (87) was observed to be the mostpromising compound because it significantly inhibited thegeneration of thromboxane B2 (IC50=4.7 μM) from activatedrat brain macrophages. Although the molecular mechanism ofaction of pseudopterosin R remains currently undetermined, theauthors concluded that it “could become an anti-inflammatory leadcompound” for anti-neuroinflammatory drug design if itsinhibitory effect on thromboxane B2 release was further enhanced.


3.2. Cardiovascular compounds

Trevisi et al. (2004) reported novel studies on the mecha-nism of action of callipeltin A (88), a previously describedcyclic depsidecapeptide isolated from the marine spongesCallipelta sp. and Latrunculia sp. In contrast to the lack ofeffect on guinea pig aortic ring contractions, callipeltin Aaffected resting aorta contraction in a concentration-dependentmanner (IC50=0.44 μM) by a mechanism that caused anincrease in sodium influx, a phenomenon the authors describe as a“Na+-ionophore action”. Thus callipeltin A's cardiovascular effectsare probably caused by “its capacity of mediating Na+ transport”.

3.3. Compounds affecting the immune system

With the purpose of contributing to the discovery of smallmolecule agonists and antagonists of chemokine receptors, Yanget al. (2003d), reported a new sesterterpene sulfircin (89) purifiedfrom the marine sponge Ircinia sp. that inhibited the CCR7chemokine receptor, a receptor involved in the regulation ofTcells and dendritic cell mobilization into lymphoid organs. Anti-adhesive mucin-type glycoproteins were characterized from themucus secretions of starfishMarthasterias glacialis and Poraniapulvillus, and the brittlestarOphiocomina nigra (Bavington et al.,2004). The investigators observed that partially purified mucusglycoproteins from all three species were not cytotoxic andinhibited neutrophil adhesion in a dose-dependent manner, thussuggesting that by blocking adhesion of leukocytes these mucinsmight be of therapeutic value to treat inflammatory disorders.Yamada et al. (2004) contributed a new series of eremophilanesesquiterpenoids, peribysins A–D (90–93), isolated from a strainof Periconia byssoides, a fungus previously isolated from the seahare Aplysia kurodai. Although the molecular mechanismof action of the four peribysins currently remains undeter-mined, inhibition of the adhesion of HL-60 cells to HUVEC(IC50=0.1–2.7 μM), was significantly more potent than thatobserved with the control agent herbimycin A (IC50=38 μM). A1,3 β glucan, named phycarine, chemically indistinguishablefrom the known polysaccharide laminarin, was isolated from thealga Laminaria digitata (Vetvicka and Yvin, 2004). A detailedpharmacological investigation revealed that phycarine stimulatedphagocytic activity in peritoneal macrophages and potentiated thesynthesis and release of interleukin-1, 6 and tumor necrosis factorα. Interestingly, phycarine increased NK cell-mediated killing oftumor cells both in vitro and in vivo by interacting with theCD11b/CD18 receptor (the complement receptor type 3 receptor).Three studies were reported on the pharmacology of a sulfatedpolymannuroguluronate (SPMG) (94) a polysaccharide with anaverage molecular weight of 8.0 kDa isolated from brown algae,which recently entered Phase II clinical trial in China as the firstanti-AIDS drug candidate. While SPMG was initially reported tobind to 28 amino acids located in the HIV viral glycoproteingp120 V3 loop (Meiyu et al., 2003), more recently, SPMG wasshown by flow cytometry and fluorescent microscopy analysis tobind to lymphocyte CD4 receptors, a receptor type known tointeract with the HIV virus gp120 envelope glycoprotein, afinding that might contribute to additional mechanistic ex-

planations for the clinical efficacy of SPMG in HIV-infectedpatients (Miao et al., 2004). Two previous studies by the sameresearch group noted that SPMG upregulated endothelialintercellular adhesion molecule-1 expression in human umbil-ical vein endothelial cells (Meiyu et al., 2003; Wang et al.,2003b).

3.4. Compounds affecting the nervous system

Reports on both central and autonomic nervous systempharmacology of marine natural products during 2003–4 studiesinvolved aplidine, aspermytin A, cribronic acid, dysibetaines,esmodil, jamaicamides, labuanine A, linckosides C–E, acidicoligosaccharide sugar chain, parguerol and isoparguerol,petrosaspongiolide M, sargaquinoic acid, SJG-2 ganglioside,δ-conotoxin, ω-conopeptide MVIIA and χ-conopeptide MrIA.

Perez et al. (2003) investigated the inhibitory effect of theproline-containing cyclic peptide aplidine (95), isolated fromthe tunicate Aplidium albican, on the in vitro aggregation ofpeptide PrP 106–126, a fraction of the prion protein which hasbeen hypothesized to be involved in fatal neurodegenerativediseases and which can kill neuronal cells in culture. The factthat aplidine was observed to be a strong inhibitor of theaggregation of PrP 106–126 into β-sheet fibrils at a 1:1 molarratio prompted these investigators to propose that it may be “aleading compound for drug development efforts”.

Induction of neurite outgrowth in vitro was reported for themarine natural compounds aspermytin A, labuanine A, lincko-sides C–E, parguerol and isoparguerol, ganglioside species SJG-2 and sargaquinoic acid. Tsukamoto et al. (2004a) isolated a newpolyketide, aspermytin A (96) from a cultured marine fungus,Aspergillus sp. that induced neurite outgrowth at 50 μM inmore than 50% of rat pheochromocytoma (PC-12) cells after twodays of in vitro treatment, an effect comparable to that of 50 ng/mL of nerve growth factor. Aoki et al. (2003) purified a novelpyridoacridine alkaloid labuanine A (97) from the Indonesianmarine sponge Biemna fortis that induced multipolar typeneurite outgrowth in Neuro 2 A neuroblastoma cells (1–3 μM)by a putative mechanism that “may relate with inhibition oftopoisomerase II”, a hypothesis currently under investigation.Qi et al. (2004) contributed three new bioactive steroidglycosides linckosides C–E (98–100) from the Okinawanmarine sea star Linckia laevigata, which potently inducedneurite outgrowth in rat PC-12 cells, as well as synergisticallyenhanced the neuritogenic activity of nerve growth factor, achemical that has been shown to be essential for neuronaloutgrowth, survival, function maintenance and prevention ofaging in the central and peripheral nervous system. Bioassay-guided fractionation lead to the isolation of parguerol (101) andisoparguerol (102) from the sea hare A. kurodai (Tsukamotoet al., 2004b). Both compounds, the first neurotrophic com-pounds reported from sea hare metabolites, stimulated neuriteoutgrowth in PC-12 cells treated with either 25 or 50 μg/mL ofthe compounds for two days. Further pharmacological researchwill be required to determine the molecular mechanism leadingto morphological changes in PC-12 cells. Two studies werereported on the pharmacology of the low molecular weight


quinonic compound sargaquinoic acid (103) isolated from themarine brown alga Sargassum macrocarpum, and previouslynoted to possess a novel nerve growth factor-dependent neuriteoutgrowth promoting activity at the nanogram range. Kamei andTsang (2003) investigated the signaling pathways involvedusing a pharmacological approach and concluded that sargaqui-noic acid enhanced neurite outgrowth in PC-12 neuronal cells byinvolving both TrkA-mitogen-activated protein kinase andadenylate cyclase-protein kinase A signal transduction path-ways. In a subsequent study, the neuroprotective effect ofsargaquinoic acid was shown to be independent of nerve growthfactor and phosphatidylinositol 3 kinase, a key signalingmolecule(Tsang and Kamei, 2004). Kaneko et al. (2003) reported thestructure of a novel ganglioside SJG-2 (104) isolated from the seacucumber Stichopus japonicus which appears to be the “firstganglioside containing either the branched sugar chain moiety orthe N-acetylgalactosamine residue”. While SJG-2 only displayedneuritogenic activity in the presence of nerve growth factor, it wasmore potent than the GM1 mammalian ganglioside.

Four marine compounds (105–108; Fig. 2) were shown totarget receptors present in the nervous system. Sakai et al. (2003)contributed to the search for novel ionotropic glutamate receptorligands by reporting the isolation of the novel amino acid cribronicacid (105) from the marine sponge Cribrochalina olemda.Cribronic acid-induced potent convulsive behavior in mice uponintracerebroventricular injection (ED50=29±3 pmol/mouse), aswell as inhibited binding of anN-methyl-D-aspartic acid (NMDA)receptor ligand (IC50=83±15 nM). In 2004, Sakai et al. (2004)isolated two novel cyclopropane amino acids dysibetaine CPa(106) and dysibetaine CPb (107) from the marine spongeDysideaherbacea collected in Micronesia, that showed weak affinitytoward the NMDA-type and the kainic acid-type ionotropicglutamate receptors in a radioligand binding assay. Theinvestigators concluded that the binding of these compounds tothe glutamate receptor was of interest because they both lacked “aglutamate equivalent structure in the molecules”. A screeningprogram for bioactive compounds from marine cyanobacteria ledto the isolation of the novel lipopeptides jamaicamide A (108), Band C (Edwards et al., 2004), compounds that exhibited sodiumchannel blocking activity at 5 μM, producing about half theresponse of saxitoxin applied at 0.15 μM.

During 2003–4, additional marine compounds (109–112;Fig. 2) were reported to exhibit pharmacological effects on thenervous system. Bioassay-guided fractionation of the marinesponge Raspailia sp. yielded the known synthetic compoundesmodil (109), reported in the patent literature in 1935 (Caponet al., 2004a). More than six decades ago, esmodil, anacetylcholine mimic, was shown to be potentially “useful intreating retention of urine in humans and as influencing theparasympathetic nervous system in cats, rabbits and the Indianbuffalo”. Hu et al. (2004) reported interactions of an acidicoligosaccharide sugar chain (AOSC) from the brown algaEchlonia kurome with the amyloid beta protein. AOSC wasobserved to inhibit the toxicity induced by amyloid beta proteinin both rat cortical cells as well as human neuroblastoma cells bya mechanism that involved inhibition of apoptosis, reduction ofintracellular Ca2+ and the generation of reactive oxygen species

(ROS). Thus the authors concluded that AOSC “might be apotentially therapeutic compound for Alzheimer's disease”.Capasso et al. (2003) reported that petrosaspongiolide M (79)reduced morphine withdrawal in an in vitromodel. Although themechanism underlying petrosaspongiolide M-induced inhibi-tion of morphine withdrawal remains undetermined, onepossibility raised by the investigators was the putative inhibitionof extracellular type II phospholipase A2 by this potent anti-inflammatory marine sesterterpene.

Extensive research on the preclinical and clinical pharma-cology of conotoxin molecules resulted in the syntheticequivalent of ω-conopeptide MVIIA (110), a 25-amino acidpolybasic peptide derived from the marine snail Conus magus,receiving approval from the Food and Drug Administration onDecember 23, 2004. Currently, Ziconotide (Prialt®), which ismarketed by Elan Biopharmaceuticals, Inc., constitutes the thirddrug in the U.S. Pharmacopeia which has been derived frommarine chemicals. Staats et al. (2004) reported a double-blind,placebo-controlled, randomized trial conducted from 1996–1998 in 32 study centers in the United States, Australia and theNetherlands which assessed the safety and efficacy of intrathecalziconotide. Ziconotide selectively binds to the N-type voltage-sensitive calcium channels located in neurons thereby blockingneurotransmission and resulting in significant analgesia. In thisclinical study, intrathecal ziconotide provided clinically andstatistically significant analgesia in 111 patients with pain fromcancer or AIDS. As part of a program to explore the diversity ofconotoxins produced by Conus marine snails found off theIndian coast, Sudarslal et al. (2003) reported the isolation andcharacterization of a novel 26 peptide δ-conotoxin (111) isolatedand purified from the venom of the marine snail Conus amadis,collected in the Bay of Bengal. The observation that this novelδ-conotoxin inhibited the inactivation of sodium current incloned rat brain IIA α-subunit channels led the investigators toconclude that “conotoxins from some molluscivorous snailsmay also be active on mammalian Na+ channels”. Sharpe et al.(2003) extended the molecular pharmacology ofχ-conopeptideMrIA (112), a 13-residue peptide isolated form the venom of themarine snail Conus marmoreus. The investigators reported thatthe χ-conopeptide MrIA inhibited the norepinephrine trans-porter by a non-competitive mechanism that possibly involve abinding site “predicted to be distinct from the substrate bindingsite but to share some commonality with the antidepressantbinding site”.

4. Marine compounds with miscellaneous mechanisms ofaction

Table 3 lists marine compounds with miscellaneous pharma-cological mechanisms of action, with their respective structurespresented in Fig. 3. Interestingly, and in contrast with the 109chemicals included in Tables 1 and 2, this third group of 54marine compounds which was isolated from a variety of marineorganisms, includes not only nitrogen-containing compounds(i.e. proteins, peptides), but also terpenes and polyketides.

As shown in Table 3, for a limited number of these marinenatural products, namely acylspermidine D and E (113, 114),


ageladine A (115), alkylpyridiniums (117, 118), Atriolumrobustum nucleoside (121), calyculin A (123), Cell-III, meridia-nin E (139), Psammocinia sp. diterpenes (143–147), punaglan-dins (148–152) and strobilin-felixinins (163, 164), both thepharmacological activity and a molecular mechanism ofaction have been investigated and reported. In contrast, forall the other compounds shown in Table 3, although apharmacological activity was reported, no additional infor-mation was available on the molecular mechanism of actionof these chemicals during 2003–2004.

5. Reviews on marine pharmacology

Specific areas of marine pharmacology research benefitedfrom a number of excellent reviews published during 2003–4:(a) general marine pharmacology: natural products as sourcesof new drugs over the period 1981–2002 (Newman et al., 2003);marine natural products from marine invertebrates and sponge-associated fungi (Proksch et al., 2003a,b); the biopotential ofmarine sponges from China oceans (Zhang et al., 2003); marinenatural products as therapeutic agents (patents): part 2 (Frenzet al., 2004); natural product diversity of New Caledonia: apharmacologically oriented view (Laurent and Pietra, 2004);(b) antimicrobial marine pharmacology: genomic screening toidentify novel marine antimicrobial peptides (Patrzykat andDouglas, 2003); marine natural products as anti-infective agents(Donia and Hamann, 2003); mining marine microorganisms as asource of new antimicrobials and antifungals (Bernan et al.,2004); antimicrobial peptides from marine invertebrates (Tincuand Taylor, 2004); bioactive peptides from marine sources:pharmacological properties and isolation procedures (Aneirosand Garateix, 2004); (c) anticoagulant marine pharmacology:recent advances in marine algal anticoagulants (Matsubara,2004); the use of algae and invertebrate sulfated fucans asanticoagulant and antithrombotic agents (Mourao, 2004);(d) antituberculosis, antimalarial and antifungal marinepharmacology: antimycobacterial natural products (Copp,2003); naturally occurring peroxides from marine spongeswith antimalarial and antifungal activities (Jung et al., 2003);antifungal compounds frommarine organisms (Molinski, 2004);(e) antiviral marine pharmacology: algae as a potential sourceof antiviral agents (Luescher-Mattli, 2003); marine naturalproducts as lead anti-HIV agents (Gochfeld et al., 2003); anti-HIV activity from marine organisms (Tziveleka et al., 2003);proteoglycans from sponges as tools to develop new agents forAIDS and Alzheimer's disease (Fernandez-Busquets andBurger, 2003); antiviral marine natural products (Gustafsonet al., 2004); (f) anti-inflammatory marine pharmacology: anti-inflammatory metabolites from marine sponges (Keyzersand Davies-Coleman, 2005); (g) nervous system marinepharmacology: conotoxins as Drug-leads for neuropathic painand other neurological conditions (Alonso et al., 2003);conotoxins and structural biology: a prospective paradigm fordrug discovery (Grant et al., 2004); drugs from the sea:conopeptides as potential therapeutics (Livett et al., 2004);ziconotide: neuronal calcium channel blocker for treating severechronic pain (Miljanich, 2004).

6. Conclusion

During 2003–4, and for the first time in many decades, amarine natural product, namely ziconotide (Prialt®) (110)was approved for patient care by the U.S. Food and DrugAdministration for the management of severe chronic pain inpatients for whom intrathecal therapy is necessary, and whoappear to be intolerant of or refractory to other treatments, such assystemic analgesics, adjunctive therapies or intrathecal morphine.Although research into the non-antitumor and cytotoxic pharma-cology of marine natural products remained concentrated in thespecific areas we have highlighted in our present review, thiscontribution together with our previous ones (Mayer andLehmann, 2000; Mayer and Hamann, 2002, 2004, 2005),demonstrates that marine pharmacology research continued toproceed at a very active pace in 2003–4, involving natural productchemists and pharmacologists from 28 foreign countries andthe United States. Thus, if the rate of preclinical and clinicalpharmacological research continues to be sustained over time,additional marine natural products will probably becomeavailable as novel therapeutic agents to treat multiple diseasecategories.

Acknowledgements

This publication was made possible by grant number 1R15ES012654, from the National Institute of Environmental HealthSciences, NIH, to AMSM, and 1R01A136596, from theNational Institute of Allergy and Infectious Diseases, NIH,and the Medicines for Malaria Venture (MMV), to MTH. Itscontent is solely the responsibility of the authors and does notnecessarily represent the official views of the NIEHS, NIH.Additional financial support by Midwestern University isgratefully acknowledged. Jennifer Allman is acknowledgedfor her assistance with the preparation of Fig. 1 (MTH). Theexcellent support for literature searches in PubMed, Marinlit,Current Contents® and Chemical Abstracts®, as well as articleretrieval by library staff members as well as medical andpharmacy students of Midwestern University is most gratefullyacknowledged. The authors specially thank Ms. Mary Hall forcarefully reviewing this manuscript.

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Marine pharmacology in 2003 4: Marine compounds...

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