Marine Pharmacology in 2003–4: Marine

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Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 www.elsevier.com/locate/cbpc

Marine pharmacology in 2003–4: Marine compounds with anthelmintic antibacterial, 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, USA c 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 2007 Available 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' 1998–2002 reviews, and highlights the preclinical pharmacology of 166 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 67 marine chemicals. Additionally 45 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as possessing anti-inflammatory effects. Finally, 54 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2003–2004, research on the pharmacology of marine natural 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 novel therapeutic agents with broad spectrum activity. © 2007 Elsevier Inc. All rights reserved.

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

1. Introduction chemicals whose structures have been established are included in the present review. As in our previous reviews, we have used The purpose of this article is to review the 2003–4primary Schmitz's chemical classification (Schmitz et al., 1993) to assign literature on pharmacological studies with marine natural each marine compound to a major chemical class, namely, products using the same format as in our previous reviews of polyketides, terpenes, nitrogen-containing compounds or poly- the marine pharmacology peer-reviewed literature (Mayer and saccharides. Those publications reporting anthelmintic antibac- Lehmann, 2000), (Mayer and Hamann, 2002, 2004, 2005). terial, anticoagulant, antifungal, antimalarial, antiplatelet, Consistent with our previous reviews, only those articles antiprotozoal, antituberculosis or antiviral properties of 67 marine reporting on the bioactivity or pharmacology of 166 marine chemicals have been tabulated in Table 1 with the corresponding structures shown in Fig. 1. The articles reporting on 45 marine ⁎ Corresponding author. Tel.: +1 630 515 6951; fax: +1 630 971 6414. compounds affecting the cardiovascular, immune and nervous E-mail address: [email protected] (A.M.S. Mayer). systems, as well as those with anti-inflammatory effects are

Table 1 Marine 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 Polyketide d Nematocidal activity to Undetermined AUS (Capon et al., 2004b) Haemonchus contortus Antibacterial Kalihinol Y and X (5,6)/ Diterpene e B. subtilis inhibition Folate biosynthesis PHIL, USA (Bugni et al., 2004) sponge inhibition Antibacterial MC21A (7)/bacterium Bromophenol Methicillin-resistant Permeabilization of JAPN (Isnansetyo et al., 2003) S. aureus inhibition cell membrane comparable to vancomycin Antibacterial Nagelamide A (8)/sponge Alkaloidf M. luteus, B. subtilis and Protein phosphatase AUS, JAPN (Endo et al., 2004) E. coli inhibition 2A inhibition Antibacterial Plicatamide (9)/tunicate Peptidef Methicillin-resistant Bind to plasma USA (Tincu et al., 2003) S. aureus, L. monocytogenes, membrane causing E. coli and P. aeruginosa K+ efflux and inhibition depolarization Antibacterial Manoalide (10)/sponge Sesterterpene e S. aureus inhibition Undetermined JAPN (Namikoshi et al., 2004) Antibacterial Melophlin C (11)/sponge Polyketide d B. subtilis and S. aureus Undetermined CHI, INDO, (Wang et al., 2003a) inhibition GER, NETH Antibacterial Eudistomin X (12)/tunicate Alkaloidf S. aureus, B. subtilis and Undetermined GER (Schupp et al., 2003) E. coli inhibition Antibacterial Dolabellanin B2 (13)/sea hare Peptidef B. subtilis, H. influenza and Undetermined JAPN (Iijima et al., 2003) V. vulnificus inhibition Antibacterial Pseudopterosin X and Y Diterpene e S. aureus, S. pyogenes, and Undetermined CAN, USA (Ata et al., 2004) (14,15)/soft coral E. faecalis inhibition Antibacterial Sinularia lipids (16–18)/ Polyketide d B. subtilis, B. pumilus, Undetermined RUS (Dmitrenok et al., 2003) soft coral E. coli and P. aeruginosa inhibition Antibacterial Rhodomela Bromophenol d S. aureus, S. epidermidis Undetermined CHI (Xu et al., 2003) bromophenol (19)/alga and P. aeruginosa inhibition Antibacterial Cribrostatin 6 (20)/sponge Alkaloidf S. pneumoniae inhibition Undetermined USA (Pettit et al., 2004) Antibacterial Purpuramine L (21)/sponge Bromotyrosine S. aureus, B. subtilis and Undetermined IND (Goud et al., 2003b) alkaloids f C. violaceum inhibition Antibacterial Germacrane (22)/sponge Sesquiterpene e S. aureus and B. subtilis Undetermined THAI (Satitpatipan et al., 2004) inhibition Antibacterial Ptilocaulis Alkaloidf S. aureus inhibition Undetermined USA (Yang et al., 2003c) guanidine (23)/sponge Antibacterial Membranolides C and Diterpene e S. aureus and E. coli Undetermined USA (Ankisetty et al., 2004) D(24,25)/sponge inhibition Antibacterial Arenicins 1 and 2 Peptidef E. coli, L. monocytogenes Undetermined RUS (Ovchinnikova et al., (26,27)/polychaeta and C. albicans inhibition 2004) Antibacterial Perinerin (28)/ Peptidef Gram-negative, Gram- Undetermined CHI (Pan et al., 2004) polychaeta positive and fungal inhibition Antibacterial Hippoglossoides peptide Peptidef P. aeruginosa and S. aureus Undetermined CAN (Patrzykat et al., 2003) (29)/American plaice inhibition Anticoagulant Dysinosin C (30)/sponge Peptidef Factor VIIa and thrombin Two structural AUS (Carroll et al., 2004) inhibition motifs contribute to protease binding Anticoagulant Fucosylated Polysaccharide g Anticoagulant, bleeding Accelerated BRA (Zancan et al., 2004) chondroitin sulfate and antithrombotic effects thrombin inhibition (31)/sea cucumber in vivo Anticoagulant Sulfated galactans Polysaccharide g Antithrombin-mediated Interaction holds BRA (Melo et al., 2004) (32,33)/alga and sea urchin anticoagulant activity antithrombin inactive Antifungal Astroscleridae sterol Sterol sulfated S. cerevisiae inhibition Undetermined USA (Yang et al., 2003b) (34)/sponge Antifungal Dysidea arenaria Terpene e Fluconazole resistance MDR1-type efflux USA (Jacob et al., 2003) sterol (35)/sponge reversal in C. albicans pump inhibition Antifungal Massadine (36)/sponge Alkaloidf Geranylgeranyltransferase I Undetermined JAPN, NETH (Nishimura et al., 2003) inhibition Antifungal Naamine G (37)/sponge Alkaloidf C. herbarum inhibition Undetermined GER, NETH (Hassan et al., 2004) Antifungal Utenospongin B (38)/sponge Diterpene e C. tropicales and Undetermined NETH, MOR, (Rifai et al., 2004) F. oxysporum inhibition PORT Antifungal (2S,3R)-2-aminododecan-3-ol Polyketide d C. albicans inhibition Undetermined BRA, USA (Kossuga et al., 2004) (39)/ascidian Antimalarial Bielschowskysin (40)/coral Diterpene e P. falciparum inhibition Undetermined PAN, USA (Marrero et al., 2004) Antimalarial Briarellins (41–43)/coral Diterpene e P. falciparum inhibition Undetermined PAN, USA (Ospina et al., 2003) A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 555

Table 1 (continued ) Drug class Compound/organisma Chemistry Pharmacologic activity MMOAb Countryc References Antimalarial Cembradiene (44)/sea whip Diterpene e P. falciparum inhibition Undetermined PAN, USA (Wei et al., 2004) Antimalarial Dolastatin 10 (45)/sea hare Peptidef P. falciparum FCH5.C2 Microtubule and USA (Fennell et al., 2003) inhibition mitotic inhibition Antimalarial Manzamine A (46)/sponge Alkaloidf P. falciparum D6 and W2 Undetermined USA (Rao et al., 2003) inhibition Antimalarial Trioxacarcin A and D Glycosided, g P. falciparum strains NF54 Undetermined NETH, GER (Maskey et al., 2004) (48,49)/bacterium and K1 inhibition Antiprotozoal Renieramycin A (50)/sponge Alkaloidf Leishmania amazonensis Undetermined JAPN (Nakao et al., 2004a) inhibition Antiprotozoal Euplotin C (51)/ciliate Sesquiterpene e Leishmania major Undetermined ITA (Savoia et al., 2004) and infantum inhibition Antiprotozoal Defensins/mussel Peptidef T. brucei and L. major Undetermined BEL, FRA (Roch et al., 2004) inhibition Antituberculosis (+)-8-hydroxymanzamine A Alkaloidf M. tuberculosis inhibition Undetermined USA (Rao et al., 2003) (47)/sponge Antituberculosis Homopseudopteroxazole Diterpene e M. tuberculosis inhibition Undetermined USA (Rodríguez et al., 2003) (52)/soft coral Antituberculosis Ingenamine G (53)/sponge Alkaloidf S. aureus, E. coli and Undetermined BRA, GER (De Oliveira et al., 2004) resistant S. aureus inhibition Antituberculosis 12-Deacetoscalarin Sesterterpene e M. tuberculosis inhibition Undetermined THAI (Wonganuchitmeta et al., 19-acetate (54)/sponge 2004) Antituberculosis Oceanapiside sp. compounds Polyketide d Mycothiol-S-conjugate Non-competitive USA (Nicholas et al., 2003) (55–57)/sponge amidase inhibition inhibition Antiplatelet Xetospongin A (58)/sponge Alkaloidf Collagen-induced platelet Undetermined PHIL, USA (Pimentel et al., 2003) aggregation inhibition Antiplatelet Zoanthamine alkaloids Alkaloidf Agonist-induced platelet Undetermined BRA, SPA (Villar et al., 2003) (59–60)/zoanthids aggregation inhibition Antiviral Crambescidin 826 Alkaloidf HIV-1 envelope-mediated Undetermined USA (Chang et al., 2003) (61)/sponge fusion inhibition in vitro Antiviral Dehydrofurodendin Furanoterpene e Reverse transcriptase RNA- Undetermined ISRA, FRA (Chill et al., 2004) (62)/sponge and DNA-directed DNA polymerase inhibition Antiviral Neamphamide A (63)/sponge Depsipeptide f HIV-growth inhibition Undetermined USA (Oku et al., 2004) Antiviral Dictyota diterpenes Diterpene e Inhibition of HIV-1 RNA-dependent BRA (Pereira et al., 2004) (64,65)/alga replication in cell line DNA-polymerase RT inhibition Antiviral Petrosins (66,67)/sponge Alkaloidf HIV-growth inhibition Giant cell formation IND (Goud et al., 2003a) and RT inhibition a Organism, Kingdom Animalia: flounder (American plaice) and tunicates (Phylum Chordata); polychaeta (Phylum Annelida); sea urchins and cucumbers (Phylum Echinodermata), mussels and sea hares (Phylum Mollusca), sponges (Phylum Porifera); corals, sea whips and zoanthids (Phylum Cnidaria); Kingdom Monera: 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.

grouped in Table 2 and the structures presented in Fig. 2. Finally Botryocladia leptopoda (Lakshmi et al., 2004); antiviral effects 54 marine compounds targeting a number of distinct cellular and of a sulfated exopolysaccharide from the marine microalga molecular targets and mechanisms are shown in Table 3 and their Gyrodinium impudicum (Yim et al., 2004) and Sargassuum structures depicted in Fig. 3. Publications on the biological or patens (Zhu et al., 2004); a polyhydroxylated fucophlorethol pharmacological activity of marine extracts or as yet structurally isolated from the marine brown alga Fucus vesiculosus uncharacterized marine compounds have been excluded from the shown to be bactericidal towards selected Gram-positive and present review, although several promising reports were pub- Gram-negative bacteria in vitro (Sandsdalen et al., 2003); and lished during 2003–4: a specific inhibitor of a thyrotropin an improvement of “current cytokine-based therapies” releasing hormone-specific peptidase (Pascual et al., 2004); by sulphated polysaccharides purified from the green alga antimicrobial activity in sub-Arctic marine invertebrates Codium fragile, as well as fucoidan and carrageenan, isolated (Lippert et al., 2003); antifilarial activity of the red alga from brown and red algae, respectively (Nika et al., 2003). 556 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

2. Marine compounds with anthelminthic, antibacterial, 2.1. Anthelminthic and antibacterial compounds anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities One study contributed to the search of novel anthelmintic marine natural products during 2003–4. The novel acyclic Table 1 summarizes new pharmacological findings reported lipids thiocyanatins (1–4), were isolated from the Australian during 2003–4 on the preclinical anthelminthic, antibacterial, sponge Oceanapia sp. (Capon et al., 2004b) and were shown to anticoagulant, antifungal, antimalarial, antiplatelet, antiproto- be nematocidal (LD99 =3.1–8.3 μg/mL) to the commercial zoal, antituberculosis, and antiviral pharmacology of the 67 livestock parasite Haemonchus contortus. Although the mech- marine natural products shown in Fig. 1. anism of action of these compounds remains undetermined, the

Fig. 1. A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 557

Fig. 1 (continued ). investigators noted that both the 2°-alcohol, SCN functionalities pyranyl-type kalihinols Y (5) and X (6), although potent and chain length influenced the nematocidal activity. antibacterials (MIC=1.56 μg/mL), were however less selective In view of the fact that resistance to current antibiotics remains a inhibitors of bacterial folate biosynthesis than the furanyl type significant challenge for pathogenic bacterial infections, during kalihinols, with the “C-10 position important for potency”. 2003–4, 19 studies contributed to the search for novel antibacterial Isnansetyo and Kamei (2003) reported that a bactericidal marine natural products, an increase from 1998–2002 (Mayer and compound named MC21-A (7), a 3,3′,5,5′-tetrabromo-2,2′- Lehmann, 2000; Mayer and Hamann, 2002, 2004, 2005). Four biphenyldiol, from the new marine bacterium Pseudoalteromonas studies reported on the mechanism of action of novel marine phenolica sp. nov. MC21-A was bactericidal (MIC=1–2 μg/mL) antibacterial agents (2–6; Fig. 1). Bugni et al. (2004) investigated a against 10 clinical isolates of methicillin-resistant Staphylococcus series of kalihinols, diterpenes isolated from the Philippine marine aureus, and displayed comparable bioactivity to vancomycin sponge Acanthella cavernosa, as potential bacterial folate (MIC=0.25–2 μg/mL). The mechanism of action of MC21-A biosynthesis inhibitors. The investigators reported that the involved permeabilizing bacterial cell membranes, and thus “might 558 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

Fig. 1 (continued ). be a useful compound” because of a mode of action that differs extensive and detailed mechanistic study these investigators from vancomycin. A new dimeric bromopyrrole alkaloid, discovered that despite its small size, the octapeptide plicatamide nagelamide G (8) was isolated from the Okinawan marine sponge proved to be a potent, rapidly acting and broad spectrum Agelas sp. (Endo et al., 2004). Nagelamide G exhibited antimicrobial. The fact that both wild type and methicilin-resistant antibacterial activity against M. luteus, B. subtilis and E. coli, but S. aureus responded to plicatamide with a massive and rapid weakly inhibited protein phosphatase 2 A (IC50 =13 μM), thus potassium efflux is “consistent with an antimicrobial mechanism suggesting that this enzyme may not be the main molecular target that targets their cell membrane”. responsible for the antibacterial activity of this compound. Tincu Although additional novel marine antibacterials were et al. (2003) reported a new antimicrobial octapeptide plicatamide reported in 2003–4, no mechanism of action studies were (9) from the hemocytes of the marine tunicate Styela plicata.Inan reported for compounds (10–29). Nevertheless, these studies A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 559

Fig. 1 (continued ). highlight the fact that novel antibiotics are present in marine antibacterial activity” against B. subtilis and S. aureus. One bacteria, tunicates, sea hares, soft corals, algae, sponges, worms, paper reported on new antimicrobial compounds isolated and fish. Two papers reported on antibacterial activity in from marine tunicates: Schupp et al. (2003) discovered that compounds isolated from marine sponges: Namikoshi et al. the β-carboline eudistomin X (12), isolated from the Microne- (2004) reported the isolation of several manoalide derivatives sian ascidian Eudistoma sp. was active against B. subtilis, (10) from a Luffariella sp. sponge collected in Palau, which S. aureus and E. coli. One paper reported on a new antimicrobial were active against S. aureus at 5–10 μg/disk. The investigators peptide isolated from sea hares: Iijima et al. (2003) reported a noted that the presence of an “OH group at the C-25 position novel 33 amino acid antimicrobial peptide dolabellanin B2 (13) (hemiacetal moiety) is important for antibacterial activity.” from the sea hare Dolabella auricularia. One hundred percent Wang et al. (2003a) reported thirteen novel tetramic acids inhibition of growth of B. subtilis, H. influenza and Vibrio isolated from the marine sponge Melophlus sarassinorum. vulnificus was reported with 2.5–5 μg/mL dolabellanin B2. Interestingly, only melophlin C (11) displayed “pronounced Two papers reported on new antimicrobial peptides isolated 560 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

Fig. 1 (continued ). from marine soft corals: Ata et al. (2004) reported two new the MIC were not reported, “preliminary tests for antibacterial diterpenes, pseudopterosin X and Y (14–15) from the soft coral activity of lipids” demonstrated that these compounds inhibited Pseudopterogorgia elisabethae which showed antibacterial the growth of E. coli, Pseudomonas aeruginosa, B. subtilis and activity against Gram-positive bacteria Streptococcus pyogenes, B. pumilus on solid agar. One paper reported on the presence of S. aureus, and Enterococcus faecalis, while being inactive antibacterial compounds in marine algae: Xu et al. (2003) against Gram-negative bacteria. Dmitrenok et al. (2003) reported that among 5 bromophenols isolated from the marine reported several sphingolipids and glycolipids (16–18) from red alga Rhodomela confervoides, the known compound bis soft corals of the Andaman Islands (Indian Ocean). Although (2,3-dibromo-4,5-dihydroxybenzyl) ether (19)showed A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 561

Table 2 Marine pharmacology in 2003–4: marine compounds with anti-inflammatory activity, and affecting the cardiovascular, immune and nervous systems Drug class Compound/organism a Chemistry Pharmacological activity MMOAb Countryc References Anti-inflammatory Astaxanthin (68)/salmon, Tetraterpene d Inhibition of endotoxin- iNOS, NO, TNF-α JAPN (Ohgami et al., 2003)

sea stars induced uveitis in rats and PGE2 inhibition d Anti-inflammatory Bolinaquinone (69)/ Merosesquiterpene Inhibition of cytokine, sPLA2 inhibition SPA, ITA (Lucas et al., 2003b) sponge iNOS and eicosanoids d Anti-inflammatory Cacospongionolide B Sesterterpene Nitric oxide, PGE2 and Nuclear factor-κB SPA, ITA (Posadas et al., 2003a) (70)/sponge TNF-α inhibition in inhibition vitro and in vivo Anti-inflammatory Clathriol B (71)/sponge Sterold Neutrophil superoxide Undetermined NZEL (Keyzers et al., 2003) inhibition Anti-inflammatory Conicamin (72)/tunicate Indole alkaloide Histamine antagonist Undetermined ITA (Aiello et al., 2003) Anti-inflammatory Cycloamphilectene 2 Diterpene d Nitric oxide inhibition Inhibition of NF-κB ITA, SPA (Lucas et al., 2003a) (73)/sponge pathway Anti-inflammatory Plakohypaphorine D Indole alkaloide Histamine antagonist Undetermined ITA (Borrelli et al., 2004) (74)/sponge Anti-inflammatory Pourewic acid A and Diterpenes d Superoxide inhibition Undetermined NZEL (Keyzers et al., 2004) methylpourewate B (75,76)/sponge Anti-inflammatory Cadlinolide C (77)/sponge Diterpene d Superoxide inhibition Undetermined NZEL (Keyzers et al., 2004) Anti-inflammatory Petrocortyne A (78)/sponge Polyacetylene g Macrophage NO and TNF-α SKOR (Hong et al., 2003) inflammatory inhibition mediator inhibition d Anti-inflammatory Petrosaspongiolide M Sesterterpene Nitric oxide, PGE2 and Nuclear factor-κB ITA, SPA (Posadas et al., 2003b) (79)/sponge TNF-α inhibition in inhibition vitro and in vivo d Anti-inflammatory Petrosaspongiolides M-R Sesterterpenes Macrophage PLA2 inhibition ITA (Monti et al., 2004) (79–83)/sponge inflammatory mediator inhibition Anti-inflammatory Pseudopterosin N Diterpene d Inhibition of mouse ear Undetermined USA (Ata et al., 2003) (84)/sea whip inflammation Anti-inflammatory Seco-pseudopterosin E Diterpene d Inhibition of mouse ear Undetermined USA (Ata et al., 2003) (85)/sea whip inflammation Anti-inflammatory Elisabethadione(86)/ Diterpene d Inhibition of mouse ear Undetermined USA (Ata et al., 2003) sea whip inflammation Anti-inflammatory Pseudopterosin R Diterpene d Microglia thromboxane Undetermined USA (Rodríguez et al., 2004)

(87)/sea whip B2 inhibition Cardiovascular Callipeltin A (88)/sponge Depsipeptide e Affected resting aorta Na+-ionophore ITA (Trevisi et al., 2004) contraction action Immune system Codium fragile Polysaccharide f Binding to IL-2, IL-7 Undetermined UK (Nika et al., 2003) polysaccharide/alga and INF-γ Immune system Sulfircin (89)/sponge Sesterterpene d Mobilization of T cells CCR7 chemokine USA (Yang et al., 2003d) and dendritic cells receptor binding Immune system Mucins/sea star Polysaccharide f Inhibition of neutrophil Undetermined UK (Bavington et al., 2004) adhesion Immune system Perybysins A–D Sesquiterpenes d Inhibition of human Undetermined JAPN (Yamada et al., 2004) (90–93)/fungus leukemia cell adhesion Immune system Phycarine/alga Polysaccharide f Stimulation of IL-1, IL-6 and FRA, USA (Vetvicka et al., 2004) macrophage phagocytosis TNF-α synthesis Immune system Sulfated PMG (94)/alga Polysaccharide f Inhibition of HIV virus Binding to CD4 CHI (Meiyu et al., 2003) infection of lymphocytes receptor on lymphocytes Immune system Sulfated PMG (94)/alga Polysaccharide f Binding to lymphocytes Interaction with CHI (Miao et al., 2004) CD4 receptor Nervous system Petrosaspongiolide Sesterterpene d Reduction of morphine Undetermined ITA (Capasso et al., 2003) M(79)/sponge withdrawal in vitro Nervous system Aplidine(95)/tunicate Depsipeptide e Inhibition of aggregation Undetermined SPA,USA (Perez et al., 2003) of prion petide into β-sheet fibrils Nervous system Aspermytin A (96)/fungus Polyketide g Induction of neurite Undetermined JAPN (Tsukamoto et al., outgrowth 2004a) Nervous system Labuanine A (97)/sponge Pyridoacridine Induction of neuite Undetermined JAPN, INDO (Aoki et al., 2003) alkaloide outgrowth Nervous system Linckosides C–E Steroidal Induction of neurite Undetermined JAPN (Qi et al., 2004) (98–100)/sea star glycoside d outgrowth (continued on next page) 562 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

Table 2 (continued ) Drug class Compound/organism a Chemistry Pharmacological activity MMOAb Countryc References Nervous system Parguerol-isoparguerol Diterpene d Induction of neurite Undetermined JAPN (Tsukamoto et al., (101–102)/sea hare outgrowth 2004b) Nervous system Sargaquinoic acid Meroditerpene d Induction of neurite PI-3 kinase JAPN (Tsang et al., 2004; (103)/alga outgrowth independent; Kamei et al., 2003) TrKA-MAP kinase and adenylate cyclase-PKA dependent Nervous system SJG-2 ganglioside Ganglioside Induction of neurite Undetermined JAPN (Kaneko et al., 2003) (104)/sea cucumber outgrowth Nervous system Cribronic acid Amino acid e Convulsant activity Binding to JAPN (Sakai et al., 2003) (105)/sponge in mice NMDA-type receptor Nervous system Dysibetaine CPa–CPb Betaine Binding to ionotropic Undetermined JAPN (Sakai et al., 2004) (106,107)/sponge glutamate receptors Nervous system Jamaicamide A Lipopeptide e Sodium channel blocking Undetermined USA (Edwards et al., 2004) (108)/cyanobacterium Nervous system Esmodil (109)/sponge Quaternary amine Acetylcholine mimetic Undetermined AUS (Capon et al., 2004a) Nervous system ω-conopeptide MVIIA Peptide e Inhibition of refractory Binding to N-type USA (Staats et al., 2004) (110)/snail pain in patients with Ca2+ channels AIDS or Cancer Nervous system δ-conotoxin (111)/snail Peptide e Na+ current inhibition Undetermined IND (Sudarslal et al., 2003) Nervous system χ-conopeptide Peptide e Norepinephrine Non-competitive AUS (Sharpe et al., 2003) MrIA (112)/snail transporter inhibition binding at the antidepressant binding site Nervous system Acidic oligosaccharide/alga Polysaccharide f Inhibition of amyloid Inhibition of CHI (Hu et al., 2004) beta toxicity apoptosis and intracellular Ca2+ 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- 25) derived from an Antarctic cactus sponge, displayed “modest phylococcus epidermidis and P. aeruginosa (MIC=70 μg/mL). yet broad spectrum” Gram-negative antibiotic activity (Anki- Additional antibacterial marine natural products were isolated setty et al., 2004). Two novel antibacterial peptides were isolated from sponges: Pettit et al. (2004) reported the antibacterial from marine worms: Ovchinnikova et al. (2004) purified and activity of a novel nitrogen heterocyclic compound cribrostatin characterized two small 21-residue peptides arenicin-1 and-2 6(20) isolated from the dark-blue marine Cribochalina sp. (26–27), from the coelomocytes of the marine lugworm Areni- sponge. Cribrostatin 6 showed antibacterial activity against cola marina. Both arenicins were active against Gram-positive L. Gram-positive bacteria, and it was most active against monocytogenes, Gram-negative E. coli and the fungus S. pneumoniae (MIC=0.5 μg/mL), a leading cause of infection C. albicans. Pan et al. (2004) isolated and characterized a 51- and mortality worldwide. Goud et al. (2003b) reported a novel amino acid highly basic and hydrophobic peptide perinerin (28), purpuramine L (21) from the Indian marine sponge Psamma- from the marine clamworm Perinereis aibuhitensis,anorganism plysilla purpurea which was active against S. aureus, B. subtilis that is extensively used as bait in fisheries and aquaculture. and C. violaceum. A new nitrogenous sesquiterpene germa- Perinerin, a peptide that is constitutively present in the marine crane (22) was isolated from an Axinyssa n. sp. sponge that worm and whose sequence appears to be novel among all know demonstrated strong antimicrobial activity against S. aureus antimicrobial peptides, was active against Gram-negative and and B. subtilis (Satitpatipan and Suwanborirux, 2004). Yang Gram-positive bacteria as well as fungi. Patrzykat et al. (2003) et al. (2003c) isolated a new bicyclic guanidine alkaloid (23) reported active novel antimicrobials peptides by screening both from the marine sponge Ptilocaulis spiculifer, contributing a genomic and mRNA transcripts from a number of different new member to the crambescin A class of compounds. species of flatfish. The most active peptide coded as NRC-13 (29) Interestingly, 50 μg of the guanidine alkaloid was as potent as which was derived from the American plaice Hippoglossoides 10 μg gentamicin. Two diterpenes membranolides C and D (24, platessoides Frabricius, “rapidly (5 to 10 min) and efficiently A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 563

(95–100%)” killed antibiotic-resistant P. aeruginosa, methicillin- new peptides, dysinosins B, C (30) and D, isolated from the resistant S. aureus and C. albicans. sponge Lamellodysidea chlorea, that inhibited the blood coagulation cascade serine proteases factor VIIa and thrombin. 2.2. Anticoagulant compounds Furthermore, the study revealed that two structural motifs of the dysinosins contributed to the binding of these compounds to During 2003–4 three articles reported on the anticoagulant factor VIIa and thrombin proteases. Zancan and Mourao (2004) properties of marine natural products, an increase from our extended the antithrombotic pharmacology of fucosylated previous reviews (Mayer and Lehmann, 2000; Mayer and chondroitin sulfate (31), a glycosaminoglycan isolated from Hamann, 2002, 2004, 2005). Carroll et al. (2004) reported three the Brazilian sea cucumber Ludwigothurea grisea.The

Fig. 2. 564 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

Fig. 2 (continued ).

researchers noted that it was possible to dissociate the 2.3. Antifungal compounds anticoagulant, bleeding and antithrombotic effect of this compound, i.e. the antithrombotic effect varied depending on the Six studies during 2003–4reportedontheantifungal in vivo experimental model being used, and that it was properties of 6 novel marine natural products isolated from “apparently unrelated to its effect on platelet aggregation”. marine sponges and ascidians, a slight decrease from 1998– Melo et al. (2004) extended the pharmacology of antico- 2002 (Mayer and Lehmann, 2000; Mayer and Hamann, 2002, agulant sulfated galactans (32–33) isolated from the red alga 2004, 2005). Botryocladia occidentalis and the sea urchin Echinometra Several novel marine antifungals (34–38) were isolated from lucunter. The studies demonstrated that the antithrombin- marine sponges. Yang et al. (2003b) reported a new sterol sulfate activating conformational change appeared to be of minor (34) isolated from a deep-water marine sponge of the family significance for the sulfated galactans's anticoagulant activity, Astroscleridae, which exhibited antifungal activity against and that the antithrombin-sulfated galactan complex differed “supersensitive” Saccharomyces cerevisiae (MIC=15 μg/mL). from the antithrombin–heparin complex, thus leading the As part of an ongoing project to discover potential new drugs to researchers to propose that “the paradigm of the heparin– treat resistant opportunistic fungal infections, Jacob et al. (2003) antithrombin interaction cannot necessarily be extended to other reinvestigated the antifungal properties of a previously described sulfated polysaccharides”. sterol (35) isolated from the marine sponge Dysidea arenaria. A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 565

Fig. 2 (continued ).

Interestingly, they observed a reversal of fluconazole resistance GGTase. Bioassay-guided fractionation resulted in the isola- from 300 to 8.5 μM when combined with 3.8 μM of the tion of a novel alkaloid massadine (36) from the marine D. arenaria sterol, putatively as a result of inhibition of the sponge Stylissa aff. massa, which inhibited fungal GGTase MDR1-type efflux pump in multidrug-resistant C. albicans. (IC50 =3.9 μM). One novel imidazole alkaloid, naamine With the purpose of finding more selective antifungal agents, G(37) was reported from the Indonesian marine sponge Nishimura et al. (2003) focused their research efforts in Leucetta chagosensis that exhibited strong antifungal activity identifying inhibitors of the pathogenic fungus C. albicans against the phytopathogenic fungus Cladosporium herbarum geranylgeranyltransferase (GGTase), an enzyme that shares (Hassan et al., 2004). It remains to be determined if this com- only 30% amino acid sequence homology with the human pound will also be effective against fungi that infect mammalian 566 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

Fig. 2 (continued ). hosts. Rifai et al. (2004) reported that untenospongin B (38), (chloroquine-resistant) strain by the novel cembradiene diterpe- isolated from the Moroccan marine sponge Hippospongia noid (44) isolated from the Caribbean gorgonian octocoral Euni- communis, was more potent than amphotericin B, a clinically cea sp., (IC50 =23, 15 and 16 μg/mL, respectively). Fennell et al. used antifungal agent, against Candida tropicalis (MIC=4–8 μg/ (2003) reported the antimalarial activity of dolastatin 10 (45), a mL) and Fusarium oxysporum (MIC=2–4 μg/mL). Further peptide microtubule inhibitor isolated from the sea hare D. studies are required to determine the toxicity of untenospongin B auricularia which is a potent anticancer drug. Although an in vivo as well as its molecular mechanism of action. extensive structure–activity relationship study was described and Kossuga et al. (2004) reported a new antifungal agent dolastatin 10 showed potent inhibition of P. falciparum polyketide, (2S,3R)-2-aminododecan-3-ol (39), isolated from (IC50 =0.1 nM) by affecting the schizont stage of intraerythrocytic the Brazilian ascidian Clavelina oblonga, which was very development, which has the highest concentration of tubulin, the active against C. albicans (MIC=0.7±0.05 μg/mL). Although investigators concluded that dolastatin 10 was an “unpromising the mechanism of action of this compound remains undeter- basis for further antimalarial evaluation” because of the lack of mined its bioactivity was comparable to the clinically used marked selectivity for parasite over mammalian cells. Rao et al. antifungal agents nystatin (MIC=1–4 μg/mL) and ketocona- (2003) reported structure–activity relationship studies with the zole (MIC=1–4 μg/mL). manzamine alkaloids as potential antimalarial agents. Manzamine A(46) was observed to be particularly active against P. f alc ip ar um 2.4. Antimalarial, antiprotozoal, antituberculosis and antipla- (D6 clone, IC50 =4.5 ng/mL) and P. falciparum (chloroquine- telet compounds resistant W2 clone, IC50 =8.0 ng/mL), which compared well with artemisinin used as a control in these studies (IC50 =10and6.3ng/ During 2003–4, and as shown in Table 1, 16 studies were mL, respectively). As part of an ongoing screening program for reported in the area of antimalarial, antiplatelet, antiprotozoal novel bioactive compounds from marine Streptomycetes, Maskey and antituberculosis pharmacology of structurally characterized et al. (2004) reported that the trioxacarcins A and D (48,49) marine natural products. Ten compounds (40–49; Fig. 1) were isolated from the marine Streptomyces sp. isolate B8652 BCC shown to possess antimalarial activity. Moderate antimalarial 5149 possessed “extremely high antiplasmodial activity” against activity (IC50 =10 μg/mL) against Plasmodium falciparum was the parasite P. f alc ip ar um K1 and NF54 strains (IC50 =1.5–1.6 observed with bielschowskysin (40), a new and highly oxygen- and 2.3–1.7 ng/mL, respectively) which was much higher than the ated hexacyclic diterpene isolated from the Caribbean gorgonian clinically used compound chloroquine (IC50 =70 and 3.7 ng/mL, octocoral Pseudopterogorgia kallos (Marrero et al., 2004), as well respectively). as the novel diterpenes of the eunicellin class, briarellins K Three compounds were shown to possess antiprotozoal hydroperoxide (41), D hydroperoxide (42)andL(43), isolated activity. Nakao et al. (2004a) reported the isolation of from the gorgonian Briareum polyanthes (IC50 =9, 9 and 8 μg/ renieramycin A (50) a new compound from the Japanese sponge mL, respectively) (Ospina et al., 2003). Wei et al. (2004) reported Neopetrosia sp. that dose-dependently inhibited recombinant moderate cytotoxic activity against the P. falciparum W2 Leishmania amazonensis proliferation (IC50 =0.2 μg/mL) while A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 567 showing cytotoxicity at “ten times higher concentration strong inhibition of thrombin-, collagen- and arachidonic acid- (IC50 =2.2 μg/mL)”. Savoia et al. (2004) examined the activity induced platelet aggregation which appeared related to the of the sesquiterpene euplotin C (51), isolated from the marine hydroxyl group at C-11; in contrast, aromatization in ring A was ciliate Euplotes crassus on pathogenic protozoa Leishmania probably responsible for the selectivity of zoanthenol (60) major and Leishmania infantum. Because a significant leishma- towards collagen-induced aggregation. nicidal activity was noted against both Leishmania species (LD50 =4.6–8.1 μg/mL), the authors proposed evaluation of this 2.5. Antiviral compounds natural product as “synergistic compound(s) for current antiprotozoon chemotherapeutics”. Roch et al. (2004) reported As shown in Table 1 interest in the antiviral pharmacology of that novel non-cytotoxic variant analogues of truncated marine natural products remained high during 2003–4. During defensins isolated from the Mediterranean mussel Mytilus this two-year period 7 novel marine compounds (61–67) (Fig. 1) galloprovincialis were antiprotozoal. Two defensin fragments, were reported to possess antiviral properties against the human designated D (Sequence CGGWKRKRC) and P (Sequence immunodeficiency (HIV) virus by targeting a number of diverse CGGYCGGWKRKRCTSYRCG), killed both the African molecular targets. As a result of an effort to identify small trypanosome Trypanosoma brucei (ID50 =4–12 μM), which molecules that disrupt protein–protein interactions involved causes sleeping sickness, and the causative agent of cutaneous in HIV-1 cellular entry, a new polycyclic guanidine alkaloid leishmaniasis, namely L. major (ID50 =12–45 μM), in a time- crambescidin 826 (61) was reported from the marine sponge and concentration-dependent manner. The mechanism may Monanchora sp. (Chang et al., 2003). Crambescidin 826 involve binding of the defensin fragments “to parasite mem- inhibited HIV-1 envelope-mediated fusion in vitro (IC50 =1– branes”, perhaps affecting membrane fluidity. 3 μM), thus suggesting that this class of compounds might Seven novel compounds (47, 52–57; Fig. 1) were contributed ultimately aid in “the rational design…of small molecule HIV-1 to the search for novel antituberculosis agents. Rodríguez and fusion inhibitors”. Chill et al. (2004) isolated a new C22 Rodríguez (2003) reported that a novel diterpene alkaloid furanoterpene designated dehydrofurodendin (62)froma homopseudopteroxazole (52), isolated from the Caribbean sea Madagascan Lendenfeldia sponge, that was active against plume P. elisabethae, inhibited growth of Mycobacterium HIV-1 reverse transcriptase-associated RNA- and DNA-directed tuberculosis H37Rv (MIC=12.5 μg/mL). As part of a manzamine DNA polymerase (IC50 =3.2–5.6 μM). As a result of the alkaloid structure–activity relationship study, Rao et al. (2003) National Cancer Institute's HIV-inhibitory natural product lead noted that (+)-8-hydroxymanzamine A (47) was very potent discovery program, a new HIV-inhibitory depsiundecapeptide against M. tuberculosis (H37Rv, MIC=0.91 μg/mL), comparing neamphamide A (63) was isolated from the Papua New Guinea favorably with rifampin (MIC=0.5 μg/mL). De Oliveira et al. marine sponge Neamphius huxleyi (Oku et al., 2004). Neam- (2004) reported a new alkaloid ingenamine G (53)that phamide A potently inhibited the cytopathic effect of HIV-1 demonstrated activity against M. tuberculosis H37Rv at 8 μg/mL. infection in a cell-based in vitro assay (EC50 =28 nM). Pereira et A new scalarane-type bioactive sesterterpene, 12-deacetoxysca- al. (2004) reported an extensive study on the mechanism of larin 19-acetate (54), which was purified from the Thai sponge action of two diterpenes, Da-1 and AcDa-1 (64, 65), isolated Brachiaster sp. (Wonganuchitmeta et al., 2004), inhibited growth from the marine alga Dictyota menstrualis, that inhibited HIV-1 of a nonvirulent strain of M. tuberculosis by 50% at MIC=4 μM, virus replication in the PM-1 cell line in vitro. Although both comparing favorably with kanamycin sulfate (MIC=3.5–8.5 μM). diterpenes did not affect viral attachment nor internalization of As a result of a research program designed to identify marine the virus into PM-1 cells, they inhibited the RNA-dependent natural products that inhibit the mycothiol-S-conjugate amidase, a DNA polymerase activity of the viral reverse transcriptase mycobacterial detoxification enzyme, Nicholas et al. (2003) enzyme (IC50 =10 and 35 μM, for Da-1 and AcDa-1, reported several active compounds: a mixture of 1,3 pyridinium respectively) in a cell-free in vitro assay. These results strongly polymers (55) isolated from the marine sponge Amphimedon sp., suggested that “inhibition of synthesis of the proviral DNA by IC50 =0.1 μM; an Oceanapiside sp.-derived bromotyrosine the diterpenes” was the probable mechanism involved in HIV compound (56), IC50 =3μM; and the glycosphingolipid oceanapi- replication inhibition in PM-1 cells. Goud et al. (2003a) reported side (57), IC50=10 μM. Oceanapiside, was observed to be a inhibition of HIV by two bis-quinolizidine alkaloids petrosins “simple non-competitive inhibitor” of the mycothiol-S-conjugate (66, 67) isolated from the Indian marine sponge Petrosia similis. amidase enzyme. The extensive investigation determined that both petrosins Two studies contributed to antiplatelet pharmacology of inhibited HIV-1 replication (IC50 =41.3–86.8 μM), formation of marine natural products during 2003–4. Pimentel et al. (2003) giant cells (IC50 =21.2–36.1 μM) and recombinant reverse 2+ using a new microplate assay for Ca -induced platelet aggre- transcriptase in vitro (IC50 =10.6–14.8 μM). gation, determined that xestospongin A (58), isolated from the marine sponge Xestospongia sp., inhibited both collagen- and 3. Marine compounds with anti-inflammatory effects and epinephrine-induced platelet aggregation more potently than affecting the cardiovascular, immune and nervous system aspirin. Villar et al. (2003) evaluated the effects of several zoanthamine-type alkaloids isolated from the zoanthids Table 2 summarizes the preclinical pharmacological research Zoanthus numphaeus and Zoanthus sp. on the aggregation of completed during 2003–2004 with the 45 marine chemicals human platelets: 11-hydroxyzoanthamine (59) demonstrated shown in Fig. 2. 568 ...Myre l oprtv iceityadPyilg,Pr 4 20)553 (2007) 145 C Part Physiology, and Biochemistry Comparative / al. et Mayer A.M.S. Table 3 Marine pharmacology in 2003–4: marine compounds with miscellaneous mechanisms of action a b c d Compound/organism Chemistry Pharmacological activity IC50 MMOA Country References Acylspermidine D and Polyaminee Vacuolar H+-pyrophosphatase 0.98 μM No inhibition of F–P- and JAPN (Hirono et al., 2003) E(113,114)/soft coral inhibition V-type H+ ATPases and cytosolic pyrophosphatase Ageladine A (115)/sponge Alkaloide Matrix metalloprotease 0.33–2 μg/mL Non-competitive inhibition NETH, JAPN (Fujita et al., 2003a) (MMP) inhibition of MMP-2 Agosterol C (116)/sponge Sterolf Proteasome inhibition 10 μg/mL Undetermined NETH, JAPN (Tsukamoto et al., 2003) Alkylpyridinium/(117)/sponge Pyridinium oligomere Pore formation on neuronal ND Reversible and irreversible TUR, SLO, UK (McClelland et al., 2003) membranes increase [Ca2+ ]i; membrane properties attenuated by zinc Alkylpyridinium(poly-APS) Pyridinium oligomere Stable DNA transfection 0.5 μg/mL Transient and reversible SLO, UK (Tucker et al., 2003) (118)/sponge pore formation Arenarol and isoarenarol Merosesquiterpenef Protein kinases inhibition 4–7 μM Undetermined NETH, CAN (Yoo et al., 2003) (119, 120)/sponge e Atriolum robustum nucleoside Amino acid derived Partial agonist at rat brain 23±0.2 μM Binding to A1 and A3 GER (Kehraus et al., 2004) (121)/ascidian A1 adenosine receptors adenosine receptors Callysponginol sulfate A Polyketideg MT1-matrix metalloproteinase 15.0 μg/mL Undetermined JAPN, NETH (Fujita et al., 2003b) (122)/sponge inhibition Calyculin A (123)/sponge Polyketideg Histone H1 kinase ND Type 1 phosphatase inhibition JAPN (Tosuji et al., 2003) phosphorylation induction CEL-III/sea cucumber Proteine Erythrocyte hemolysis ND Crystal structure suggests JAPN (Uchida et al., 2004) lectin domain 3 involved in pore formation Clionasterol (124)/sponge Sterolf Complement component 4.1 μM Undetermined THAI, (Cerqueira et al., 2003) C1 inhibition NETH, PORT f 2+ Cucumarioside A -2 Triterpene glycoside Increased [Ca ]i and ND Undetermined RUS (Agafonova et al., 2003) – 2 581 (125)/sea cucumber lysosomal activity in mouse macrophages Cymopol (126) and Meromonoterpenef/polyketg Antioxidant 4.0–6.1 μM Undetermined USA (Takamatsu et al., 2003) avrainvilleol (127)/alga Dictyoceratida Diterpenef DNA polymerase B lyase 20.6–26 μg/mL Undetermined USA (Chaturvedula et al., 2004) diterpenoids (128–130)/sponge activity inhibition Furano- and aromatic Terpenesf CDC25 phosphatase inhibition 0.4–4 μM Undetermined ITA, FRA, SPA, (Erdogan-Orhan et al., 2004) terpenoids (131–133)/sponge TUR, USA f Halistanol sulfate (134)/sponge Sterol P2Y12 purinergic receptor 0.48 μM Undetermined USA (Yang et al., 2003a) inhibition Lamellarin G and I Alkaloidse Free radical scavenging activity 2.96–3.28 mM Undetermined IND (Krishnaiah et al., 2004) (135, 136)/ascidian Table 3 (continued ) a b c d Compound/organism Chemistry Pharmacological activity IC50 MMOA Country References Lysophosphatidylcholine Polyketideg Increased Ca2+ mobilization ND Undetermined S.KOR (Lee et al., 2004) (137)/sponge in HL-60 cells (+)-Subersic acid (138)/sponge Meroterpenef MAPKAP kinase 2 inhibition 9.6–20 μM Undetermined CAN, INDO, (Williams et al., 2004b) NETH, USA Meridianin E (139)/ascidian Alkaloidse Cell proliferation and apoptosis 0.18–0.6 μM Cyclin B, p25, protein ARG, FRA (Gompel et al., 2004) inhibition kinase A and G inhibition Penasulfate A (140)/sponge Amino acid/ α-glucosidase inhibition 3.5 μg/L Undetermined JAPN, NETH (Nakao et al., 2004b) polyketideg Pregnanes 1 and 2 Steroidsf Mitochondrial respiratory 1.1–1.9 μM Undetermined ITA, IND (Ciavatta et al., 2004) (141–142)/coral chain inhibition f Psammocinia sp. diterpenes Terpene Human 15-lipoxygenase 0.3–0.8 μM Reduction of lipoxygenase USA (Cichewicz et al., 2004) 553 (2007) 145 C Part Physiology, and Biochemistry Comparative / al. et Mayer A.M.S. (143–147)/sponge inhibition non-heme ferric center Punaglandins (148–152)/coral Polyketideg Cytotoxicity and apoptosis 0.04–0.37 μM P53 accumulation and USA (Verbitski et al., 2004) ubiquitin isopeptidase activity in vivo and in vitro Schulzeienes A–C Alkaloide/ α-glucosidase inhibition 0.048–0.1 μM Undetermined JAPN, NETH (Takada et al., 2004) (153–155)/sponge polyketide Sinularia and Lobophytum Glycosidic steroidf 5α-reductase inhibition ND Undetermined IND, MEX (Radhika et al., 2004) sp. steroids (156–159)/ soft coral Siphonodictyal C (160)/sponge Merosesquiterpenee CDK4/cyclin D1 inhibition 9 μg/mL Undetermined NZEL, SWI, (Mukku et al., 2003) USA Spirastrellolide A (161)/sponge Polyketideg Protein phosphatase 2 A 0.001 μM Undetermined CAN, USA (Williams et al., 2004a) inhibition Spongia sesquiterpenoid Merosesquiterpenef DNA polymerase B lyase 16.2 μg/mL Undetermined USA (Cao et al., 2004) (162)/sponge activity inhibition Strobilin-felixinin Sesterterpenef Antioxidant and radical ND Superoxide scavenging CHI, S.KOR (Jiang et al., 2004) (163, 164)/sponge scavenger inhibition and H2O2 induced DNA strand scission protection Sulfatobastadins 1 and 2 Bromotyrosine Inhibition of ryanodine 13–29 μM Undetermined USA (Masuno et al., 2004) (165, 166)/sponge peptidese binding hPolysaccharide. a Organism, Kingdom Animalia: ascidians (Phylum Chordata), corals (Phylum Cnidaria), sea cucumber (Phylum Echinodermata), sponge (Phylum Porifera); Kingdom Plantae: alga. b IC50, ND: not determined. c MMOA: molecular mechanism of action. d Country: ARG: Argentina; CAN: Canada; CHI: China; FRA: France; GER: Germany; IND: India; INDO: Indonesia; ITA: Italy; JAPN: Japan; MEX: Mexico; NETH: The Netherlands; NZEL: New Zealand; POR: Portugal; RUS: Russia; S. KOR: South Korea; SLO: Slovenia; SPA: Spain; THAI: Thailand; TUR: Turkey; UK: United Kingdom. e Nitrogen-containing compound. f Terpene. – g Polyketide. 581 569 570 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

3.1. Anti-inflammatory compounds Ohgami et al. (2003) reported the effect of astaxanthin (68), a carotenoid found in crustacean cells, salmon and sea stars on The anti-inflammatory pharmacology of the marine com- lipopolysaccharide-induced uveitis in rats both in vitro and in pounds astaxanthin, bolinaquinone, cacospongionolide B, vivo. The investigators observed that astaxanthin, at 100 mg/kg, clathriol B, conicamin, cycloamphilectene 2, elisabethadione, suppressed development of uveitis and was as potent as 10 mg/kg plakohypaphorine, pourewic acid A, methylpourewate B, prednisolone. The mechanism of action determined for astax- cadlinolide C, petrocortyne A, petrosaspongiolides M-R, anthin probably involved inhibition of nitric oxide, prostaglandin pseudopterosin N, pseudopterosin R, and seco-pseudopterosin E2 and TNF-α generation. Lucas et al. (2003b) described a E was reported during 2003–4, a large increase from our detailed mechanistic study on the modulatory effect of bolina- previous reports (Mayer and Lehmann, 2000; Mayer and quinone (69), a sesquiterpenoid isolated from a Dysidea sp. Hamann, 2002, 2004, 2005). sponge, in several models of acute and chronic inflammation. The

O N N N H acylaspermidine D (113) O N N N

acylaspermidine E (114)

OHOH Br H Br N N N Cl H H H N n = 29, 99 ageladine A (115) NH AcO H agosterol C (116) alkylpyridinium (117) H2N OAc OAc

HO HO

N OH OH H H

N n = 19-29 or 99

arenarol (119) isoarenarol (120) polyalkylpyridinium (poly-APS) (118) N

NH2

N N OH OMe N N O O O O HO2C S O OSO3Na callysponginol sulfate A (122) NH N

unnamed nucleoside derivative (121)

Fig. 3. A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 571

OH O O MeO N H NMe2OH N

H H O H O PO HO CN 2 3 O clionasterol (124)

OH OH OMe calyculin A (123)

O O OH Br

OH O cymopol (126) OH O

cucumarioside A2-2 (125) OH MeOSO3O OH OH OH O Br O O OMe OHO O OH O Br OH OH HO O OH O OH OH OH OH avrainvilleol (127) unnamed diterpenoid (128)

OH O O H 4 R1 furospinosulin-1 (131) CO2R

unnamed nor-bisditerpenoids (129) R = H R2 (130) R = Me 4-OH-3-tetraprenylphenylacetic acid (132) R1 = OH, R2 = CH2CO2H 4-OAc-3-tetraprenyl benzoic acetate (133) R1 = OAc, R2 = CO2H

H O3SO H H

O3SO H OSO3

halistanol sulfate (134)

Fig. 3 (continued ).

observation that bolinaquinone significantly inhibited cytokine, peritoneal macrophages in vitro,aswellasinanin vivo model of iNOS expression and eicosanoid (LTB4, PGE2) generation inflammation, cacospongionolide B decreased nitric oxide, in vitro and in vivo in several models of inflammation through prostaglandin E2 and TNF-α generation as well as the secretory PLA2 inhibition led the authors to propose that corresponding gene expression. At the molecular level, cacos- bolinaquinone is a marine compound of “potential interest in pongionolide B inhibited nuclear factor-κ-DNA binding activity the search for new anti-inflammatory agents”. Posadas et al. and enhanced IκB-α expression. Keyzers et al. (2003) contributed (2003a) extended the cellular and molecular pharmacology of the a novel anti-inflammatory sterol, clathriol B (71) from the New sesterterpene cacospongionolide B (70) isolated from the Zealand sponge Clathria lissosclera. Clathriol B was shown to Mediterranean sponge Fasciospongia cavernosa, and previously moderately inhibit production of superoxide anion from agonist- shown to be an inhibitor of secretory phospholipase A2.Inmouse stimulated human peripheral blood neutrophils. A novel indole 572 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

HO O O

MeO N O OMe OH R1 R3 compound D (137) O O R2 P N OMe OMe O MeO O

135 R1 = OMe, R2 = H, R3 = OH 136 R1 = H, R2 = OMe, R3 = OMe

lamellarin G (135) H2N lamellarin I (136) N N OH HO

CO2H N H Br meridianin E (139) (+)-subersic acid (138)

CO2Me OSO3Na H N 4 O OSO3Na

penasulfate A (140)

AcO HO

H CO2H

H H OAc H O O unnamed pregnane (141) H unnamed pregnane (142) jaspic acid (143)

HO O

OH HO jaspaquinol (144) chromarol A (145)

Fig. 3 (continued ). alkaloid histamine antagonist, conicamin (72), was isolated from antihistamine activity was isolated from the Caribbean sponge the Mediterranean tunicate Aplidium conicum (Aiello et al., Plakortis simplex (Borrelli et al., 2004). The authors noted that 2003). Ex vivo studies with guinea pig ileum demonstrated a the antihistamine activity appeared to be “connected to the concentration-dependent reduction of histamine-induced contrac- number and nature of the halogen atoms”, because replacement of tions, probably by a non-competitive mechanism. Lucas et al. the iodine atom by chlorine resulted in a loss of the antihistamine (2003a) examined the effects of a series of 6 new cycloamphi- property of this compound. Three novel diterpenes, namely lectenes isolated from the Vanuatu sponge Axinella sp. on murine pourewic acid A (75), methylpourewate B (76) and cadlinolide C macrophage and human neutrophil functions. All compounds (77), were purified from the New Zealand sponge Chelonaply- tested reduced nitric oxide (NO) production in the submicromolar silla violacea (Keyzers et al., 2004). The three diterpenes range. Interestingly, cycloamphilectene 2 (73), which reduced NO moderately inhibited production of the inflammatory superoxide production and elastase release without affecting TNF-α release, anion from human peripheral blood neutrophils stimulated with inhibited the nuclear factor-κB pathway and also exhibited in vivo phorbol myristate acetate or N-formyl-methionine-leucine- activity. One novel iododinated plakohypaphorine (74)with phenylalanine. Hong et al. (2003) investigated the anti- A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 573

O HO2C

HO OH chromarol D (146) 4-hydroxy-3-tetraprenylbenzoic acid (147)

AcO OAc OAc O O CO Me CO2Me 2 HO HO OAc OAc OH OH

punaglandin 2 (148) punaglandin 3 (149)

OAc OAc OAc O AcO O CO Me 2 O CO2Me HO HO OAc OAc HO OH OH OH

punaglandin 4 (150) punaglandin 6 (152) Z-punaglandin 4 (151)

HO OSO3Na

N O R O NaO3SO OH N H OSO3Na schulzeine A (153) R = Me schulzeine C (155) R = H

HO OSO3Na

N O O NaO3SO OH OH N H OSO Na schulzeine B (154) 3 O R

O OH PR-01 (156) R = OH PR-02 (157) R = H HO HO

Fig. 3 (continued ).

inflammatory properties of petrocortyne A (78), a C46 poly- and in vivo while concomitantly inhibiting NF-κBsignaling.The acetylenic alcohol isolated from the marine sponge Petrosia sp. authors' results suggested that petrosaspongiolide M had Petrocortyne A inhibited release of both TNF-α (IC50 =2.35μM) “potentially (a) wide therapeutic spectrum” in inflammatory and nitric oxide from macrophages and induced homotypic conditions. Monti et al. (2004) extended the molecular pharma- aggregation of U937 human leukemic monocytes, a process that cology of the marine anti-inflammatory petrosaspongiolides M-R appears to involve phosphorylation of several intracellular (79–83), bioactive sesterterpenes isolated from the marine sponge signaling molecules. The molecular pharmacology of petrosas- Petrosaspongia nigra. The irreversible inhibition of bee-venom pongiolide M (79) was characterized by Posadas et al. (2003b), phospholipase A2 (PLA2) was investigated by mass spectrometry who determined that this marine sesterterpenoid inhibited and molecular modelling approaches and demonstrated that production of nitrite, prostaglandin E2 and TNF-α both in vitro petrosaspongiolides N, O, P and R shared the same inhibition 574 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581

CHO

NaO3SO OSO3Na

R2 OSO3Na

HO R OH 1 OH

PR-03 (158) R1 = OH, R2 = H siphonodictyial (160) PR-04 (159) R1 = H, R2 = OH

MeO O OH O OMe HO C O OH 2 O O Cl

O O HO HO ilimaquinone (162) O O OH HO OMe OH

spirastrellolide A (161) O

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

OH N H OH Br N

O O

O O Br O O OH (7E,13Z,20Z)-strobillinin (164) Br Br

HO O

Br N OH H N N H OH Br N bastadin-5 (165)

O NaO3SO

Br OH 1-O-sulfatohemibastadin-1(166)

Fig. 3 (continued ). mechanism and covalent binding site already reported for petro- pseudopterosins from the Caribbean sea whip P. elisabethae were saspongiolide M. Ata et al. (2003) reported two new diterpenes evaluated in an in vitro anti-neuroinflammatory assay (Rodríguez pseudopterosin N (84) and seco-pseudopterosin E (85) and the et al., 2004). Pseudopterosin R (87) was observed to be the most hydroxyquinone elisabethadione (86) from the marine gorgonian promising compound because it significantly inhibited the P.elisabethae with in vivo anti-inflammatory activity. Interestingly generation of thromboxane B2 (IC50 =4.7 μM) from activated all three compounds inhibited edema (inflammation) in a mouse rat brain macrophages. Although the molecular mechanism of ear anti-inflammatory assay more potently than “the well action of pseudopterosin R remains currently undetermined, the characterized pseudopterosins A and E”. With the purpose of authors concluded that it “could become an anti-inflammatory lead contributing to the search of novel agents to treat neuroinflamma- compound” for anti-neuroinflammatory drug design if its tion, several novel diterpene glycoside pseudopterosins and seco- inhibitory effect on thromboxane B2 release was further enhanced. A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 575

3.2. Cardiovascular compounds planations for the clinical efficacy of SPMG in HIV-infected patients (Miao et al., 2004). Two previous studies by the same Trevisi et al. (2004) reported novel studies on the mecha- research group noted that SPMG upregulated endothelial nism of action of callipeltin A (88), a previously described intercellular adhesion molecule-1 expression in human umbil- cyclic depsidecapeptide isolated from the marine sponges ical vein endothelial cells (Meiyu et al., 2003; Wang et al., Callipelta sp. and Latrunculia sp. In contrast to the lack of 2003b). effect on guinea pig aortic ring contractions, callipeltin A affected resting aorta contraction in a concentration-dependent 3.4. Compounds affecting the nervous system manner (IC50 =0.44 μM) by a mechanism that caused an increase in sodium influx, a phenomenon the authors describe as a Reports on both central and autonomic nervous system “Na+-ionophore action”. Thus callipeltin A's cardiovascular effects pharmacology of marine natural products during 2003–4 studies are probably caused by “its capacity of mediating Na+ transport”. involved aplidine, aspermytin A, cribronic acid, dysibetaines, esmodil, jamaicamides, labuanine A, linckosides C–E, acidic 3.3. Compounds affecting the immune system oligosaccharide sugar chain, parguerol and isoparguerol, petrosaspongiolide M, sargaquinoic acid, SJG-2 ganglioside, With the purpose of contributing to the discovery of small δ-conotoxin, ω-conopeptide MVIIA and χ-conopeptide MrIA. molecule agonists and antagonists of chemokine receptors, Yang Perez et al. (2003) investigated the inhibitory effect of the et al. (2003d), reported a new sesterterpene sulfircin (89)purified proline-containing cyclic peptide aplidine (95), isolated from from the marine sponge Ircinia sp. that inhibited the CCR7 the tunicate Aplidium albican, on the in vitro aggregation of chemokine receptor, a receptor involved in the regulation of peptide PrP 106–126, a fraction of the prion protein which has Tcells and dendritic cell mobilization into lymphoid organs. Anti- been hypothesized to be involved in fatal neurodegenerative adhesive mucin-type glycoproteins were characterized from the diseases and which can kill neuronal cells in culture. The fact mucus secretions of starfish Marthasterias glacialis and Porania that aplidine was observed to be a strong inhibitor of the pulvillus, and the brittlestar Ophiocomina nigra (Bavington et al., aggregation of PrP 106–126 into β-sheet fibrils at a 1:1 molar 2004). The investigators observed that partially purified mucus ratio prompted these investigators to propose that it may be “a glycoproteins from all three species were not cytotoxic and leading compound for drug development efforts”. inhibited neutrophil adhesion in a dose-dependent manner, thus Induction of neurite outgrowth in vitro was reported for the suggesting that by blocking adhesion of leukocytes these mucins marine natural compounds aspermytin A, labuanine A, lincko- might be of therapeutic value to treat inflammatory disorders. sides C–E, parguerol and isoparguerol, ganglioside species SJG- Yamada et al. (2004) contributed a new series of eremophilane 2 and sargaquinoic acid. Tsukamoto et al. (2004a) isolated a new sesquiterpenoids, peribysins A–D(90–93), isolated from a strain polyketide, aspermytin A (96) from a cultured marine fungus, of Periconia byssoides, a fungus previously isolated from the sea Aspergillus sp. that induced neurite outgrowth at 50 μMin hare Aplysia kurodai. Although the molecular mechanism more than 50% of rat pheochromocytoma (PC-12) cells after two of action of the four peribysins currently remains undeter- days of in vitro treatment, an effect comparable to that of 50 ng/ mined, inhibition of the adhesion of HL-60 cells to HUVEC mL of nerve growth factor. Aoki et al. (2003) purified a novel (IC50 =0.1–2.7 μM), was significantly more potent than that pyridoacridine alkaloid labuanine A (97) from the Indonesian observed with the control agent herbimycin A (IC50 =38μM). A marine sponge Biemna fortis that induced multipolar type 1,3 β glucan, named phycarine, chemically indistinguishable neurite outgrowth in Neuro 2 A neuroblastoma cells (1–3 μM) from the known polysaccharide laminarin, was isolated from the by a putative mechanism that “may relate with inhibition of alga Laminaria digitata (Vetvicka and Yvin, 2004). A detailed topoisomerase II”, a hypothesis currently under investigation. pharmacological investigation revealed that phycarine stimulated Qi et al. (2004) contributed three new bioactive steroid phagocytic activity in peritoneal macrophages and potentiated the glycosides linckosides C–E(98–100) from the Okinawan synthesis and release of interleukin-1, 6 and tumor necrosis factor marine sea star Linckia laevigata, which potently induced α. Interestingly, phycarine increased NK cell-mediated killing of neurite outgrowth in rat PC-12 cells, as well as synergistically tumor cells both in vitro and in vivo by interacting with the enhanced the neuritogenic activity of nerve growth factor, a CD11b/CD18 receptor (the complement receptor type 3 receptor). chemical that has been shown to be essential for neuronal Three studies were reported on the pharmacology of a sulfated outgrowth, survival, function maintenance and prevention of polymannuroguluronate (SPMG) (94) a polysaccharide with an aging in the central and peripheral nervous system. Bioassay- average molecular weight of 8.0 kDa isolated from brown algae, guided fractionation lead to the isolation of parguerol (101) and which recently entered Phase II clinical trial in China as the first isoparguerol (102) from the sea hare A. kurodai (Tsukamoto anti-AIDS drug candidate. While SPMG was initially reported to et al., 2004b). Both compounds, the first neurotrophic com- bind to 28 amino acids located in the HIV viral glycoprotein pounds reported from sea hare metabolites, stimulated neurite gp120 V3 loop (Meiyu et al., 2003), more recently, SPMG was outgrowth in PC-12 cells treated with either 25 or 50 μg/mL of shown by flow cytometry and fluorescent microscopy analysis to the compounds for two days. Further pharmacological research bind to lymphocyte CD4 receptors, a receptor type known to will be required to determine the molecular mechanism leading interact with the HIV virus gp120 envelope glycoprotein, a to morphological changes in PC-12 cells. Two studies were finding that might contribute to additional mechanistic ex- reported on the pharmacology of the low molecular weight 576 A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 quinonic compound sargaquinoic acid (103) isolated from the (ROS). Thus the authors concluded that AOSC “might be a marine brown alga Sargassum macrocarpum, and previously potentially therapeutic compound for Alzheimer's disease”. noted to possess a novel nerve growth factor-dependent neurite Capasso et al. (2003) reported that petrosaspongiolide M (79) outgrowth promoting activity at the nanogram range. Kamei and reduced morphine withdrawal in an in vitro model. Although the Tsang (2003) investigated the signaling pathways involved mechanism underlying petrosaspongiolide M-induced inhibi- using a pharmacological approach and concluded that sargaqui- tion of morphine withdrawal remains undetermined, one noic acid enhanced neurite outgrowth in PC-12 neuronal cells by possibility raised by the investigators was the putative inhibition involving both TrkA-mitogen-activated protein kinase and of extracellular type II phospholipase A2 by this potent anti- adenylate cyclase-protein kinase A signal transduction path- inflammatory marine sesterterpene. ways. In a subsequent study, the neuroprotective effect of Extensive research on the preclinical and clinical pharma- sargaquinoic acid was shown to be independent of nerve growth cology of conotoxin molecules resulted in the synthetic factor and phosphatidylinositol 3 kinase, a key signaling molecule equivalent of ω-conopeptide MVIIA (110), a 25-amino acid (Tsang and Kamei, 2004). Kaneko et al. (2003) reported the polybasic peptide derived from the marine snail Conus magus, structure of a novel ganglioside SJG-2 (104) isolated from the sea receiving approval from the Food and Drug Administration on cucumber Stichopus japonicus which appears to be the “first December 23, 2004. Currently, Ziconotide (Prialt®), which is ganglioside containing either the branched sugar chain moiety or marketed by Elan Biopharmaceuticals, Inc., constitutes the third the N-acetylgalactosamine residue”. While SJG-2 only displayed drug in the U.S. Pharmacopeia which has been derived from neuritogenic activity in the presence of nerve growth factor, it was marine chemicals. Staats et al. (2004) reported a double-blind, more potent than the GM1 mammalian ganglioside. placebo-controlled, randomized trial conducted from 1996– Four marine compounds (105–108;Fig.2)wereshownto 1998 in 32 study centers in the United States, Australia and the target receptors present in the nervous system. Sakai et al. (2003) Netherlands which assessed the safety and efficacy of intrathecal contributed to the search for novel ionotropic glutamate receptor ziconotide. Ziconotide selectively binds to the N-type voltage- ligands by reporting the isolation of the novel amino acid cribronic sensitive calcium channels located in neurons thereby blocking acid (105) from the marine sponge Cribrochalina olemda. neurotransmission and resulting in significant analgesia. In this Cribronic acid-induced potent convulsive behavior in mice upon clinical study, intrathecal ziconotide provided clinically and intracerebroventricular injection (ED50 =29±3 pmol/mouse), as statistically significant analgesia in 111 patients with pain from well as inhibited binding of an N-methyl-D-aspartic acid (NMDA) cancer or AIDS. As part of a program to explore the diversity of receptor ligand (IC50 =83±15 nM). In 2004, Sakai et al. (2004) conotoxins produced by Conus marine snails found off the isolated two novel cyclopropane amino acids dysibetaine CPa Indian coast, Sudarslal et al. (2003) reported the isolation and (106) and dysibetaine CPb (107) from the marine sponge Dysidea characterization of a novel 26 peptide δ-conotoxin (111) isolated herbacea collected in Micronesia, that showed weak affinity and purified from the venom of the marine snail Conus amadis, toward the NMDA-type and the kainic acid-type ionotropic collected in the Bay of Bengal. The observation that this novel glutamate receptors in a radioligand binding assay. The δ-conotoxin inhibited the inactivation of sodium current in investigators concluded that the binding of these compounds to cloned rat brain IIA α-subunit channels led the investigators to the glutamate receptor was of interest because they both lacked “a conclude that “conotoxins from some molluscivorous snails glutamate equivalent structure in the molecules”. A screening may also be active on mammalian Na+ channels”.Sharpeetal. program for bioactive compounds from marine cyanobacteria led (2003) extended the molecular pharmacology of χ-conopeptide to the isolation of the novel lipopeptides jamaicamide A (108), B MrIA (112), a 13-residue peptide isolated form the venom of the and C (Edwards et al., 2004), compounds that exhibited sodium marine snail Conus marmoreus. The investigators reported that channel blocking activity at 5 μM, producing about half the the χ-conopeptide MrIA inhibited the norepinephrine trans- response of saxitoxin applied at 0.15 μM. porter by a non-competitive mechanism that possibly involve a During 2003–4, additional marine compounds (109–112; binding site “predicted to be distinct from the substrate binding Fig. 2) were reported to exhibit pharmacological effects on the site but to share some commonality with the antidepressant nervous system. Bioassay-guided fractionation of the marine binding site”. sponge Raspailia sp. yielded the known synthetic compound esmodil (109), reported in the patent literature in 1935 (Capon 4. Marine compounds with miscellaneous mechanisms of et al., 2004a). More than six decades ago, esmodil, an action acetylcholine mimic, was shown to be potentially “useful in treating retention of urine in humans and as influencing the Table 3 lists marine compounds with miscellaneous pharma- parasympathetic nervous system in cats, rabbits and the Indian cological mechanisms of action, with their respective structures buffalo”. Hu et al. (2004) reported interactions of an acidic presented in Fig. 3. Interestingly, and in contrast with the 109 oligosaccharide sugar chain (AOSC) from the brown alga chemicals included in Tables 1 and 2, this third group of 54 Echlonia kurome with the amyloid beta protein. AOSC was marine compounds which was isolated from a variety of marine observed to inhibit the toxicity induced by amyloid beta protein organisms, includes not only nitrogen-containing compounds in both rat cortical cells as well as human neuroblastoma cells by (i.e. proteins, peptides), but also terpenes and polyketides. a mechanism that involved inhibition of apoptosis, reduction of As shown in Table 3, for a limited number of these marine intracellular Ca2+ and the generation of reactive oxygen species natural products, namely acylspermidine D and E (113, 114), A.M.S. Mayer et al. / Comparative Biochemistry and Physiology, Part C 145 (2007) 553–581 577 ageladine A (115), alkylpyridiniums (117, 118), Atriolum 6. Conclusion robustum nucleoside (121), calyculin A (123), Cell-III, meridianin E (139), Psammocinia sp. diterpenes (143–147), punaglan- During 2003–4, and for the first time in many decades, a dins (148–152) and strobilin-felixinins (163, 164), both the marine natural product, namely ziconotide (Prialt®) (110) pharmacological activity and a molecular mechanism of was approved for patient care by the U.S. Food and Drug action have been investigated and reported. In contrast, for Administration for the management of severe chronic pain in all the other compounds shown in Table 3, although a patients for whom intrathecal therapy is necessary, and who pharmacological activity was reported, no additional infor- appear to be intolerant of or refractory to other treatments, such as mation was available on the molecular mechanism of action systemic analgesics, adjunctive therapies or intrathecal morphine. of these chemicals during 2003–2004. Although research into the non-antitumor and cytotoxic pharmacology of marine natural products remained concentrated in the 5. Reviews on marine pharmacology specific areas we have highlighted in our present review, this contribution together with our previous ones (Mayer and Specific areas of marine pharmacology research benefited Lehmann, 2000; Mayer and Hamann, 2002, 2004, 2005), from a number of excellent reviews published during 2003–4: demonstrates that marine pharmacology research continued to (a) general marine pharmacology: natural products as sources proceed at a very active pace in 2003–4, involving natural product of new drugs over the period 1981–2002 (Newman et al., 2003); chemists and pharmacologists from 28 foreign countries and marine natural products from marine invertebrates and sponge- the United States. Thus, if the rate of preclinical and clinical associated fungi (Proksch et al., 2003a,b); the biopotential of pharmacological research continues to be sustained over time, marine sponges from China oceans (Zhang et al., 2003); marine additional marine natural products will probably become natural products as therapeutic agents (patents): part 2 (Frenz available as novel therapeutic agents to treat multiple disease et al., 2004); natural product diversity of New Caledonia: a categories. pharmacologically oriented view (Laurent and Pietra, 2004); (b) antimicrobial marine pharmacology: genomic screening to Acknowledgements identify novel marine antimicrobial peptides (Patrzykat and Douglas, 2003); marine natural products as anti-infective agents This publication was made possible by grant number 1R15 (Donia and Hamann, 2003); mining marine microorganisms as a ES012654, from the National Institute of Environmental Health source of new antimicrobials and antifungals (Bernan et al., Sciences, NIH, to AMSM, and 1R01A136596, from the 2004); antimicrobial peptides from marine invertebrates (Tincu National Institute of Allergy and Infectious Diseases, NIH, and Taylor, 2004); bioactive peptides from marine sources: and the Medicines for Malaria Venture (MMV), to MTH. Its pharmacological properties and isolation procedures (Aneiros content is solely the responsibility of the authors and does not and Garateix, 2004); (c) anticoagulant marine pharmacology: necessarily represent the official views of the NIEHS, NIH. recent advances in marine algal anticoagulants (Matsubara, Additional financial support by Midwestern University is 2004); the use of algae and invertebrate sulfated fucans as gratefully acknowledged. Jennifer Allman is acknowledged anticoagulant and antithrombotic agents (Mourao, 2004); for her assistance with the preparation of Fig. 1 (MTH). The (d) antituberculosis, antimalarial and antifungal marine excellent support for literature searches in PubMed, Marinlit, pharmacology: antimycobacterial natural products (Copp, Current Contents® and Chemical Abstracts®, as well as article 2003); naturally occurring peroxides from marine sponges retrieval by library staff members as well as medical and with antimalarial and antifungal activities (Jung et al., 2003); pharmacy students of Midwestern University is most gratefully antifungal compounds from marine organisms (Molinski, 2004); acknowledged. The authors specially thank Ms. Mary Hall for (e) antiviral marine pharmacology: algae as a potential source carefully reviewing this manuscript. of antiviral agents (Luescher-Mattli, 2003); marine natural products as lead anti-HIV agents (Gochfeld et al., 2003); anti- References HIV activity from marine organisms (Tziveleka et al., 2003); proteoglycans from sponges as tools to develop new agents for Agafonova, I.G., Aminin, D.L., Avilov, S.A., Stonik, V.A., 2003. Influence of AIDS and Alzheimer's disease (Fernandez-Busquets and cucumariosides upon intracellular [Ca2+]i and lysosomal activity of Burger, 2003); antiviral marine natural products (Gustafson macrophages. J. Agric. Food Chem. 51, 6982–6986. et al., 2004); (f) anti-inflammatory marine pharmacology: anti- Aiello, A., Borrelli, F., Capasso, R., Fattorusso, E., Luciano, P., Menna, M., 2003. inflammatory metabolites from marine sponges (Keyzers Conicamin, a novel histamine antagonist from the Mediterranean tunicate Aplidium conicum. Bioorg. Med. Chem. Lett. 13, 4481–4483. and Davies-Coleman, 2005); (g) nervous system marine Alonso, D., Khalil, Z., Satkunanthan, N., Livett, B.G., 2003. Drugs from the sea: pharmacology: conotoxins as Drug-leads for neuropathic pain conotoxins as drug leads for neuropathic pain and other neurological and other neurological conditions (Alonso et al., 2003); conditions. Mini Rev. Med. Chem. 3, 785–787. conotoxins and structural biology: a prospective paradigm for Aneiros, A., Garateix, A., 2004. Bioactive peptides from marine sources: drug discovery (Grant et al., 2004); drugs from the sea: pharmacological properties and isolation procedures. J. Chromatogr. B: Analyt. 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