sign in sign up
<<
Home , Anthelmintic, Antillatoxin, Manoalide

Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

Review Marine in 1999: compounds with antibacterial, , , , anti-inflammatory, antiplatelet, and antiviral activities affecting the cardiovascular, endocrine, immune and nervous systems, and other miscellaneous mechanisms of action

Alejandro M.S. Mayera, *, Mark T. Hamannb

aDepartment of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USA bSchool of Pharmacy, The University of Mississippi, Faser Hall University, MS 38677, USA

Received 28 November 2001; received in revised form 30 May 2002; accepted 31 May 2002

Abstract

This review, a sequel to the 1998 review, classifies 63 peer-reviewed articles on the basis of the reported preclinical pharmacological properties of marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria. In all, 21 marine chemicals demonstrated anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis or antiviral activities. An additional 23 compounds had significant effects on the cardiovascular, sympathomimetic or the , as well as possessed anti-inflammatory, immunosuppressant or fibrinolytic effects. Finally, 22 marine compounds were reported to act on a variety of molecular targets, and thus could potentially contribute to several pharmacological classes. Thus, during 1999 pharmacological research with marine chemicals continued to contribute potentially novel chemical leads in the ongoing global search for therapeutic agents for the treatment of multiple disease categories. ᮊ 2002 Elsevier Science Inc. All rights reserved.

Keywords: Marine; Pharmacology; 1999; Toxicology; Review; Secondary metabolites

1. Introduction with our 1998 review, only those articles reporting on the bioactivity andyor pharmacology of marine The purpose of this article is to review the 1999 chemicals for which structures have been estab- primary literature on pharmacological and toxico- lished are included in the present review. We have logical studies with marine natural products using used the chemical classification of Schmitz et al. a similar format to that used in our 1998 review (1999) to assign each marine compound to a major (Mayer and Lehmann, 2000). The 1999 review chemical class, namely , terpenes, corresponding to marine-derived compounds with nitrogen-containing compounds or polysacchar- antitumor and cytotoxic activity has recently been ides. Those publications reporting on anthelmintic, ( ) published Mayer and Lehmann, 2001 . Consistent antibacterial, anticoagulant, antifungal, antimalari- al, antiplatelet, antituberculosis or antiviral prop- *Corresponding author. Tel.: q1-630-515-6951; fax: q1- 630-971-6414. erties of marine chemicals are tabulated in Table E-mail address: [email protected] (A.M. Mayer). 1 and the corresponding structures are shown in

1532-0456/02/$- see front matter ᮊ 2002 Elsevier Science Inc. All rights reserved. PII: S1532-0456Ž 02. 00094-7 316 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

Fig. 1. The articles reporting on marine compounds A–D, a family of new cyclic decapeptides isolated affecting the cardiovascular, sympathomimetic and from a tropical marine bacterium, exhibited in nervous systems, as well as those with anti-inflam- vitro activity against methicillin- matory, immunosuppressant and fibrinolytic resistant Staphylococcus aureus, vancomycin-resis- effects, are grouped in Table 2 and the structures tant enterococci and penicillin-resistant presented in Fig. 2.. Finally, marine compounds Streptococcus pneumoniae (Gerard et al., 1999). targeting a number of distinct cellular and molec- Although the molecular mechanism of action was ular targets and mechanisms are shown in Table 3 not fully investigated, the authors suggested that and their structures are presented in Fig. 3. their findings were an important contribution to Although publications on the biological andyor the current search for novel needed in the pharmacological activity of marine extracts or as treatment of -resistant strains of human yet structurally uncharacterized marine compounds bacterial pathogens. Two isoforms of a cysteine- have not been included in the present review, rich antibacterial peptide myticin, isolated from several interesting reports appeared during 1999 hemocytes and plasma of the mussel Mytilus gal- (Berge et al., 1999; Cancre et al., 1999; Choi et loprovincialis, were characterized (Mitta et al., al., 1999; Christophersen et al., 1999; Conquer et 1999). Although myticins A and B had marked al., 1999; Fabregas et al., 1999; Horikawa et al., activity against the Gram-positive strains Micro- 1999; Matsuda et al., 1999; Siddhanta et al., 1999). coccus luteus, Bacillus megaterium and Enterococ- cus viridans, other Gram-positive, Gram-negative 2. Marine compounds with anthelmintic, anti- bacteria and fungi were unaffected. Kim et al. bacterial, anticoagulant, antifungal, antimalari- (1999) reported that psammaplin A, a bromotyro- al, antiplatelet, antituberculosis and antiviral sine derivative from the sponge Psammaplysilla activities sp. possessed antibacterial activity against methi- cillin-resistant Gram-positive Staphylococcus Table 1 summarizes 21 publications that report- aureus that was ‘‘«almost comparable to cipro- ed on preclinical anthelmintic, antibacterial, anti- floxacin«’’, a quinolone antibiotic currently used coagulant, antifungal, antimalarial, antiplatelet, in the US. Furthermore, extensive mechanism-of- antituberculosis, and antiviral pharmacology of the action studies completed by these investigators 21 marine compounds shown in Fig. 1. determined that psammaplin A did not bind to Two studies published during 1999 with the penicillin-binding proteins, but did inhibit DNA marine natural products amphilactams A–S and synthesis of S. aureus SG511 in a dose-dependent ( s ) geodin A contributed to anthelmintic pharmacolo- manner IC50 2.83 mgyml , and inhibited the gy. Four novel amphilactams, macrocyclic lactoney supercoiling activity of DNA gyrase, similar to the lactams isolated from the sponge Amphimedon spp. quinolones, although less efficiently than cipro- ( ) showed in vitro LD99 activity in the range 0.30– floxacin Kim et al., 1999 . 7.5 mgyml (Ovenden et al., 1999). These investi- A detailed investigation on the anticoagulant gators noted that the level of in vitro activity for pharmacology of algal and echinoderm marine amphilactams A, C and D was comparable to that sulfated furans and sulfated polysaccharides was of existing commercial , such as lev- reported during 1999. Pereira et al. (1999) inves- amisole and closantel, but the mechanism of action tigated the possible correlation between structure of these compounds was not determined. A new and anticoagulant activity of echinoderm-derived macrocyclic lactam tetramic acid, geo- and brown algae-derived fucans, noting that, while din A Mg salt, was isolated from the sponge the highly branched sulfated fucans from brown Geodia sp. (Capon et al., 1999). Although the algae directly inhibited thrombin, the linear fucans mechanism of action of the pure Geodin A was from echinoderms required the presence of antith- not explored, this marine compound, which occurs rombin or heparin cofactor II for inhibition of naturally as the Mg salt, was nematocidal to the thrombin, a molecular mechanism also observed ( s ( LD99 1 mgy with mammalian glycosaminoglycans Pereira et ml). al., 1999). These investigators support the use of Studies with loloatins A–D, myticin and psam- structural analysis of sulfated polysaccharides from maplin A contributed to the antibacterial pharma- algae and echinoderms and their testing on specific cology of marine natural products. The loloatins biological assays as an important biochemical A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 317

Fig. 1. Marine pharmacology in 1999: compounds with anthelmintic, antibacterial, anticoagulant, antifungal, antiplatelet, antimalarial, antituberculosis and antiviral activities. 318 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

Fig. 1. (Continued). approach to investigate molecular mechanisms of wminimum inhibitory concentration (MIC) 0.8–1.5 anticoagulant activity in mammalian systems. mgymlx. Oceanapiside, a new glycosidicyamino Five studies with the marine chemicals bengam- lipid from the sponge Oceanapia philli- ide and bengazole derivatives, oceanapiside, spon- pensis, demonstrated antifungal activity against the gistatin 1, tanikolide, and theopederins F–J fluconazole-resistant yeast Candida glabrata (MIC resulted in novel contributions to antifungal phar- 10 mgyml)(Nicholas et al., 1999). Although macology. Six new bengazole derivatives and a additional mechanism-of-action studies remain to new bengamide L were reported from the sponge be completed with oceanapiside, these investiga- Pachastrissa sp. (Fernandez et al., 1999). tors noted that the aglycon exerted higher antifun- Although no mechanism-of-action studies were gal activity than the glycoside, possibly due to completed, the bengazole derivatives were better cell penetration. In perhaps the most note- observed to be active against Candida albicans worthy study with a marine broad-spectrum anti- A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 319

Fig. 1. (Continued). 320 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

Fig. 1. (Continued). A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 321

Fig. 1. (Continued). fungal compound, Ovechkina et al. (1999) from the sponge Hyrtios erecta. This appears to demonstrated potent microtubule-severing activity be an interesting observation because, if confirmed with spongistatin 1, a macrocyclic lactone isolated in future studies, the mechanism of action of 322 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

During 1999, three separate studies were report- ed in the area of antimalarial, antiplatelet and antituberculosis pharmacology of structurally char- acterized marine natural products. Although no mechanism-of-action studies were reported, the sesquiterpene 15-a-methoxypuupehenol isolated from the New Caledonian marine sponge Hyrtios sp. demonstrated antimalarial activity against chlo- roquine-susceptible and chloroquine-resistant ( s strains of Plasmodium falciparum IC50 0.4–1.4 mgyml)(Bourguet-Kondracki et al., 1999). Detailed studies on the mechanism of activation by the polyether , a Ca2q channel-activating marine causing ciguatera poisoning, were completed by Nakahata et al. (1999a). These researchers observed that the mechanism of action of maitotoxin was similar to

U46619, a thromboxane A2 receptor agonist. How- ever, the effects of maitotoxin on Ca2q mobiliza- tion, phosphoinositide hydrolysis and tyrosine phosphorylation in were strictly depend- ent on the presence of external Ca2q , an observa- tion that could explain maitotoxin toxicity to platelets in vivo. In a bioactivity study with several polyhalogenated monoterpenes isolated from the tropical marine red alga Plocamium hamatum, Konig et al. (1999) observed that one of them was antitubercular towards Mycobacterium tuberculosis (MIC 32 mgyml) and Mycobacterium avium (MIC 64 mgyml). Interest in the antiviral pharmacology of marine natural products remained high during 1999, as evidenced by the seven papers published, a number Fig. 1. (Continued). similar to that reported in our 1998 review (Mayer and Lehmann, 2000). During the screening of Spongistatin 1 would significantly differ from all diverse marine natural products for compounds other antimicrotubule agents studied to date. A against human immunodeficiency virus (HIV-1) new brine-shrimp toxic and antifungal lactone, integrase, one of the three enzymes encoded by tanikolide, was isolated from the marine cyanobac- the HIV virus, Reddy et al. (1999b) identified the terium Lyngbia majuscula (Singh et al., 1999). alkaloid lamellarin a 20-sulfate in an unidentified Although the researchers observed a 13-mm-diam- ascidian that showed selective in vitro inhibition. eter zone of inhibition (100 mgydisk) when testing The detailed mechanistic studies completed with the effect of tanikolide on the fungus Candida lamellarin a 20-sulfate led these investigators to albicans, further mechanistic research is necessary propose that their findings provided a new class to determine if the toxicity of this compound might of lead compounds for the potential development perhaps be responsible for the antifungal activity of clinically useful integrase inhibitors. Novel observed. Tsukamoto et al. (1999) isolated five cyclic depsipeptides papuamides A, B, C and D new bioactive metabolites, theopederins F–J, from were isolated from the sponges Theonella mirabilis the sponge Theonella swinhoei. Although theoped- and Theonella swinhoei (Ford et al., 1999). Pap- erin F was particularly effective against Sacchar- uamides A and B inhibited the of human ( s omyces cerevisiae at 1 mgydisk, no mechanistic T-lymphoblastoid cells by HIV-1 in vitro EC50 studies were reported. 3.6 ngyml), a particularly interesting finding, A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 323

Fig. 2. Marine pharmacology in 1999: compounds with anti-inflammatory, immunosuppressant and fibrinolytic effects and affecting the cardiovascular, simpathomimetic and nervous systems. because this is the first report of peptides from the not studied. An extensive report detailed new sponge Theonella that inhibit HIV. However, the mechanism-of-action studies with polycitone A, an mechanism of action of papuamides A and B was aromatic alkaloid isolated from the ascidian Polyc- 324 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

Fig. 2. (Continued). A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 325

Fig. 3. Marine pharmacology in 1999: compounds with miscellaneous mechanisms of action. 326 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

Fig. 3. (Continued). A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 327

Fig. 3. (Continued). itor sp., that is a potent inhibitor of the reverse polymerases (Loya et al., 1999). Although it transcriptase of HIV and both C and B retroviruses, appears that, because polycitone A is a general as well as a general inhibitor of cellular DNA inhibitor of DNA polymerases it cannot serve as 328 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

Fig. 3. (Continued). an anti-HIV , structural modifications of poly- marine clam Meretrix petechialis and examined its citone A could lead towards the rational design of anti-HIV activity in an in vitro assay. The sulfated new derivatives with anti-HIV reverse transcriptase galactan inhibited CD4q HeLa cells from forming activity. The synthesis of sulfated derivatives of a syncytia, an observation that was interpreted as glycosaminoglycan isolated from the marine bac- probably the result of a ‘‘«direct interaction of terium Pseudomonas sp. and their testing against the polysaccharide with the HIV binding site at two strains of influenza virus types A and B were the membrane protein receptor CD4’’. Comin et described by Ahmad et al. (1999). The authors al. (1999) evaluated natural disulfated polyhydrox- noted that introduction of the sulfate groups into ysteroids isolated from the Antarctic ophiuroid the polysaccharides containing L-glutamic acid Astrotoma agassizii against three pathogenic resulted in antiviral activity against influenza virus human viruses, namely herpes simplex type 2 type A, but not against type B, and that this (HSV-2), Junin (JV) and polio type 3 (PV-3) activity was similar to that of ribavirin, an antiviral viruses. The investigators concluded that the ster- drug that is clinically used in the US to treat oids with sulfate groups at C-21 and C-2 or C-3 influenza A . Amornrut et al. (1999) were very effective against HSV-2, PV-3 and JV. isolated a novel sulfated b-galactan from the Sansalvamide A, a cyclic depsipeptide isolated A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 329

Table 1 Marine pharmacology in 1999: compounds with anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis and antiviral activities

Drug class Compound Organisma Chemistry Pharmacological activity MMOAb Countryc References

Anthelmintic Amphilactams Sponge Macrolided H. contortus inhibition Undetermined AUS Ovenden et al., 1999 Anthelmintic Geodin A Sponge Macrolided H. contortus inhibition Undetermined AUS Capon et al., 1999 Antibacterial Loloatins A–D Bacterium Cyclic peptidef S. aureus, S. pneumoniae Undetermined CAN Gerard et al., 1999 and enterococci inhibition Antibacterial Myticin Mussel Peptidey M. luteus, B. megaterium, Undetermined FRA Mitta et al., 1999 proteinsf E. viridans inhibition Antibacterial Psammaplin A Sponge Tyrosine-basedf S. aureus inhibition DNA gyrase and S. KOR Kim et al., 1999 synthesis inhibition Anticoagulant Sulfated fucans Alga and Sulfated Thrombin Inhibition direct or with BRA, UK Pereira et al., 1999 cucumber polysaccharideg inhibition antithrombin or heparin cofactor II Antifungal Bengazole, bengamide Sponge Polyketided C. albicans inhibition Undetermined FRA Fernandez et al., 1999 Antifungal Oceanapiside Sponge Polyketided C. glabrata inhibition Undetermined USA Nicholas et al., 1999 Antifungal Spongistatin I Sponge Macrolided A. nidulans inhibition Induces microtuble USA Ovechkina et al., 1999 fragmentation Antifungal Tanikolide Bacterium Fatty acidd C. albicans inhibition Undetermined USA Singh et al., 1999 Antifungal Theopederins F–J Sponge Polyketided S. cerevisiae inhibition Undetermined JPN Tsukamoto et al., 1999 Antimalarial 15-a-Methoxy- Sponge Sesquiterpenee P. falciparum inhibition Undetermined FRA Bourguet-Kondracki et al., 1999 puupehenol Antiplatelet Maitotoxin Alga Polyketided Platelet activation Highly dependent on JPN Nakahata et al., 1999a external Ca2q Antituberculosis Monoterpenes Alga Terpenee M. tuberculosis inhibition Undetermined GER, SWZ Konig et al., 1999 Antiviral Lamellarin a-20- Tunicate Tyrosine-basedf In vitro HIV infection HIV integrase IND, USA Reddy et al., 1999b sulfate inhibition inhibition Antiviral Papuamides A–D Sponge Depsipeptidef In vitro HIV Undetermined CAN, USA Ford et al., 1999 infection inhibition Antiviral Polycitone A Tunicate Tyrosine-basedf In vitro anti-RT DNA polymerase ISR Loya et al., 1999 inhibition inhibition Antiviral Glycosaminoglycan Bacterium Sulfated In vitro anti- Only influenza A virus JPN Ahmad et al., 1999 polysaccharideg influenza A and B inhibition inhibition Antiviral Sulfated b-galactan Clam Sulfated In vitro syncitia Inhibition of HIV S. KOR, Amornrut et al., 1999 polysaccharideg formation inhibition binding to CD4 JPN, USA Antiviral Poly-hydroxysteroids Brittle star Sterole In vitro reduction Sulfate at C-21, C-2 ARG Comin et al., 1999 of HSV-2, JV, PV and C-3 critical for plaque formation inhibition Antiviral Sansalvamide Fungus Depsipeptidef Molluscum DNA binding and USA Hwang et al., 1999 contagiosum virus relaxation inhibition topoisomerase inhibition

a Organism: kingdom Animalia: brittle star and cucumber (Echinodermata); clam and mussel (Mollusca); sponge (Porifera); tunicate (Chordata); kingdom Fungi: fungus; kingdom Plantae: alga; kingdom Monera: bacterium (). b MMOA: molecular mechanism of action. c Country: ARG, Argentina; AUS, Australia; BRA, Brazil; CAN, Canada; FRA, France; GER, Germany; IND, India; ISR, Israel; JPN, Japan; S. KOR, South Korea; SWZ, Switzerland; UK, United Kingdom. d Polyketide. e Terpene. f Nitrogen-containing compound. g Polysaccharide. from the marine fungus Fusarium sp., inhibited larly significant study, because it determined that the topoisomerase of the pathogenic poxvirus Mol- sansalvamide A inhibited MCV topoisomerase by luscum contagiosum (MCV)(Hwang et al., 1999), inhibition of topoisomerase-catalyzed DNA relax- an important finding, because MCV may cause ation, DNA-binding and covalent complex forma- severe lesions in AIDS patients. This is a particu- tion. This finding represents the first identification 330 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

Table 2 Marine pharmacology in 1999: compounds with anti-inflammatory, immunosuppressant and fibrinolytic effects and affecting the cardiovascular, nervous and sympathomimetic systems

Drug class Compound Organisma Chemistry Pharmacological activity MMOAb Countryc References

Anti-inflammatory Africanene Coral Sesquiterpenee In vivo rat paw edema Undetermined IND Reddy et al., 1999a inhibition e Anti-inflammatory Cacospongiolide B Sponge Sesterterpene In vivo and in vitro Human sPLA2 ITAL, SPA Pastor et al., 1999 inflammation assays inhibition e Anti-inflammatory Palinurin, palinurines A, B Sponge Sesterterpene In vitro modulation of Thromboxane B2 USA, NZ El Sayed et al., 1999 activated rat brain microglia inhibition Anti-inflammatory Plakotenin Sponge Polyketided Synovial fibroblast Undetermined USA Qureshi et al., 1999 proliferation inhibition Cardiovascular Equinatoxin Anemone Proteinf Cardiotoxic LDH release SLOV Bunc et al., 1999 Cardiovascular Halenaquinol Sponge Polyketided Cardioactivity at the Naqq , K and Ca2q RUS Gorshkova et al., 1999a cellular level ATPase inhibition Cardiovascular Seal oil Seal Fatty acidsd Reduced cardiovascular Rise in serum EPA CAN Conquer et al., 1999 disease in humans and DHA Fibrinolytic C. latum protease Alga Proteinf Fibrinolysis of human Specificity for Arg JPN Matsubara et al., 1999 fibrinogen and Lys residues Immuno- Simplexides Sponge Fatty acid Lymph node cell Undetermined ITA Costantino et al., 1999 suppressant metabolitesd proliferation inhibition Nervous system 3-Alkyl-pyridinium Sponge Pyridinesf Acetylcholinesterase Aggregation and SLOV, FRA Sepcic et al., 1999 inhibition multisite binding Nervous system Ciguatoxin-1 Dinoflagellate Polyketided Differential action on Naq Modulation of Naq AUS Strachan et al., 1999 channel subtypes gating Nervous system Conantokin-G, T Snail Peptidef Neuronal NMDA-receptor Current inhibition USA Klein et al., 1999 inhibition Nervous system CcTX Snail Peptidef Axon and motor nerve Naq channel FRA Le Gall et al., 1999 terminals activation Nervous system k-Conotoxin-PVIIA Snail Peptidef Kq channel inactivation Competitive lysine MEX, AUS Garcia et al., 1999 interaction Nervous system Curacin-A, antillatoxin, Bacterium Polyketidey Cytotoxicity to rat NMDA-mediated USA Berman et al., 1999 peptidef cerebellar granule cells toxicity Nervous system Psolusosides A, B Sea Triterpene Naqq ,K -ATPase Irreversible, with RUS Gorshkova et al., 1999b cucumber glycosidese inhibition affinity Nervous system Glycosphingolipids Seastar Glycosideg Neuritogenic to rat Undetermined JPN Kawatake et al., 1999 pheochromocytoma f Sympathomimetic S1319 Sponge Tyrosine-based Potent relaxation of b2-selective JPN Suzuki et al., 1999 guinea pig tracheal adrenoreceptor muscle agonist

a Organism: kingdom Animalia: coral (Cnidaria); snail (Mollusca); sponge (Porifera); seastar and sea cucumber (Echinodermata); seal (Chordata); kingdom Plantae: dino- flagellate and alga; kingdom Monera: bacterium (Cyanobacteria). b MMOA: molecular mechanism of action. c Country: AUS, Australia; CAN, Canada; FRA, France; IND, India; ITA, Italy; JPN, Japan; NZ, New Zealand; MEX, Mexico; RUS, Russia; SLOV, Slovenia; SPA, Spain. d Polyketide. e Terpene. f Nitrogen-containing compound. g Polysaccharide. of a new inhibitor against Molluscum contagiosum in Fig. 2, affecting the cardiovascular, immune and topoisomerase in vitro. nervous systems, as well as possessing anti-inflam- matory, immunosuppressant, lipid-lowering and 3. Marine compounds with anti-inflammatory, sympathomimetic effects. immunosuppressant and fibrinolytic effects, and The anti-inflammatory pharmacology of marine affecting the cardiovascular, nervous and sym- natural products during 1999 involved studies with pathomimetic systems africanene, cacospongiolide B, palinurin, palinuri- Table 2 lists the preclinical pharmacological ne A and B, and plakotenin, an increase of one research completed on 23 marine chemicals shown compound compared to 1998 (Mayer and Leh- A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 331 mann, 2000). Reddy et al. (1999a) conducted an of arthritic cells with the carboxylic acid homo- extensive bioactivity screen with the sesquiterpene plakotenin, as well as the known compound plak- africanene, isolated from the soft coral Sinularia otenin derived from the palauan sponge Plakortis leptoclados, that included an investigation of its lita. Although both compounds inhibited the ability anti-inflammatory activity. In acute inflammation of rheumatoid synovial fibroblasts to proliferate in studies utilizing the carrageenan-induced rat edema response to platelet-derived growth factor at con- assay, an oral in vivo dose of 10 mgykg body centrations of 1 mgyml, they were unable to inhibit weight of africanene resulted in a more potent proliferation at 0.1 mgyml, suggesting that the reduction of paw volume than that produced by compounds are active over a limited range of 100 mgykg body weight of , strongly concentrations. suggesting that africanene may be worthy of fur- Immunosuppresant activity was reported for the ther anti-inflammatory characterization studies. novel glycolipids simplexides, isolated from the Pastor et al. (1999) extended the pharmacology of sponge Plakortis simplex (Costantino et al., 1999). cacospongionolide B, a novel sesterterpene inhib- Simplexides showed a 43% inhibitory effect on itor of human synovial phospholipase A2 isolated lymph node cell proliferation at 10 ngyml. Inter- from the sponge Fasciospongia cavernosa, study- estingly, this immunosuppressive activity that was ing its mechanism of action in several assays for not related to cytotoxicity is probably attributable both in vitro (secretory and cytosolic phospholi- to its sugar head, and very probably involves an pase A24 , leukotriene B , cyclooxygenase I and II, interaction with ‘‘«glycoproteins involved in the nitric oxide) and in vivo inflammation (rat air immune mechanism’’. pouch, mouse ear edema, mouse paw edema and Cardiovascular pharmacology of marine natural mouse air pouch). Their results indicated that products during 1999 involved studies with equin- cacospongionolide B irreversibly inhibited both atoxin, halenaquinol and seal oil. Bunc et al. ( ) secretory PLA2 in vitro and group II secretory 1999 studied the mechanism of cardiotoxicity of PLA2 in vivo. Perhaps the fact that cacospongion- equinatoxin II, a toxic basic protein isolated from olide B was bioavailable by the oral route and had the sea anemone Actinia equina (L.). The inves- an effect on cytokine generation suggests that tigators observed that equinatoxin II was very further research on this marine compound may potent, because in the nanomolar range it had clear lead to a novel anti-inflammatory agent. El Sayed dose-dependent, direct cardiotoxic effects, but, et al. (1999) used microbial transformation of because it also caused lactate dehydrogenase palinurin, a linear furanosesterterpene isolated release, it appeared that cytotoxicity probably from the marine sponge Ircinia echinata to pro- played an important part in the toxin’s cardiotoxic duce two novel metabolites, palinurine A and B effects. Gorshkova et al. (1999a) extended the (El Sayed et al., 1999). The effect of these three pharmacology of halenaquinol, a natural penta- ( ) compounds on thromboxane B22TXB and super- cyclic hydroquinone isolated from the sponge ( y) oxide anion O2 release from activated rat neo- Petrosia seriata with previously known cardiotonic natal microglia was investigated because these action. Halenaquinol inhibited membrane transport potentially neurotoxic mediators appear to be enzymes, such as rat brain Naqq , K -ATPase and involved in neuroinflammatory conditions (Mayer rabbit muscle sarcoplasmic reticulum Ca2q -ATP- et al., 1999). The investigators noted that, while ase, enzymatic systems involved in muscle con- ( s ) palinurin inhibited TXB250IC 0.21 mM and traction regulation. Furthermore, structure–activity y ( s ) O250IC 5 mM generation, palinurine A and B relationship studies with halenaquinol determined were relatively ineffective inhibitors of both that the inhibition of Naqq , K -ATPase observed y TXB22 and O , thus suggesting that the furan ring was dependent on the presence of a naphthohydro- appears to be required for the pharmacological quinone fragment in the molecule. Conquer et al. activity of palinurin observed. Furthermore, the (1999) completed a 6-week double-blind trial with authors suggested that palinurin, by becoming a 19 healthy male subjects on the effects of seal oil, ‘‘«lead compound for development as an anti- which contains omega-3 fatty acids, on cardiovas- inflammatory ’’, could contribute to the cular disease risk factors. A marked increase in current search for novel drugs to treat neuroinflam- both eicosapentanoic acid and docosahexaenoic matory conditions (Mayer, 1998). Qureshi et al. acid levels in serum phospholipid and non-esteri- (1999) investigated the inhibition of proliferation fied fatty acids was observed, an interesting finding 332 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 in view of the fact that both docosahexaenoic acid using the whole-cell patch-clamp technique. The and non-esterified fatty acids possess antiplatelet researchers observed that both non-compet- aggregatory and antiarrhythmic effects. Further- itively inhibited NMDA-evoked currents, a fact more, the authors noted that seal oil had a slight that is of importance because NMDA receptors beneficial effect on fibrinogen and protein C levels, play a critical role in a number of physiological and thus proposed that seal oil supplementation processes in the central nervous system, as well as may influence the balance between plasma procoa- in neuropathological states, such as stroke, chronic gulant and anticoagulant activity in healthy vol- pain, Parkinson’s disease and amyotrophic lateral unteers in the direction of reduced cardiovascular sclerosis. Conotoxin CcTX, a new 30-amino-acid disease (Conquer et al., 1999). peptide was isolated from the Indo-Pacific fish- Reports on nervous system pharmacology of hunting marine snail Conus consors (Le Gall et marine natural products increased slightly over al., 1999). The investigators demonstrated that 1998 (Mayer and Lehmann, 2000), with the 1999 CcTX showed particular selectivity to axons and studies involving 10 marine compounds, namely motor nerve terminals, because it activated neuron- 3-alkyl-pyridinium, antillatoxin, ciguatoxin-1, con- al voltage-gated sodium channels and produced antokin-G and -T, conotoxin CcTX, k-conotoxin, Naq entry into nerve terminals and axons without curacin-A, kalkitoxin and psolusosides A and B. directly affecting fibers. Interest- Sepcic et al. (1999) investigated the mechanism ingly, because conotoxin CcTX has an unusual of inhibition of the water-soluble cholinesterase sequence compared with previously reported clas- inhibitors 3-alkylpyridinium polymers isolated ses of , it defines a novel family of from the marine sponge Reniera sarai. The conotoxins. Garcia et al. (1999) extended the investigators’ extensive work determined that the pharmacology of the marine snail Conus purpur- apparently non-specific mechanism of acetylcho- ascens k-conotoxin-PVIIA (k-PVIIA), a 27-resi- linesterase inhibition was strong and irreversible, due peptide venom component that inhibits and was not due to conformational changes of the voltage-gated K channels. While studying the protein andyor its unfolding, but rather the result mechanism by which this peptide inhibited K of multisite binding between the two molecules, channels expressed in Xenopus oocytes Garcia et resulting in aggregation. Strachan et al. (1999) al. (1999) determined that there was a ‘‘«purely completed an extensive pharmacological investi- competitive interaction«’’ with ‘‘«a positively gation of the effect of ciguatoxin-1, an abundant charged side chain, possibly a lysine, interacting and potent cyclic polyether ciguatoxin isolated electrostatically with Kq ions from the intracellular from the marine dinoflagellate Gambierdiscus tox- side of the channel’’. Interestingly, the investiga- icus, on subtypes in rat dorsal- tors noted a putative convergence between k- root ganglion sensory neurons using whole-cell PVIIA and evolutionary distant scorpion toxins of patch-clamp techniques. The investigators the a-KTx family towards a common mechanism observed that ciguatoxin-1 acted in a ‘‘«differ- of action on K channels. ential manner on the two types of sodium channel Berman et al. (1999) reported on the nervous subtypes found in rat dorsal root ganglion neu- system pharmacology of curacin-A, the lipopeptide rons’’, and therefore would appear to modulate antillatoxin and the thiazoline-containing lipid sodium channel gating, thus providing a possible kalkitoxin, compounds isolated from the pantropi- explanation for the enhanced degree of neuronal cal marine cyanobacterium Lyngbia majuscula. excitation and disturbance in nerve conduction During studies designed to determine the neuro- observed in ciguatera patients. toxic activity of these compounds in primary Three studies extended the toxicology of the cultures of rat cerebellar granule cells, curacin-A conotoxins, a family of small peptide toxins was non-toxic, while under similar experimental derived from the venom of marine snails of the conditions both antillatoxin and kalkitoxin pro- genus Conus that have been shown to bind to duced concentration-dependent cytotoxicity ( s excitable tissue (Olivera, 1997). Klein et al. LC50 20.1"6.4 and 3.86"1.91 nM, respective- (1999) evaluated the effect of the marine cone ly), although clearly involving ‘‘«distinct tem- snail toxins conantokin-G and -T on N-methyl-D- poral patterns’’. Additional mechanism-of-action aspartate (NMDA) ionotropic glutamate receptors studies determined that the neurotoxicity induced in mouse primary hippocampal neuronal cultures by both toxins appeared to involve ionotropic A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 333 glutamate receptor-dependent excitotoxic mecha- activity has been investigated so far. Finally, nisms, probably mediated by N-methyl-D-aspartate although adociasulfates 1–6, iantheran A, lyso- receptor blockage. Gorshkova et al. (1999b) PAF analogues and octa- and nonaprenylhydroqui- extended the pharmacology of psolusosides A none sulfates have been explored at the molecular (PsA) and B (PsB), two membranolytic triterpene level, no pharmacological activity has been clearly glycosides isolated from the holothurian Psolus identified at this time. Hopefully, ongoing studies fabricii that form a complex with membrane sterols with these compounds will permit their assignment as well as ‘‘«solitary ion channels and large to a particular therapeutic class in the near future. aqueous pores’’. As part of their effort to charac- terize the membranotropic properties of these com- 5. Reviews on marine pharmacology pounds, they determined that both PsA and PsB differed in their inhibiting action on rat brain During 1999, several reviews covering selected Naqq ,K -ATPase, ‘‘«possibly irreversible’’ and aspects of marine pharmacology were published: probably explained by their chemical structure and the patent literature (Kerr and Kerr, 1999); the particular affinity to membrane cholesterol. Kawa- literature of marine natural product chemistry for take et al. (1999) isolated a glycosphingolipid 1997 (Faulkner, 1999); the biochemistry and bio- from the starfish Luidia maculata that appears medical applications of giant keyhole limpet hemo- ( ) similar to the mammalian ganglioside GM3 . Inter- cyanin Harris and Markl, 1999 ; sea anemone estingly, in rat pheochromocytoma PC-12 cells toxins as templates for new immunosuppressant treated with 10 mgyml of this active glycoside, drugs (Kem et al., 1999); the pharmacology of neurite outgrowth was induced. polyketides from dinoflagellates (Rein and Borro- A novel benzothiazole-2-one (S319) sympatho- ne, 1999); the biochemistry and pharmacology of mimetic agent was isolated from the marine sponge the anti-inflammatory phospholipase A2 inhibitor Dysidea sp. (Suzuki et al., 1999). While investi- manoalide (Soriente et al., 1999); and the current gating its tracheal-relaxing activity, the investiga- state of knowledge of actin-binding marine natural tors determined that this compound was more products (Spector et al., 1999). potent than isoproterenol. Because its pharmaco- Kerr and Kerr (1999) reviewed the patent liter- logical effect appeared to be mediated through b2- ature in the field of marine natural products cov- adrenoceptors, the authors suggested that this ering the period 1996–April 1999, noting that the compound might become a clinically useful and majority of the patents focused on antitumor potent (Suzuki et al., 1999). agents, although some covered antiviral and anti- inflammatory activities. Phylum Porifera was the 4. Marine compounds with miscellaneous mech- source of the majority of metabolites described in anisms of action the patents. In an extensive review, Faulkner (1999) dis- Table 3 lists 22 marine compounds with miscel- cussed some 749 novel marine compounds report- laneous mechanisms of action in Fig. 3. Interest- ed during 1997 and derived from organisms ingly, and in contrast to the chemicals included in belonging to four kingdoms, namely Animalia Tables 1 and 2, this third group of marine com- (Echinodermata, Cnidaria, Porifera, Mollusca, pounds includes nitrogen-containing compounds Chordata), Fungi, Plantae (Chlorophyta, Phaeo- (i.e. proteins, peptides, pyridines, tyrosine-based phyta, Rhodophyta) and Monera (Cyanobateria), metabolites), terpenes and polyketides, but not some of which possessed interesting ‘‘« biologi- polysaccharides. cal and pharmacological properties’’. For some of these marine chemicals, namely 1999 saw the completion of an extensive review alkylpyridinium polymers, caulerpenyne, CEL-1, of the biochemistry, structure and cellular immu- CEL-2, equistatin, eucheuma isolectins, maitotox- nology of keyhole limpet hemocyanin (KLH) in, obelin, palytoxin, Ptilota serrata lectin, sinu- (Harris and Markl, 1999), a copper-containing lamide, tridentatols and xestoquinone, both the respiratory protein isolated from the marine gastro- pharmacological activity and a molecular mecha- pod Megathura crenulata. Although the review nism of action have been investigated. For the provides extensive information on the use of KLH anabaenopeptins G and H, kelletinin A, roselipin for tumor , as a pharmaceutical and stypoquinonic acid, only the pharmacological carrier for and antigens and as a tool for 334 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 References c Country JPNJPN Hatakeyama et al., 1999 Oda et al., 1999 JPN, ITA Malaguti et al., 1999 JPN Ichida et al., 1999 2 q q 2 2 b ERK2 activation y q q q 2 2 2 1,3-Fucosyl transferase JPN, AUS Wakimoto et al., 1999 a MMOA inhibition Blocked by gangliosides JPNDependent on extra- Konoki et al., 1999 UK, JPN Woods et al., 1999 inhibition domains determined Hydra q q 2 2 selective cation channelin megakaryocytes and derivatives Pharmacological activity Cytolytic to bovineCarboxypeptidase APancreatic lipase 5.8-nminhibition pores inHemolysis Undetermined of rabbitHemolysis of rabbit Competitive inhibitionCysteine proteinase and Cacathepsin D -dependent inhibition binding Ca of enzyme Hemagglutination SLO Inhibitory -dependent activity binding of JPN first,Undetermined second JPN and third promoter in Malovrh Lectins etUndetermined with al., affinity 1999 for Itou et Bitou al., SLO 1999 et al., 1999 erythrocyte Na,K-ATPase ghosts inhibitioncell death JPN Cholesterol Lenarcic biosynthesis and Turk,hydrolysis 1999 JPNhepatocytesBioluminescence-based Kawakubo et al.,immunoassay 1999 S. for KORsmall peptides Competition ERK1 Okamoto with et obelin- al., 1999 cellular Ca Shin et al., 1999 cellularInduction Ca of octapeptide non- fusion protein USAHemagglutination Sensitivity to oubain, NiCl Matveev et al., 1999 Activity dependent on UK, BRA Sampaio et al., 1999 e d d d d d d d d e f f f f f f f f d,e polyketide polyketide polyketide polyketide polyketide Chemistry triterpene a cucumbercucumber erythrocytes erythrocytes to carbohydrates to carbohydrates Alga Protein Alga Protein Organism nonaprenyl Sponge Prenylated Undetermined y CEL-IIIEquistatin Sea Anemone Protein Protein Ptilota serrata hydroquinonesulfates hydroquinone sulfate VII inhibition Alkylpyridinium Sponge Pyridine polymerAnabaenopeptinsG and HCaulerpenyne BacteriumCEL-1 Peptide Alga Sea Sesquiterpene isolectinsIantheran AKelletinin A Protein Lyso-PAFanalogues Maitotoxin Sponge Mollusc erythrocytesMaitotoxin inhibition Sponge Polyketide Maitotoxin Complex Alga Polyketide Alga membranes Differentiation Alga ComplexOcta Complex Complex and mitogenesis Ca Undetermined increase in Cytotoxicity andlectin PhosphoinositideRoselipins mannose glycans Ca -dependent ITA Dependent on extra- Fungus De Polyketide Petrocellis et al., 1999 JPN Diacylglycerol Nakahata et al., 1999b Undetermined inhibition assays divalent cations JPN Tomoda et al., 1999 Eucheuma Table 3 Marine pharmacology in 1999: compounds with miscellaneousCompound mechanisms of action Adociasulfates 1–6 Sponge Sulfated Undetermined Kinesin motor protein USA BlackburnMaitotoxin et al., 1999 Obelin AlgaPalytoxin Cnidaria Complex Protein Coral Ca increase in single Macrolide A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 335 . ; kingdom Fungi: fungus; References ) Porifera c ( Country ; sponge ) Echinodermata ( b ; sea cucumber ) MMOA of LDL Mollusca ( ; mollusc ) q Cnidaria . 2 ( ) Pharmacological activity acyltransferase inhibition Cytotoxic to murineleukemia cells inhibition Antioxidant H,K-ATPase inhibitionsarcoplasmic reticulumCa release JPN sulfhydryl groups Inhibition of lipid peroxidation USA Sata et al., 1999 Johnson et al., 1999 f d d Cyanobacteria e d ( polyketide polyketide glycoside Chemistry a Organism (Continued) MMOA: molecular mechanism of action. Polyketide. Organisms: kingdom Animalia: anemones, corals and hydroids Country: AUS, Australia; BRA, Brazil; GER, Germany; ITA,Terpene. Italy; JPN, Japan; S. KOR, South Korea; SLO, Slovenia; SWZ, Switzerland; UK, United Kingdom Nitrogen-containing compound. a b c d e f SinulamideStypoquinonic acidTridentatols Alga Coral Hydroid Complex Diterpene Tyrosine-based Tyrosine kinase Undetermined GER Wessels et al., 1999 Xestoquinone Sponge Complex Induction of Modification of JPN Ito et al., 1999 Table 3 Compound kingdom Plantae: alga; kingdom Monera: bacterium 336 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 the investigation of immune competence in both includes more than 100 peer-reviewed articles, it animal and human health, the authors suggest that appears to be the most comprehensive to date on a number of critically important questions currently manoalide chemistry and pharmacology. remain to be addressed by the suppliers of KLH Spector et al. (1999) described the current state for both experimental and clinical use. of knowledge of actin-targeted marine natural Kem et al. (1999) reviewed a novel class of sea products. In recent years, these investigators have anemone K channel toxins as a potential template identified several marine chemicals, namely the for the design of novel immunosuppressant drugs. latrunculins, jasplakinolides, swinholide A, mis- The article is quite thought-provoking, because it akinolide A, halichondramides and pectenotoxin focuses upon a relatively novel immunosuppres- II, that bind to actin. The use of these chemicals sant strategy that is based on the inhibition of K to study fenestrae formation in liver endothelial channels to control T-lymphocyte proliferation. cells provides an example of the ‘‘«new insights The authors propose that the use of novel immu- into specific aspects of actin-mediated cellular nosuppressant agents incorporating the anemone processes’’ that can be gained using these actin- toxin pharmacophore could potentially lead to new binding marine natural products. pharmacologic treatments for autoimmune dis- eases, such as multiple sclerosis, type 1 diabetes 6. Conclusion and systemic lupus, as well as therapy for organ transplantation. Although during 1999 no new marine natural In an extensive review on human immunodefi- product was approved for patient care by the US ciency virus reverse-transcriptase inhibitors of nat- Food and Drug Administration, the present report ural origin, these inhibitors were grouped clearly documents the fact that during 1999 pre- according to their source organism, i.e. plant, clinical pharmacological research with marine micro-organism and marine organism (Matthee et chemicals continued to be an extremely active, as al., 1999). The section on marine-derived reverse well as multinational, effort involving collabora- transcriptase (RT) inhibitors describes 20 marine tions between natural product chemists and phar- chemicals, as well as algal extracts showing anti- macologists from more than 18 countries, viral activities. The authors conclude their review including the United States. by suggesting that marine compounds remain a poorly investigated source of HIV-RT inhibitors, Acknowledgments and thus could potentially represent a resource of This publication was made possible with support lead structures. ( ) The biological activities of dinoflagellates poly- from grant number R03 ES10138-01 to A.M.S.M ketides are varied and include cytotoxic, antitumor, from the National Institute of Environmental antibiotic, antifungal, immunosuppressant, and Health Sciences, National Institutes of Health ( ) and Midwestern University, grant numbers neurotoxic activities Rein and Borrone, 1999 .As ( ) to future directions in dinoflagellate polyketide 5R01AI36596 and 5K02AI01502 to MTH from pharmacology, the authors suggest that studies the National Institutes of Allergy and Infectious Diseases. Its contents are solely the responsibility aimed at ‘‘«identifying biosynthetic potential at the genomic level’’ may ultimately allow the of the authors and do not necessarily represent the discovery of novel biosynthetic capability in these official view of the NIEHS, NIH. Excellent support organisms. for extensive bibliographic searches and article The chemistry and pharmacology of manoalide, retrieval by library staff members, medical and a potent and anti-inflammatory sesterter- pharmacy students at Midwestern University is most gratefully acknowledged. The authors wish pene isolated from Luffariella variabili, were com- prehensively reviewed (Soriente et al., 1999). This to specially thank Mrs Victoria Sears for her report emphasizes the chemistry of manoalide and excellent secretarial assistance in the preparation its analogues, structure–activity relationships, of this manuscript. mechanism-of-action studies of manoalide and References related compounds on phospholipase A2 and an extensive discussion of the in vitro and in vitro Ahmad, A.S., Matsuda, M., Shigeta, S., Okutani, K., 1999. pharmacology of manoalide. Because this review Revelation of antiviral activities by artificial sulfation of a A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 337

glycosaminoglycan from a marine Pseudomonas. Mar. Bio- 1999. The biocatalytic transformation of furan to amide in technol. 1, 102–106. the bioactive marine natural product palinurin. J. Org. Chem. Amornrut, C., Toida, T., Imanari, T., et al., 1999. A new 64, 9258–9260. sulfated beta-galactan from clams with anti-HIV activity. Fabregas, J., Garcia, D., Fernandez-Alonso, M., et al., 1999. Carbohydrate Res. 321, 121–127. In vitro inhibition of the replication of haemorrhagic septi- Berge, J.P., Bourgougnon, N., Alban, S., et al., 1999. Antiviral caemia virus (VHSV) and African swine fever virus ( ) and anticoagulant activities of a water-soluble fraction of ASFV by extracts from marine microalgae. Antiviral Res. the marine diatom Haslea ostrearia. Planta Med. 65, 44, 67–73. 604–609. Faulkner, D.J., 1999. Marine natural products. Nat. Prod. Rep. Berman, F.W., Gerwick, W.H., Murray, T.F., 1999. Antillatoxin 16, 155–198. and kalkitoxin, ichthyotoxins from the tropical cyanobacter- Fernandez, R., Dherbomez, M., Letourneux, Y., Nabil, M., ium Lyngbya majuscula, induce distinct temporal patterns Verbist, J.F., Biard, J.F., 1999. Antifungal metabolites from of NMDA receptor-mediated neurotoxicity. Toxicon 37, the marine sponge Pachastrissa sp.: new bengamide and 1645–1648. bengazole derivatives. J. Nat. Prod. 62, 678–680. Bitou, N., Ninomiya, M., Tsujita, T., Okuda, H., 1999. Screen- Ford, P.W., Gustafson, K.R., McKee, T.C., et al., 1999. Pap- uamides A–D, HIV-inhibitory and cytotoxic depsipeptides ing of lipase inhibitors from marine algae. Lipids 34, from the sponges Theonella mirabilis and Theonella swin- 441–445. hoei collected in Papua New Guinea. J. Am. Chem. Soc. Blackburn, C.L., Hopmann, C., Sakowicz, R., Berdelis, M.S., 121, 5899–5909. Goldstein, L.S.B., Faulkner, D.J., 1999. Adociasulfates 1– Garcia, E., Scanlon, M., Naranjo, D., 1999. A marine snail 6, inhibitors of kinesin motor proteins from the sponge ( ) shares with scorpion toxins a convergent mech- Haliclona aka Adocia sp. J. Org. Chem. 64, 5565–5570. anism of blockade on the pore of voltage-gated K channels. Bourguet-Kondracki, M.L., Lacombe, F., Guyot, M., 1999. J. Gen. Physiol. 114, 141–157. Methanol adduct of puupehenone, a biologically active Gerard, J.M., Haden, P., Kelly, M.T., Andersen, R.J., 1999. derivative from the marine sponge Hyrtios species. J. Nat. Loloatins A–D, cyclic decapeptide produced in Prod. 62, 1304–1305. culture by a tropical marine bacterium. J. Nat. Prod. 62, Bunc, M., Drevensek, G., Budihna, M., Suput, D., 1999. 80–85. Effects of equinatoxin II from Actinia equina (L.) on Gorshkova, I.A., Gorshkov, B.A., Fedoreev, S.A., Shestak, isolated rat heart: the role of direct cardiotoxic effects in O.P., Novikov, V.L., Stonik, V.A., 1999a. Inhibition of equinatoxin II lethality. Toxicon 37, 109–123. membrane transport ATPases by halenaquinol, a natural Cancre, I., Van Wormhoudt, A., Le Gal, Y., 1999. Heparin- cardioactive pentacyclic hydroquinone from the sponge binding molecules with growth factor activities in regener- Petrosia seriata. Comp. Biochem. Physiol. 122C, 93–99. ating-tissues of the starfish Asterias rubens. Comp. Gorshkova, I.A., Kalinin, V.I., Gorshkov, B.A., Stonik, V.A., Biochem. Physiol. 123C, 285–292. 1999b. Two different modes of inhibition of the rat brain Capon, R.J., Skene, C., Lacey, E., Gill, J.H., Wadsworth, D., Naqq ,K()-ATPase by triterpene glycosides, psolusosides A Friedel, T., 1999. Geodin A salt: a novel and B from the holothurian Psolus fabricii. Comp. Biochem. nematocide from a southern Australian marine sponge, Physiol. 122C, 101–108. Geodia. J. Nat. Prod. 62, 1256–1259. Harris, J.R., Markl, J., 1999. Keyhole limpet hemocyanin Choi, D.H., Shin, S., Park, I.K., 1999. Characterization of (KLH): a biomedical review. Micron 30, 597–623. antimicrobial agents extracted from Asterina pectinifera. Int. Hatakeyama, T., Kamine, T., Konishi, Y., Kuwahara, H., J. Antimicrob. Agents 11, 65–68. Niidome, T., Aoyagi, H., 1999. Carbohydrate-dependent Christophersen, C., Crescente, O., Frisvad, J.C., et al., 1999. hemolytic activity of the conjugate composed of a C-type Antibacterial activity of marine-derived fungi. Mycopathol- lectin, CEL-I, and an amphiphilic alpha-helical peptide, ( ) ogia 143, 135–138. 4 3 -beta Ala2. Biosci. Biotechnol. Biochem. 63, 1312–1314. Comin, M.J., Maier, M.S., Roccatagliata, A.J., Pujol, C.A., Damonte, E.B., 1999. Evaluation of the antiviral activity of Horikawa, M., Noro, T., Kamei, Y., 1999. In vitro anti- methicillin-resistant Staphylococcus aureus activity found in natural sulfated polyhydroxysteroids and their synthetic extracts of marine algae indigenous to the coastline of derivatives and analogs. Steroids 64, 335–340. Japan. J. Antibiot. (Tokyo) 52, 186–189. Conquer, J.A., Cheryk, L.A., Chan, E., Gentry, P.A., Holub, Hwang, Y., Rowley, D., Rhodes, D., Gertsch, J., Fenical, W., B.J., 1999. Effect of supplementation with dietary seal oil Bushman, F., 1999. Mechanism of inhibition of a poxvirus on selected cardiovascular risk factors and hemostatic vari- topoisomerase by the marine natural product sansalvamide ables in healthy male subjects. Thromb. Res. 96, 239–250. A. Mol. Pharmacol. 55, 1049–1053. Costantino, V., Fattorusso, E., Mangoni, A., et al., 1999. A Ichida, K., Ikeda, M., Goto, K., Ito, K., 1999. Characterization new cytotoxic diterpene with the dolabellane skeleton from of a palytoxin-induced non-selective cation channel in the marine sponge Sigmosceptrella quadrilobata. Eur. J. mouse megakaryocytes. Jpn. J. Pharmacol. 81, 200–208. Org. Chem., 227–230. Ito, M., Hirata, Y., Nakamura, H., Ohizumi, Y., 1999. Xesto- De Petrocellis, L., Orlando, P., Pierobon, P., et al., 1999. quinone, isolated from sea sponge, causes Ca()2q release Kelletinin A, from the marine mollusc Buccinulum corneum, through sulfhydryl modification from skeletal muscle sar- promotes differentiation in Hydra vulgaris. Res. Commun. coplasmic reticulum. J. Pharmacol. Exp. Ther. 291, 976–981. Mol. Pathol. Pharmacol. 103, 17–28. Itou, Y., Suzuki, S., Ishida, K., Murakami, M., 1999. Ana- El Sayed, K.A., Mayer, A.M.S., Kelly, M., Hamann, M.T., baenopeptins G and H, potent carboxypeptidase A inhibitors 338 A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339

from the cyanobacterium Oscillatoria agardhii (NIES-595). Matthee, G., Wright, A.D., Konig, G.M., 1999. HIV reverse Bioorg. Med. Chem. Lett. 9, 1243–1246. transcriptase inhibitors of natural origin. Planta Med. 65, Johnson, M.K., Alexander, K.E., Lindquist, N., Loo, G., 1999. 493–506. Potent antioxidant activity of a dithiocarbamate-related com- Matveev, S.V., Lewis, J.C., Daunert, S., 1999. Genetically pound from a marine hydroid. Biochem. Pharmacol. 58, engineered obelin as a bioluminescent label in an assay for 1313–1319. a peptide. Anal. Biochem. 270, 69–74. Kawakubo, A., Makino, H., Ohnishi, J., Hirohara, H., Hori, Mayer, A.M.S, 1998. Therapeutic implications of microglia K., 1999. Occurrence of highly yielded lectins homologous activation by lipopolysaccharide and reactive oxygen species within the genus Eucheuma. J. Appl. Phycol. 11, 149–156. generation in septic shock and central nervous system Kawatake, S., Inagaki, M., Miyamoto, T., Isobe, R., Higuchi, pathologies: a review. Medicina (Buenos Aires) 58, R., 1999. Biologically active glycoside from Asteroidea, 38. 377–385. Glycosphingolipids from the starfish Luidia maculata,2. Mayer, A.M.S., Lehmann, V.K.B., 2000. Marine pharmacology Eur. J. Org. Chem., 765–769. in 1998: marine compounds with antibacterial, anticoagu- Kem, W.R., Pennington, M.W., Norton, S., 1999. Sea anemone lant, antifungal, anti-inflammatory, anthelmintic, antiplatelet, toxins as templates for the design of immunosuppressant antiprotozoal, and antiviral activities; with actions on the drugs wReviewx. Perspect. Drug Discov. Design 15y16, cardiovascular, endocrine, immune, and nervous systems; 111–129. and other miscellaneous mechanisms of action. Pharmacol- Kerr, R.G., Kerr, S.S., 1999. Marine natural products as ogist 42, 62–69. Available at http:yywww.aspet.orgypublicy therapeutic agents wReviewx. Expert Opin. Ther. Patents 9, interest groupsymarine pharmacologyydefault.html. 1207–1222. Mayer, A.M.S., Lehmann, V.K.B., 2001. Marine pharmacology Kim, D., Lee, I.S., Jung, J.H., Yang, S.I., 1999. Psammaplin in 1999: antitumor and cytotoxic compounds. Anticancer A, a natural bromotyrosine derivative from a sponge, pos- Res. 21, 2489–2500. sesses the antibacterial activity against methicillin-resistant Mayer, A.M.S., Oh, S., Ramsey, K.H., Jacobson, P.B., Glaser, Staphylococcus aureus and the DNA gyrase-inhibitory activ- K.B., Romanic, A.M., 1999. Escherichia coli lipopolysac- ity. Arch. Pharm. Res. 22, 25–29. charide potentiation and inhibition of rat neonatal microglia Klein, R.C., Galdzicki, Z., Castellino, F.J., 1999. Inhibition of superoxide anion generation: correlation with prior lactic NMDA-induced currents by conantokin-G and conantokin- dehydrogenase, nitric oxide, tumor necrosis factor-a, throm-

T in cultured embryonic murine hippocampal neurons. boxane B2 , and metalloprotease release. Shock 11, 180–186. Neuropharmacology 38, 1819–1829. Mitta, G., Hubert, F., Noel, T., Roch, P., 1999. Myticin, a Konig, G.M., Wright, A.D., Linden, A., 1999. Plocamium novel cysteine-rich antimicrobial peptide isolated from hae- hamatum and its monoterpenes: chemical and biological mocytes and plasma of the mussel Mytilus galloprovincialis. investigations of the tropical marine red alga. Phytochem- Eur. J. Biochem. 265, 71–78. istry 52, 1047–1053. Nakahata, N., Ohkubo, S., Ito, E., Nakano, M., Terao, K., Konoki, K., Hashimoto, M., Murata, M., Tachibana, K., 1999. Ohizumi, Y., 1999a. Comparison of maitotoxin with throm-

Maitotoxin-induced calcium influx in erythrocyte ghosts and boxane A2 in rabbit platelet activation. Toxicon 37, rat glioma C6 cells, and blockade by gangliosides and other 1375–1389. membrane lipids. Chem. Res. Toxicol. 12, 993–1001. Nakahata, N., Yaginuma, T., Ohizumi, Y., 1999b. Maitotoxin- Le Gall, F., Favreau, P., Benoit, E., et al., 1999. A new induced phosphoinositide hydrolysis is dependent on extra- conotoxin isolated from Conus consors venom acting selec- cellular but not intracellular Ca2q in human astrocytoma tively on axons and motor nerve terminals through a Naq - cells. Jpn. J. Pharmacol. 81, 240–243. dependent mechanism. Eur. J. Neurosci. 11, 3134–3142. Nicholas, G.M., Hong, T.W., Molinski, T.F., Lerch, M.L., Lenarcic, B., Turk, V., 1999. Thyroglobulin type-1 domains in Cancilla, M.T., Lebrilla, C.B., 1999. Oceanapiside, an anti- equistatin inhibit both papain-like cysteine proteinases and fungal bis-alpha,omega-amino alcohol glycoside from the cathepsin D. J. Biol. Chem. 274, 563–566. marine sponge Oceanapia phillipensis. J. Nat. Prod. 62, Loya, S., Rudi, A., Kashman, Y., Hizi, A., 1999. Polycitone 1678–1681. A, a novel and potent general inhibitor of retroviral reverse Oda, T., Shinmura, N., Nishioka, Y., Komatsu, N., Hatakeya- transcriptases and cellular DNA polymerases. Biochem. J. ma, T., Muramatsu, T., 1999. Effect of the hemolytic lectin 344, 85–92. CEL-III from Holothuroidea Cucumaria echinata on the Malaguti, C., Yasumoto, T., Paolo, R.G., 1999. Transient ANS fluorescence responses in sensitive MDCK and resis- Ca2q -dependent activation of ERK1 and ERK2 in cytotoxic tant CHO cells. J. Biochem. (Tokyo) 125, 713–720. responses induced by maitotoxin in breast cancer cells. Okamoto, Y., Ojika, M., Sakagami, Y., 1999. Iantheran A, a FEBS Lett. 458, 137–140. dimeric polybrominated benzofuran as a Na,K-ATPase Malovrh, P., Sepcic, K., Turk, T., Macek, P., 1999. Character- inhibitor from a marine sponge, Ianthella sp. Tetrahedron ization of hemolytic activity of 3-alkylpyridinium polymers Lett. 40, 507–510. from the marine sponge Reniera sarai. Comp. Biochem. Olivera, B.M., 1997. E.E. Just Lecture, 1996. Conus venom Physiol. 124C, 221–226. peptides, receptor and targets, and drug design: Matsubara, K., Hori, K., Matsuura, Y., Miyazawa, K., 1999. 50 million years of neuropharmacology. Mol. Biol. Cell 8, A fibrinolytic enzyme from a marine green alga, Codium 2101–2109. latum. 52, 993–999. Ovechkina, Y.Y., Pettit, R.K., Cichacz, Z.A., Pettit, G.R., Matsuda, M., Shigeta, S., Okutani, K., 1999. Antiviral activi- Oakley, B.R., 1999. Unusual antimicrotubule activity of the ties of marine Pseudomonas polysaccharides and their over- antifungal agent spongistatin 1. Antimicrob. Agents Chem- sulfated derivatives. Mar. Biotechnol. 1, 68–73. other. 43, 1993–1999. A.M. Mayer, M.T. Hamann / Comparative Biochemistry and Physiology Part C 132 (2002) 315–339 339

Ovenden, S.P.B., Capon, R.J., Lacey, E., Gill, J.H., Friedel, T., from the sea sponge Reniera sarai with insect acetylcholin- Wadsworth, D., 1999. Amphilactams A–D: novel nemato- esterase. J. Protein Chem. 18, 251–257. cides from southern Australian marine sponges of the genus Shin, B.A., Kim, Y.R., Lee, I.S., et al., 1999. Lyso-PAF Amphimedon. J. Org. Chem. 64, 1140–1144. analogues and lysophosphatidylcholines from the marine Pastor, P.G., De Rosa, S., De Giulio, A., Paya, M., Alcaraz, sponge Spirastrella abata as inhibitors of cholesterol bio- M.J., 1999. Modulation of acute and chronic inflammatory synthesis. J. Nat. Prod. 62, 1554–1557. processes by cacospongionolide B, a novel inhibitor of Siddhanta, A.K., Shanmugam, M., Mody, K.H., Goswami,

human synovial phospholipase A2 . Br. J. Pharmacol. 126, A.M., Ramavat, B.K., 1999. Sulphated polysaccharides of 301–311. Codium dwarkense Boergs. from the west coast of India: Pereira, M.S., Mulloy, B., Mourao, P.A., 1999. Structure and chemical composition and anticoagulant activity. Int. anticoagulant activity of sulfated fucans. Comparison J. Biol. Macromol. 26, 151–154. between the regular, repetitive, and linear fucans from Singh, I.P., Milligan, K.E., Gerwick, W.H., 1999. Tanikolide, echinoderms with the more heterogeneous and branched a toxic and antifungal lactone from the marine cyanobacter- polymers from brown algae. J. Biol. Chem. 274, 7656–7667. ium Lyngbya majuscula. J. Nat. Prod. 62, 1333–1335. Qureshi, A., Stevenson, C.S., Albert, C.L., Jacobs, R.S., Soriente, A., De Rosa, M.M.C., Scettri, A., et al., 1999. Faulkner, D.J., 1999. Homo- and nor-plakotenin, new car- Manoalide. Curr. Med. Chem. 6, 415–431. boxylic acids from the palauan sponge Plakortis lita. J. Nat. Spector, I., Braet, F., Shochet, N.R., Bubb, M.R., 1999. New Prod. 62, 1205–1207. anti-actin drugs in the study of the organization and function Reddy, B.S., Rao, V., Rao, B., Dhananjaya, N., Kuttan, R., of the actin cytoskeleton. Microsc. Res. Technol. 47, 18–37. Babu, T.D., 1999a. Isolation and structural determination of Strachan, L.C., Lewis, R.J., Nicholson, G.M., 1999. Differen- new sphingolipids and pharmacological activity of africa- tial actions of pacific ciguatoxin-1 on sodium channel nene and other metabolites from Sinularia leptoclados. subtypes in mammalian sensory neurons. J. Pharmacol. Exp. Chem. Pharm. Bull. (Tokyo) 47, 1214–1220. Ther. 288, 379–388. Suzuki, H., Shindo, K., Ueno, A., et al., 1999. S1319: a novel Reddy, M.V., Rao, M.R., Rhodes, D., et al., 1999b. Lamellarin beta -andrenoceptor agonist from a marine sponge Dysidea alpha 20-sulfate, an inhibitor of HIV-1 integrase active 2 sp. Bioorg. Med. Chem. Lett. 9, 1361–1364. against HIV-1 virus in cell culture. J. Med. Chem. 42, Tomoda, H., Ohyama, Y., Abe, T., et al., 1999. Roselipins, 1901–1907. inhibitors of diacylglycerol acyltransferase, produced by Rein, K.S., Borrone, J., 1999. Polyketides from dinoflagellates: Gliocladium roseum KF-1040. J. Antibiot. (Tokyo) 52, origins, pharmacology and biosynthesis. Comp. Biochem. 689–694. Physiol. 124B, 117–131. Tsukamoto, S., Matsunaga, S., Fusetani, N., Toh, E., 1999. Sampaio, A.H., Rogers, D.J., Barwell, C.J., Saker-Sampaio, S., Theopederins F–J: five new antifungal and cytotoxic metab- Costa, F.H.F., Ramos, M.V., 1999. A new isolation procedure olites from the marine sponge, Theonella swinhoei. Tetra- and further characterisation of the lectin from the red marine hedron 55, 13697–13702. alga Ptilota serrata. J. Appl. Phycol. 10, 539–546. Wakimoto, T., Maruyama, A., Matsunaga, S., Fusetani, N., Sata, N.U., Sugano, M., Matsunaga, S., Fusetani, N., 1999. Shinoda, K., Murphy, P.T., 1999. Octa- and nonaprenylhy- Sinulamide: an H,K-ATPase inhibitor from a soft coral droquinone sulfates, inhibitors of alpha1,3-fucosyltransfera- Sinularia sp. Tetrahedron Lett. 40, 719–722. se VII, from an Australian marine sponge Sarcotragus sp.. Schmitz, F.J., Bowden, B.F., Toth, S.I., 1999. Antitumor and Bioorg. Med. Chem. Lett. 9, 727–730. cytotoxic compounds from marine organisms. In: Attaway, Wessels, M., Konig, G.M., Wright, A.D., 1999. A new tyrosine D.H., Zaborsky, O.R. (Eds.), Marine Biotechnology, vol. 1, kinase inhibitor from the marine brown alga Stypopodium Pharmaceutical and Bioactive Natural Products. Plenum zonale. J. Nat. Prod. 62, 927–930. Press, New York and London, pp. 197–308. Woods, N.M., Dixon, C.J., Yasumoto, T., Cuthbertson, K.S., Sepcic, K., Poklar, N., Vesnaver, G., Fournier, D., Turk, T., Cobbold, P.H., 1999. Maitotoxin-induced free Ca changes Macek, P., 1999. Interaction of 3-alkylpyridinium polymers in single rat hepatocytes. Cell Signal. 11, 805–811.