key: cord-271068-rwx171oj
authors: Mayer, Alejandro M.S.; Rodríguez, Abimael D.; Berlinck, Roberto G.S.; Fusetani, Nobuhiro
title: Marine pharmacology in 2007–8: Marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous system, and other miscellaneous mechanisms of action
date: 2010-09-03
journal: Comp Biochem Physiol C Toxicol Pharmacol
DOI: 10.1016/j.cbpc.2010.08.008
sha: 
doc_id: 271068
cord_uid: rwx171oj

The peer-reviewed marine pharmacology literature in 2007–8 is covered in this review, which follows a similar format to the previous 1998–2006 reviews of this series. The preclinical pharmacology of structurally characterized marine compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 74 marine natural products. Additionally, 59 marine compounds were reported to affect the cardiovascular, immune and nervous systems as well as to possess anti-inflammatory effects. Finally, 65 marine metabolites were shown to bind to a variety of receptors and miscellaneous molecular targets, and thus upon further completion of mechanism of action studies, will contribute to several pharmacological classes. Marine pharmacology research during 2007–8 remained a global enterprise, with researchers from 26 countries, and the United States, contributing to the preclinical pharmacology of 197 marine compounds which are part of the preclinical marine pharmaceuticals pipeline. Sustained preclinical research with marine natural products demonstrating novel pharmacological activities, will probably result in the expansion of the current marine pharmaceutical clinical pipeline, which currently consists of 13 marine natural products, analogs or derivatives targeting a limited number of disease categories.

The current article presents the preclinical pharmacology of marine natural products during 2007-8 maintaining the format used in the previous reviews (Mayer and Lehmann, 2000; Mayer and Hamann, 2002 , 2005 Mayer et al., 2007 Mayer et al., , 2009 . The preclinical pharmacology of antitumor and cytotoxic marine compounds has been reported in separate reviews (Mayer, 1999; Mayer and Lehmann, 2001; Mayer and Gustafson, 2003 , 2006 .

We have restricted the current as well as previous reviews to peerreviewed articles reporting the bioactivity or pharmacology of structurally characterized marine compounds. As we have done previously, we have continued to use a modification of Schmitz's chemical classification (Schmitz et al., 1993) to assign marine natural product structures to six major chemical classes, namely, polyketides, terpenes, peptides, alkaloids, shikimates, and sugars. Novel antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral preclinical pharmacology of marine metabolites are presented in Table 1 with the corresponding structures shown in Fig. 1 . Marine compounds that affect the immune and nervous systems, as well as those with anti-inflammatory effects are grouped in Table 2 , with their corresponding structures presented in Fig. 2 . Finally, marine compounds that have been demonstrated to affect a variety of cellular and molecular targets are exhibited in Table 3 , and their structures depicted in Fig. 3 . Several articles were published during 2007-8 reporting the preclinical pharmacology of extracts or structurally uncharacterized marine compounds, and although these have not been included in the present review, they probably may warrant further investigation: antimicrobial effects of the Turkish red alga Jania rubens (Karabay-Yavasoglu et al., 2007) ; antimicrobial activity in Portuguese marine cyanobacteria Synechocystis sp. and Synechococcus sp. extracts towards Gram-positive bacteria (Martins et al., 2008) ; antibacterial activity against human and fish bacteria from the sub-Arctic colonial ascidian Synoicum pulmonaria from northern Norway (Tadesse et al., 2008) ; strong antibiotic-producing potential in actinomycetes from sediments in the Trondheim fjord in Norway (Bredholt et al., 2008) ; antibacterial activity of deep-sea bacteria from sediments of the West Pacific Ocean ; potent antimicrobial activity in the green alga Enteromorpha intestinalis collected in Gujarat, India (Nair et al., 2007) ; a nonhemolytic antimicrobial lipopeptide derived from the marine bacterium Bacillus circulans (Das et al., 2008) ; a T-antigen binding lectin with bioactivity against a broad spectrum of Gram-positive and Gram-negative bacteria from the sea cucumber Holothuria scabra (Gowda et al., 2008) ; anticoagulant activity of a 100-500 kDa polysaccharide isolated from the fermented red seaweed Lomentaria catenata which was greater than the clinical anticoagulant heparin (Pushpamali et al., 2008) ; antimycobacterial activity in long-chain fatty acids isolated from the red alga Polysiphonia virgata (Saravanakumar et al., 2008) ; antileishmanial and anti-trichomonal activity in organic extracts of several Mexican red and brown algae Moo-Puc et al., 2008) ; anti-HIV-1 activity of novel sulfated galactans isolated from the Chinese red algae Grateloupia longifolia and Grateloupia filicina ; significant anti-herpes simplex virus activity in a 30 kDa polysaccharide isolated from the red alga Gracilaria corticata ; immunomodulatory effects of an enzymatic extract from the South Korean marine brown alga Ecklonia cava on murine splenocytes (Ahn et al., 2008) ; immunostimulant properties of a sulfated polysaccharide isolated from the Brazilian red alga Champia feldmannii ; antioxidant and antimicrobial activity of the Indian red and brown seaweed methanolic extracts with high phenolic contents (Devi et al., 2008) ; and decreased expression of key regulatory genes involved in cholesterol and fatty acid biosynthetic pathways by the lipid extract of the cyanobacterium Nostoc commune var. sphaeroides Kützing (Rasmussen et al., 2008) .

2. Marine compounds with antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis, and antiviral activities Table 1 presents preclinical pharmacology reported during 2007-8 on the antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis, and antiviral pharmacology of the marine natural products (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74) shown in Fig. 1 .

Contributing to the global search for new antimicrobials to combat antibiotic-resistant strains of pathogenic bacteria, marine ecological niches have been described recently as "particularly promising" (Fischbach and Walsh, 2009) . During 2007-8, 38 studies reported novel antibacterial marine natural products isolated from marine bacteria, fungi, sponges, worms and fish, a larger effort than the ones reported in previous years (Mayer et al., 2009) , and previous reviews of this series.

Only six papers provided detailed mechanism of action studies with marine antimicrobial compounds. Kanoh et al. (2008b) reported the discovery of the novel bioactive spirodioxynaphthalene ascochytatin (1) isolated from cultures of a marine-derived fungus Ascochyta sp. NGB4, which inhibited B. subtilis growth (MID= 0.3 μg/disk) by targeting the function of the bacterial growth regulatory system TCS (YycG/YycF). Kitani et al. (2008) discovered that the 120 kDa acidic glycoprotein L-amino acid oxidase termed SSAP (2), isolated from the rockfish Sebastes schlegelli (Kitani et al., 2007) , acted selectively on Gram-negative bacteria (minimum inhibitory concentration (MIC) = 0.078-0.63 μg/mL). While H 2 O 2 was shown to mediate the antibacterial action of SSAP, electron microscopy analysis revealed that SSAP induced cell surface damage and morphological changes in several bacterial species. reported that the 21-residue peptide arenicin-1 (3) isolated from the marine polychaete Arenicola marina exhibited significant antibacterial activity against P. aeruginosa and Staphylococcus aureus (MIC = 2 μg/mL). Interestingly, arenicin-1 induced release of calcein from PE/PG liposomes, thus suggesting that the bacterial cell membrane is the main molecular target of the peptide. Jang et al. (2007c) extended the pharmacology of the alkaloid isoaaptamine (4), isolated from the marine sponge Aaaptos aaptos. Isoaaptamine inhibited sortase A (IC 50 =3.7 μg/mL), an enzyme involved in S. aureus cell wall protein anchoring and virulence, thus potentially providing a novel lead compound "for further development" of potent antibacterials. Lee et al. (2008) isolated seven sesterterpenes (5, 6, 7, 8, 9, 10, 11 ) from a tropical sponge Dysidea sp. which demonstrated antibacterial activity against B. subtilis (MIC = 1.56-12.5 μg/mL) by inhibiting isocitrate lyase activity, a key enzyme in the glyoxylate cycle which is present in most prokaryotes, lower eukaryotes and plants, but not in vertebrates. Kanoh et al. (2008a) described a new sulfoalkylresorcinol (12) isolated (Kossuga et al., 2008) (continued on next page) from the marine-derived fungus Zygosporium sp. KNC52, which showed antimicrobial activity against methicillin-resistant S. aureus. The mechanism of action appeared to involve inhibition (IC 50 =12.5 μg/ mL) of the in vitro polymerization of FtsZ, a protein which is a structural homolog of eukaryotic tubulin, and that participates in bacterial cell division. As shown in Table 1 , several new marine antibacterials were also reported in 2007-8 ( Fig. 1) with MICs less than 10 μg/mL against antibiotic-resistant bacterial strains, although no mechanism of action studies were reported: the alkaloids ambiguine isonitriles H and I (13 14) isolated from a marine cyanobacterium Fischerella sp. (Raveh and Carmeli, 2007) ; the polyketides ariakemicins A and B (15, 16) isolated from a marine gliding bacterium Rapidithrix sp. (Oku et al., 2008) ; ayamycin (17) isolated from a bacterium Nocardia sp. ALAA 2000 (El-Gendy et al., 2008a) ; the alkaloids batzelladines L and M (18, 19) isolated from the Caribbean sponge Monanchora unguifera (Hua et al., 2007) ; a diphenyl ether (20) isolated from the Indonesian sponge Lamellodysidea herbacea (Hanif et al., 2007) ; essramycin (21) obtained from the culture broth of a marine Streptomyces sp. isolate Merv8102 (El-Gendy et al., 2008b) ; a meroditerpene (+)-isojaspic acid (22) isolated from the Papua New Guinean sponge Cacospongia sp. (Rubio et al., 2007) ; the bisindole pyrroles lynamicins A-D (23, 24, 25, 26) isolated from a novel marine actinomycete Marinispora sp. (McArthur et al., 2008) ; lipoxazolidinones A and B (27, 28) isolated from a marine actinomycete Marinispora sp. (Macherla et al., 2007) ; marinopyrrole A (29) isolated from an obligate marine Streptomyces strain (Hughes et al., 2008) ; a furanosesquiterpene (-)-microcionin-1 (30) isolated from a marine sponge Fasciospongia sp. (Gaspar et al., 2008) ; a macrolide phomolide B (31) isolated from a fungus Phomopsis sp. ; a sargaquinoic acid derivative (32) isolated from the brown alga Sargassum sagamianum (Horie et al., 2008) , and tauramamide (33), a lipopeptide isolated from the bacterium Brevibacillus laterosporus PNG276 (Desjardine et al., 2007) .

Furthermore during this period, several novel marine metabolites with moderate antimicrobial activity (MIC or IC 50 ranging from 10 to 50 μg/mL, or 10 to 50 μM, respectively), were also reported, but their weaker antibacterial activity precluded their inclusion in either Table 1 or Fig. 1 : acetylmajapolene A (MIC = 20 μg/disk) (Vairappan et al., 2008) , callophycoic acids A, B, G and H (MIC = 16-63.9 μg/mL) (Lane et al., 2007) ; corallidictyals A, B, C and D (MIC less than 20 μg/ mL) ; (S)-(+)-curcuphenol analogs (IC 50 = 34-44 μM) (Gul et al., 2007) ; cyclomarazines A and B (MIC = 13-18 μg/ mL) (Schultz et al., 2008) ; dehydroxychlorofusarielin B (MIC = 62.5 μg/mL) (Nguyen et al., 2007) , nodosol (MIC = 16 μg/ mL) (Kontiza et al., 2008) ; paeciloxanthone (MIC = 40 μg/disk) , palmitoleic acid (IC 50 = 10-20 μM) (Desbois et al., 2008) ; puupehenone-metabolites (MIC = 8-16 μg/mL) ; Tripalea clavaria C-secosteroids (MIC = 25 μg/disk) (Rodriguez Brasco et al., 2007) , shishididemniols A and B (MIC = 20 μg/disk) (Kobayashi et al., 2007b) , and zafrin (MIC = 50-125 μg/mL) (Uzair et al., 2008) .

Noteworthy were reports of novel marine antimicrobial peptides: dicentracin, a new component of the moronecidin family isolated from head kidney leukocytes from the sea bass Dicentrarchus labrax (Salerno et al., 2007) ; hepcidins, three novel antimicrobial peptides isolated from the tilapia Oreochromis mossambicus, with MICs (50-100 μg/mL) against Listeria monocytogenes, S. aureus, and Enterococcus faecium (Huang et al., 2007) ; scygonadin, a novel anionic antimicrobial peptide from the seminal plasma of the mud crab, Scylla serrata , and tunichromes, small dehydrodopaminecontaining peptides found in hemocyte cells of the ascidian Ascidia nigra that are capable of crosslinking proteins in vitro (Cai et al., 2008) .

Four articles published during 2007-8, reported anticoagulant marine natural products isolated from algae and clams, a number very similar to that reported in our previous review (Mayer et al., 2009) , and other reviews of this marine pharmacology series. Jung et al. (2007b) characterized a novel 7.7 kDa anticoagulant polypeptide termed TGAP with a partial sequence (34) from the muscle protein of the South Korean bivalve Tegillarca granosa. The anticoagulant polypeptide, which demonstrated low in vitro cytotoxicity to venous endothelial cells, specifically inhibited the blood coagulation factor Va, as well as the molecular interaction between factor IIa and factor Va in a ascochytatin (1 thrombin as well as potentiated antithrombin III-mediated inhibition of coagulation factor Xa.

Ten studies during 2007-8 reported on the antifungal activity of several novel marine natural products isolated from marine algae, bacteria, sponges and sea cucumbers, a decrease from our last review (Mayer et al., 2009) , and previous reviews of this series.

As shown in Table 1 , only one report extended the molecular pharmacology of novel antifungal marine metabolites. Symphyocladia latiuscula bromophenols (192, 193, 194, 195 Furthermore, several marine natural products showed significant antifungal activity (i.e. MICs that were either less than 10 μg/mL, 10 μM, or 10 μg/disk) (Table 1 and Fig. 1; 38 , 39, 40, 41, 42, 43, 44) , although no mechanism of action studies were reported in the published articles: callipeltins J and K (38, 39), MIC = 1 μM (D' Auria et al., 2007) , the triterpene glycoside holothurin B (40), MIC = 1.56 μg/ mL (Kumar et al., 2007) , the macrolide neopeltolide (41), MIC = 0.62 μg/mL , the cyclopeptide pedein A (42), MIC= 0.6-1.6 μg/mL (Kunze et al., 2008) , and pseudoceratins A and B (43, 44), MIC = 6.5-8.0 μg/disk (Jang et al., 2007b) . Hopefully, future studies on the molecular pharmacology of these marine compounds will elucidate their mechanisms of action.

Finally, several novel structurally characterized marine molecules isolated from sponges demonstrated MICs or IC 50 s greater than 10 μg/ mL or 10 μM, and therefore, because of the reported weaker antifungal activity, they have been excluded from Table 1 and Fig. 1 : eurysterols A and B (MIC = 15.6-62.5 μg/mL) (Boonlarppradab and Faulkner, 2007) ; nagelamides M and N (MIC = 33.3 μg/mL) (Kubota et al., 2008) , nortetillapyrone (MIC = 31-62 μg/mL) (Wattanadilok et al., 2007) , and Tydemania expeditionis triterpenoids (IC 50 = 26-55 μM) (Jiang et al., 2008) . These marine compounds may yet provide additional pharmacological leads in the ongoing global search for clinically useful antifungal agents.

As shown in Table 1 an increase from our previous review (Mayer et al., 2009) , and previous reviews of this series.

As shown in Table 1 , nine marine molecules were shown during 2007-8 to possess significant antimalarial activity, although mechanism of action studies were reported for only two compounds. Tasdemir et al. (2007) reported that (E)-oroidin (45) and (E)-oroidin TFA salt (46) isolated from the Turkish marine sponge Agelas oroides potently inhibited cultures of multidrug resistant K1 strain of Plasmodium falciparum (IC 50 = 3.9 and 7.9 μg/mL, respectively) with concomitant inhibition of FabI (enoyl-ACP reductase), a key enzyme of the type II fatty acid synthase cascade (IC 50 = 0.3 and 5.0 μg/mL, respectively). Further studies revealed that oroidin free base appeared to bind to "the enzyme-substrate complex or enzyme-cofactor complex" by an uncompetitive mechanism, providing further pharmacological characterization of the "first antimalarial marine natural product that targets P. falciparum FabI".

Additional antimalarial activity was reported for seven marine compounds. Two reports were contributed during 2007 by the Panama International Cooperative Biodiversity Groups project: McPhail et al. (2007) isolated a novel linear lipopeptide dragomabin (47) from the cyanobacterium Lyngbya majuscula with moderate antimalarial activity (IC 50 =6.0 μM), and significant differential toxicity between the malarial parasite and mammalian cells. Linington et al. (2007) discovered that the new cyclic hexapeptides venturamides A and B (48, 49) isolated from a Panamanian marine cyanobacterium Oscillatoria sp., demonstrated significant in vitro antiplasmodial activity against the W2 chloroquinone-resistant strain of the parasite (IC 50 =5.6-8.2 μM), with mild cytotoxicity to mammalian cells, the first "example of the identification of cyanobacterial peptides with selective antimalarial activity". Kasettrathat et al. (2008) proved that a new tetronic acid, nodulisporacid A (50), from a marine-derived fungus Nodulisporium sp. CRIF1 isolated from a Thai soft coral, was moderately antiplasmodial (IC 50 =1-10 μM) against chloroquine-resistant P. falciparum strain 94. Na et al. (2008) identified a new marine Streptomyces sp. H668 polyether (51) from Hawaii that showed in vitro antimalarial activity (IC 50 =0.1-0.2 μg/mL) against both P. falciparum chloroquine-susceptible (D6) and -resistant (W2) clones, with minimal cytotoxicity towards mammalian cells. Clark et al. (2008) found that a novel acylproline derivative, tumonoic acid I (52) from the Papua New Guinean marine cyanobacterium Blennothrix cantharidosmum, showed moderate antimalarial activity against P. falciparum (IC 50 =2 μM). Pontius et al. (2008a) isolated a heterocyclicsubstituted xanthone, chaetoxanthone B (53) from cultures of a marinederived fungus Chaetomium sp. that showed selective activity towards P. falciparum K1 strain (IC 50 =0.5 μg/mL).

Four marine compounds were reported to possess antiprotozoal activity. Kossuga et al. (2008) re-isolated the previously reported plakortide P (54) from the marine sponge Plakortis angulospiculatus. The compound displayed selective effects against both Leishmania chagasi (IC 50 = 0.5-1.9 μg/mL) and Trypanosoma cruzi (IC 50 = 2.3 μg/ mL), with low concomitant hemolytic and cytotoxic activities towards human macrophages. Reportedly, the mechanism of action towards intracellular L. chagasi did not appear to involve nitric oxide. Simmons et al. (2008) found that two novel lipopeptides viridamides A and B (55, 56) were nearly "equipotent" in inhibiting both Leishmania mexicana (IC 50 = 1.1 μM) and T. cruzi (IC 50 = 1.5 μM). Besides the antimalarial activity, Pontius et al. (2008a) discovered that chaetoxanthone B (53) had selective effects towards T. cruzi (IC 50 = 1.5 μg/ mL), with minimal cytotoxicity towards rat skeletal L6 myoblasts (IC 50 = 47 μg/mL).

Ten new marine compounds were reported in the global search for novel antituberculosis agents, a considerable increase from our previous reviews (Mayer et al., 2009) , and previous reviews of this series. Ospina et al. (2007) isolated a bioactive oxapolycyclic diterpene bipinnapterolide B (57) from the Colombian gorgonian coral Pseudopterogorgia bipinnata which weakly inhibited growth of M. tuberculosis H 37 Rv (66% inhibition at 128 μg/mL). Zhang et al. (2008) identified two new dimeric naphtha-γ-pyrones 8′-O-demethylnigerone (58) and 8′-O-demethylisonigerone (59) from the marinederived fungus Aspergillus carbonarius which showed weak antimycobacterial activity against M. tuberculosis (H 37 Rv, MIC = 43 and 21.5 μM, respectively). Interestingly, the presence of conjugated C=C-C=O bonds in the pyrane ring appeared to be crucial for antifungal activity. As a result of a continued investigation of the Caribbean sea whip Pseudopterogorgia elisabethae, Wei et al. (2007a) reported that the novel tricarbocyclic norditerpenes caribenols A (60) and B (61) weakly inhibited M. tuberculosis (H 37 Rv, MIC = 128 and 63 μg/mL, respectively). Furthermore, Wei et al. (2007b) discovered two novel ring B abeo-sterols parguesterols A (62) and B (63) in the Caribbean sponge Svenzea zeai, which inhibited M. tuberculosis (H 37 Rv, MIC = 7.8 and 11.2 μg/mL, respectively). Hopefully future information on the selectivity index of these two compounds will provide additional information to support the notion that they might "constitute important lead structures for the development of novel tuberculosis drugs due to their strong activity, specificity, and low toxicity". Berrue et al. (2007) noted that several bioactive polyketides, 24-norisospiculoic acid A (64), dinorspiculoic acid A (65), and norspiculoic acid A (66) from the Caribbean sponge Plakortis zyggompha also inhibited M. tuberculosis (H 37 Rv, MIC 99 = 50 μg/mL). Although all of these studies demonstrate that marine terpenes and polyketides constitute potentially novel antituberculosis leads, they unfortunately did not provide detailed mechanism of action pharmacology at the time of their publication.

As shown in Table 1 , three reports were published on the antiviral pharmacology of novel marine natural products against severe acute respiratory syndrome (SARS) Corona virus, herpes simplex, and dengue virus during 2007-8. de Lira et al. (2007) discovered that the new esculetin-4-carboxylic acid ethyl ester (67) from the Brazilian marine sponge Axinella cf. corrugata inhibited the SARS 3CL protease (IC 50 =46 μM). This is a potentially significant finding because the 3CL protease is a "high profile target" in SARS drug development as it appears to be involved in the release of replicative viral proteins as well as the RNA polymerase. Talarico et al. (2007) reported that a D,L-galactan hybrid C2S-3 (68) isolated from the Brazilian marine alga Cryptonemia crenulata showed potent antiviral activity against three clinical strains of dengue virus serotype 2 (IC 50 =0.8-16 μg/mL), together with low cytotoxicity. Further mechanistic work determined that C2S-3 appeared to be a "promising DENV-2 entry inhibitor". Mandal et al. (2008) described a sulfated xylomannan isolated from the Indian red seaweed Scinaia hatei which inhibited HSV-1 and HSV-2 (IC 50 =0.5-1.4 μg/mL), with low cytotoxicity, probably interfering with the HSV-1 multiplication cycle. Interestingly the "very good antiviral activity against the wide spectrum of HSV strains tested" suggested this compound might be a good candidate for further preclinical research.

Five reports contributed preclinical pharmacology of marine compounds active against the human immunodeficiency virus type-1 (HIV-1), the causative agent of the acquired immunodeficiency disease syndrome (AIDS), an increase from our previous reviews (Mayer et al., 2009) , and previous reviews of this series. Artan et al. (2008) reported that the phlorglucinol derivative 6, 6′-bieckol (69) isolated from the brown alga E. cava inhibited HIV-induced syncytia formation (IC 50 = 1.72 μM), viral p24 antigen production (IC 50 = 1.26 μM), and the activity of the HIV reverse transcriptase (IC 50 = 1.07 μM), with "no cytotoxicity" at concentrations that inhibited HIV replication "almost completely". Cirne-Santos et al. (2008) extended the molecular pharmacology of the diterpene dolabelladienetriol (70) isolated from the marine brown alga Dictyota pfaffii. The dolabellane diterpene blocked both synthesis and integration of the HIV-1 provirus by noncompetitively inhibiting the reverse transcriptase enzyme (Ki = 7.2 μM). The investigators proposed dolabelladienetriol (70) as a "potential new agent for anti-HIV-1 therapy". Plaza et al. (2007) described three new depsipeptides mirabamides A, C and D (71, 72, 73) isolated from the sponge Siliquariaspongia mirabilis that potently inhibited both HIV-1 in neutralization (IC 50 = 0.14-0.19 μM) and HIV-1 envelope-mediated cell fusion (IC 50 = 0.14-3.9 μM), suggesting these compounds act at an early stage of HIV-1 cell infection, "presumably through interactions with HIV-1 envelope proteins". Lu et al. (2007) added a "novel mechanistic profiling" of the previously reported sulfated polymannuroguluronate (SPMG) (74), a polysaccharide with an average molecular weight of 8.0 kDa isolated from the brown alga Laminaria japonica, that has been reported to be in Phase II clinical trials in China as an anti-AIDS drug candidate. SPMG appeared to eliminate the viral gene product known as transactivator of transcription protein (Tat)induced signal transduction as well as angiogenesis in AIDSassociated Kaposi's sarcoma cells. Furthermore, in 2008, Hui et al. (2008) demonstrated that SPMG appeared to show a neuroprotective effect because it decreased apoptosis caused by Tat-stimulated calcium overload in PC12 neuronal cells, thus suggesting SPMG might warrant further clinical studies in HIV-associated dementia. Table 2 summarizes the preclinical pharmacological research completed during 2007-8 with the marine compounds (75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132) shown in Fig. 2. 

The anti-inflammatory pharmacology of marine compounds reported during 2007-8 showed a considerable increase from our previous review (Mayer et al., 2009) , and previous reviews of this series. Several marine natural products were shown in preclinical pharmacological studies to target arachidonic metabolism in neutrophils and macrophages. Pearce et al. (2007a) reported two new tricyclic alkaloids ascidiathiazone A (75) and B (76) isolated from a New Zealand ascidian Aplidium species that affected superoxide production by human neutrophils in vitro (IC 50 = 0.44-1.55 μM), as well as murine peritoneal neutrophis ex vivo, with concomitant "low or nonexistent" liver and renal toxicity, thus suggesting that these two compounds might become "potential anti-inflammatory pharmaceutical" leads. Chao et al. (2008) identified the new cembranolides crassumolides A and C (77, 78) from the soft coral Lobophytum crassum which inhibited expression of iNOS and COX-2 (apparent IC 50 less than 10 μM). Similarly, from the same university, Cheng et al. (2008) found that new cembranolides from the soft coral Lobophytum duru, durumolides A-C (79, 80, 81) inhibited both the iNOS and COX-2 proteins in LPS-activated RAW 264.7 cells in vitro (apparent IC 50 less than 10 μM), suggesting that the α-methylene-γ-lactone moiety of these compounds was necessary for the observed activity. Shen et al. (2007) showed that new briarane-type diterpenoids frajunolides B and C (82, 83), isolated from the Taiwanese gorgonian Junceella fragilis, significantly inhibited superoxide anion and elastase generation from human neutrophils in vitro (apparent IC 50 greater than 10 μg/mL). Dang et al. (2008) demonstrated that the previously described fatty acids (84, 85) from the South Korean marine red alga Gracilaria verrucosa inhibited release by LPS-activated murine macrophages of the inflammatory nitric oxide, tumor necrosis factor α and interleukin-6 (apparent IC 50 less than 20 μg/mL), thus revealing that the conjugated enone moiety played a critical role in the antiinflammatory activity observed in vitro. Bittencourt et al. (2008) contributed novel preclinical pharmacology on a previously reported 90 amino acid polypeptide (86) isolated from the red alga Hypnea cervicornis. The mucin-binding agglutinin, which was extensively characterized with several in vivo models of nociception and inflammation, probably exerted its anti-inflammatory activity (apparent IC 50 = 0.1-1 mg/kg) via interaction of the polypeptide with the lectin carbohydrate-binding site, although the exact mechanism of action remains undetermined. El Sayed et al. (2008) demonstrated that manzamine A (87), (−)-8-hydroxymanzamine A (88), and hexahydro-8-hydroxymanzamine A (89) potently inhibited TXB 2 generation (IC 50 = 0.25, less than 0.1, and 1.97 μM, respectively) in brain microglia. These findings provide further support to the notion that manzamine alkaloids appear to be "viable anti-inflammatory leads" for the preclinical pharmaceutical development of agents to modulate both activated brain microglia and eicosanoid generation. Treschow et al. (2007) investigated four novel ω-3 polyunsaturated fatty acids (90, 91, 92, 93) from the New Zealand green-lipped mussel Perna canaliculus with an in vitro bioassay that used stimulated human neutrophil 5-lipoxygenase, demonstrating that the putative antiinflammatory potential of these compounds might be related to inhibition of leukotriene and prostaglandin metabolite production. Sansom et al. (2007) reported a bis-prenylated quinone (94) from the New Zealand brown alga Perithalia capillaris which inhibited superoxide anion production in human neutrophils (IC 50 = 2.1 μM) in vitro, with low toxicity. An explanation as to why the authors decided not to investigate the quinone "as an anti-inflammatory lead" remains unclear, although it was strongly cytotoxic towards human leukemia cells (IC 50 = 0.34 μM). Sugiura et al. (2007) characterized a novel antiallergic phlorotannin phlorofucofuroeckol B (PFF-B) (95) from the edible brown alga Eisenia arborea. PFF-B, inhibited β-hexosaminidase release from rat basophilic leukemia cells (IC 50 = 7.8 μM) in vitro, thus showing higher potency than Tranilast (Rizaben®) (IC 50 = 46.6 μM), a pharmaceutical agent used for treatment of allergic disorders such as asthma, allergic rhinitis and atopic dermatitis in Japan and South Korea. Kossuga et al. (2008) demonstrated that the polyketide plakortide P (54) isolated from the Brazilian sponge P. angulospiculatus, potently inhibited thromboxane B 2 release (IC 50 = 0.93 μM) from activated rat brain microglia, thus extending the preclinical pharmacology of this compound, which besides being antiparasitic as discussed earlier in this review, also appears to be a potentially "novel antineuroinflammatory agent". Pearce et al. (2007b) examined a halogenated furanone rubrolide O (96) isolated from a New Zealand ascidian Synoicum n. sp., which inhibited superoxide anion production in human neutrophils (IC 50 = 35 μM) in vitro with low toxicity. Although rubrolides have been reported to be cytotoxic and antibacterial, the authors proposed that the anti-inflammatory activity for these tunicate metabolites though moderate was "unprecedented". Khan et al. (2007) identified a ω-3 polyunsaturated fatty acid stearidonic acid (97) from the South Korean brown seaweed Undaria pinnatifida, which was shown to be very active against PMAinduced mouse ear inflammation symptoms, edema, erythema and blood flows (IC 50 = 160, 314 and 235 μg/per ear, respectively). The in vivo data compared well with indomethacin which was used as a positive control (IC 50 = 90, 172, 179 μg/per ear, respectively), and thus supported claims that this "seaweed can be used as a remedy for inflammation-related symptoms". Kobayashi et al. (2007a) discovered a novel dimeric oroidin derivative carteramine A (98) in the marine sponge Stylissa carteri, and showed that it inhibited neutrophil chemotaxis (IC 50 = 5 μM). The authors suggested that because carteramine A has no structural resemblance to known compounds that inhibit neutrophil chemotaxis, their finding provides a "novel platform to develop a new class of anti-inflammatory agents". Taori et al. (2007) identified three new analogues of dolastatin 13, lyngbyastatins 5-7 (99, 100, 101), isolated from marine cyanobacteria Lyngbya spp. from South Florida. Although the three compounds selectively and potently inhibited porcine pancreatic elastase (IC 50 = 3-10 nM), suggesting a potential therapeutic use in pathophysiological conditions where elastase overactivity is involved, no mechanism of action studies were reported at the time. Oh et al. (2008) purified a novel polyketide salinipyrone A (102) from the marine actinomycete Salinispora pacifica, which moderately inhibited interleukin-5 (IC 50 = 10 μg/mL) in a mouse splenocyte model of allergic inflammation, with low cell cytotoxicity.

The pharmacology of the marine compounds reporting activity on the immune system during 2007-8 showed a considerable increase from our previous review (Mayer et al., 2009) , and previous reviews of this series. Kawauchi et al. (2007) investigated the red pigment cycloprodigiosin hydrochloride (103) isolated from the marine bacterium Pseudoalteromonas denitrificans. Interestingly, the compound suppressed activator protein 1 (AP-1) (apparent IC 50 = 1 μM), and downstream gene expression of interleukin 8, a chemokine involved in the innate immune system. Courtois et al. (2008) assessed the effect of the known compound floridoside (104), isolated from the French red alga Mastocarpus stellatus on the complement system. Floridoside was observed to potently activate the classical complement pathway (apparent IC 50 = 5.9-9.3 μg/mL) by recruiting immunoglobulin M (IgM), suggesting that the compound might be an "important step in the development of a potent new anticomplementary agent" useful in therapy aimed at addressing complement depletion. Greve et al. (2007) reported that the novel iso-iantheran A and 8-carboxy-iso-iantheran A (105, 106) purified from the Australian marine sponge Ianthella quadrangulata demonstrated agonist activity at P2Y 11 receptors (IC 50 = 1.29 and 0.48 μM, respectively). This finding represents an interesting contribution to ionotropic purine receptor P2Y 11 pharmacology, because these receptors have been shown to affect the maturation and differentiation of dendritic cells. Huh et al. (2007) extended the pharmacology of prodigiosin (107) isolated from the marine bacterium Hahella chejuencis collected in South Korea. Prodigiosin inhibited iNOS mRNA expression and NO production (apparent IC 50 = 0.1 μg/mL) by a mechanism that involved inhibition of NF-κB and p38 MAPK and JNK phosphorylation. He et al. (2007) characterized the pharmacology of a water soluble polysaccharide (108) isolated from the mollusc Arca subcrenata Lischke, a popular Chinese seafood, and named it ASLP. ASLP stimulated mouse spleen lymphocyte proliferation in a concentration-dependent manner (apparent IC 50 less than 100 μg/mL), and with the "branches of ASLP" being required for the immunomodulatory bioactivity. Aminin et al. (2008) described the immunostimulant activity of frondoside A (109), a triterpene glycoside isolated from the sea cucumber Cucumaria frondosa. The glycoside was shown to stimulate lysosomal activity and phagocytosis in mouse macrophages, as well as reactive oxygen species formation. Oda et al. (2007) provided novel information on the molecular mechanisms affected by smenospongidine, smenospongiarine and smenospongine (110, 111, 112) , sesquiterpene quinones previously isolated from a Palauan marine sponge Hippospongia sp. The observation that at 10 μg/mL, these compounds promoted interleukin-8 release, a member of the C-X-C chemokine superfamily which is involved in tumor progression and metastasis, suggested that "the functional group at C-18" might play a yet undetermined role in the observed results. Yamada et al. (2007) isolated the novel macrosphelide M (113) and peribysin J (114) from Periconia byssoides, a fungal strain discovered from the sea hare Aplysia kurodai. Significantly, both fungal metabolites inhibited the adhesion of human promyelocytic leukemia HL-60 cells to human umbilical vein endothelial cells (IC 50 = 33.2 and 11.8 μM, respectively) more potently than herbimycin A (IC 50 = 38 μM). The latter compound, a benzochinoid ansamycin antibiotic isolated from Streptomyces sp. was used as a positive control in these studies. Lu et al. (2008) contributed a novel cembranolide querciformolide C (115) from the soft coral Sinularia querciformis, which significantly inhibited the activation of the iNOS and COX-2 enzymes (apparent IC 50 less than 10 μM) in LPS-activated murine macrophages in vitro. Ponomarenko et al. (2007) discovered that new diterpenoids (116, 117) isolated from a Northern Cook Islands marine sponge Spongia (Heterofibria) sp. moderately activated murine splenocytes lysosomes (apparent IC 50 greater than 100 μg/mL). Oh et al. (2007) characterized a novel cyclic peptide thalassospiramide B (118) isolated from a marine bacterium Thalassospira sp., which showed immunosuppressive activity in an interleukin-5 (IL-5) inhibition assay (IC 50 = 5 μM); an interesting finding because IL-5 is expressed both in eosinophils and mast cells in asthmatic patients.

Pharmacological studies with marine compounds affecting the nervous system involved three areas of neuropharmacology: the stimulation of neurogenesis, the targeting of receptors, and other miscellaneous activities on the nervous system.

Marine natural products reported to be neuritogenic, might be used to treat damaged neuronal cells, and potentially neurodegenerative diseases. As shown in Table 2 , compounds (119, 120, 121, 122, 123, 124, 125, 126) isolated from sea stars and a brown alga were observed to enhance the neuritogenic properties of nerve growth factor (NGF), a compound that has a critical role in differentiation, survival, and neuronal regeneration. Kicha et al. (2007b) contributed two new steroid glycosides, linckosides L1 (119) and L2 (120) isolated from the Vietnamese blue sea star Linckia laevigata. All three glycosides (apparent IC 50 = 0.3 μM) showed synergistic effects on NGF-induced (2 ng/mL) neurite outgrowth of murine neuroblastoma C-1300 cells. Han et al. (2007) contributed the novel steroid glycosides linckosides M-Q (121, 122, 123, 124, 125) from the Japanese sea star L. laevigata. Linckoside P (124) induced neurite outgrowth in 55% of rat pheochromocytoma PC12 cells at 10 μM in the presence of nerve growth factor (NGF), while linckosides M-O appeared less active (21-32%), suggesting the importance of "the xylose on a side chain". Ina et al. (2007) characterized pheophytin A (126) purified from the Japanese brown alga Sargassum fulvellum as a novel neurodifferentiation compound. Pheophytin A at 3.9 μg/mL was observed to synergize with NGF (50 ng/mL) in promoting neurite outgrowth in rat pheochromocytoma PC12 cells by a mechanism that appeared to involve activation of mitogen-activated protein kinase signaling.

As shown in Table 2 , during 2007-8, three marine compounds (127, 128, 129) were reported to target receptors in the nervous system. Peng et al. (2008) reported on the preclinical pharmacology of the α4/7conotoxin Lp1.1 (127) originally isolated from the marine cone snail Conus leopardus. The conotoxin induced seizure and paralysis in goldfish, and selectively yet reversibly inhibited acetylcholine-evoked currents in Xenopus oocytes expressing rat α6α3β2 and α3β2 nicotinic receptors (apparent IC 50 less than 10 μM). Aiello et al. (2007) characterized two novel bromopyrrole alkaloids damipipecolin (128) and damituricin (129) isolated from the Mediterranean sponge Axinella damicornis that were observed to modulate serotonin receptor activity in vitro. Although damipipecolin inhibited Ca 2+ entry in neurons (apparent IC 50 =1 μg/mL), the serotonin receptor subtype involved in the mechanism of action remains undetermined.

Finally, as shown in Table 2 , during 2007-8, additional marine compounds (74 and 130, 131, 132) were reported to have miscellaneous effects on components of the nervous system. Contributing to the ongoing search for acetylcholinesterase inhibitors useful in the treatment of Alzheimer's disease, Langjae et al. (2007) reported a new stigmastane-type steroidal alkaloid 4-acetoxy-plakinamine B (130), isolated from a Thai marine sponge Corticium sp. that significantly inhibited acetylcholinesterase (IC 50 = 3.75 μM). Compound 130 was reported to be the "first marine-derived acetylcholinesterase-inhibiting steroidal alkaloid" with a mechanism of action involving an unusual mixed-competitive mode of inhibition. Choi et al. (2007) extended the molecular pharmacology of two known meroditerpenes, sargaquinoic acid (131) and sargachromenol (132) isolated from the brown alga S. sagamianum. Sargaquinoic acid potently inhibited butyrylcholinesterase (IC 50 = 26 nM), a novel target for the treatment of Alzheimer's disease, with potency comparable to or greater than anticholinesterases in current clinical use. Hui et al. (2008) further characterized the neuroprotective effects of the polysaccharide sulfated polymannuroguluronate (SPMG) (74), noted earlier as currently being in Phase II clinical trials in China as an anti-AIDS drug candidate. SPMG appeared to decrease the Tat-stimulated calcium overload in PC12 neuronal cells as well as concomitant apoptosis-signaling cascades, thus demonstrating a potential for further clinical development as a therapeutic intervention in HIVassociated dementia. Table 3 lists 65 marine compounds with miscellaneous pharmacological mechanisms of action, and their respective structures (133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197) are presented in Fig. 3 . Because during 2007-8 additional pharmacological data were unavailable, it was not possible to assign these marine compounds to a particular drug class as was possible with the compounds included in Tables 1  and 2.  Table 3 shows 14 marine natural products that the peer-reviewed literature reported with a pharmacological activity, an IC 50 , and a molecular mechanism of action affected by the respective compound: azumamide E (133), 1-deoxyrubralactone (134), fucoxanthin (135), okadaic acid (136), saproxanthin and myxol (137, 138), sarcomilasterol (139), spirastrellolides C, D, and E (140, 141, 142), Spongia sesterterpenoid (143), stylissadines A and B (144, 145) and symbiodinolide (146).

In contrast, although a pharmacological activity was described, and an IC 50 for inhibition of an enzyme or receptor determined, detailed molecular mechanism of action studies were unavailable at the time of publication for the following 51 marine compounds included in Table 3 : Asterias amurensis saponin (147), Botrytis sp. α-pyrone derivative (148) (185), Sargassum siliquastrum meroditerpenoids (186, 187, 188, 189, 190, 191) , Symphyocladia latiuscula bromophenols (192, 193, 194, 195) , and tenacibactins C and D (196, 197) .

Several reviews covering both general and specific subject areas of marine pharmacology were published during 2007-8: (a) general marine pharmacology: marine natural products with an emphasis on source organisms and relevant biological activities (Blunt et al., 2007 (Blunt et al., , 2008 ; the value of natural products to future pharmaceutical discovery ; the structures and bioactivities of secondary metabolites from cyanobacteria (Gademann and Portmann, 2008) ; bioactive natural products from marine cyanobacteria for drug discovery (Tan L.T., 2007) ; bioactive compounds from fungi in the South China Sea (Pan et al., 2008) ; biochemical and pharmacological functions of β-carboline alkaloids (Cao et al., 2007) ; pharmacological properties of lamellarin alkaloids (Kluza et al., 2008) ; biological activity of brown seaweed fucoidans (Kusaykin et al., 2008; ; potential pharmacological uses of the marine green alga polysaccharide ulvan (Lahaye and Robic, 2007) ; pharmacological properties of marine bis-and tris-indole alkaloids (Gupta et al., 2007) ; (b) antimicrobial marine pharmacology: a renaissance of genomics in antibacterial discovery from actinomycetes (Baltz R.H., 2008) ; mining marine genomics for novel drug discovery from phytosymbionts of marine invertebrates (Dunlap et al., 2007) ; (c) anticoagulant and cardiovascular pharmacology: structure, biology, evolution and medical importance of sulfated fucans and galactans as potential antithrombotic compounds (Pomin and Mourao, 2008) ; (d) antituberculosis, antimalarial and antifungal marine pharmacology: natural product growth inhibitors of Mycobacterium tuberculosis (Copp and Pearce, 2007) ; new advances in novel marine fatty acids as antimalarials, antimycobacterial and antifungal agents (Carballeira N.M., 2008) ; depsipeptides from microorganisms as a new class of antimalarials (Fotie and Morgan, 2008) ; the manzamine alkaloids for the control of malaria and tuberculosis (Hamann M.T., 2007) ; (e) immuno-and anti-inflammatory marine pharmacology: chemistry and biology of anti-inflammatory marine natural products (Abad et al., 2008) ; marine natural products as targeted modulators of the transcription factor NF-κB (Folmer et al., 2008) ; glycolipids as immunostimulating agents ); (f) nervous system marine pharmacology: marine-derived drugs in neurology (Martinez A., 2007) ; neuritogenic gangliosides from marine echinoderms (Higuchi et al., 2007) ; (g) miscellaneous molecular targets: enzyme inhibitors from marine invertebrates (Nakao and Fusetani, 2007) ; natural products as aromatase inhibitors (Balunas et al., 2008) ; biology of the aeruginosin family of serine protease inhibitors (Ersmark et al., 2008) ; and marine natural products affecting membrane and intracellular processes, and ion channels (Folmer et al., 2007) .

Six years after the approval of the marine compound ziconotide (Prialt®) by the U.S. Food and Drug Administration (Williams et al., 2008) , the global marine preclinical pharmaceutical pipeline remains very active. The marine pharmaceutical clinical pipeline is available at http://marinepharmacology.midwestern.edu/clinDev.htm and has recently been reviewed (Mayer et al., 2010) .

The current marine preclinical pipeline review contributes to the annual review series which was initiated in 1998 (Mayer and Lehmann, 2000; Mayer and Hamann, 2002 , 2005 Mayer et al., 2007 Mayer et al., , 2009 ) and reveals the breadth of preclinical pharmacological research during 2007-8, which resulted from the global effort of natural products chemists and pharmacologists from Argentina, Australia, Brazil, Canada, China, Egypt, France, Germany, India, Israel, Italy, Japan, the Netherlands, New Zealand, Panama, Papua New Guinea, Portugal, Russia, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, Vietnam, and the United States.

Thus, it appears that the marine preclinical pharmaceutical pipeline continues to contribute novel pharmacological lead compounds that will probably enable a future expansion of the marine clinical pharmaceutical pipeline, which currently consists of 13 compounds in Phase I, II and III of clinical development (Mayer et al., 2010) .

Natural marine anti-inflammatory products

Chaetominedione, a new tyrosine kinase inhibitor isolated from the algicolous marine fungus Chaetomium sp

Isolation and structure determination of malevamide E, a dolastatin 14 analogue, from the marine cyanobacterium Symploca laete-viridis

Immunomodulatory effects of an enzymatic extract from Ecklonia cava on murine splenocytes

Damipipecolin and damituricin, novel bioactive bromopyrrole alkaloids from the Mediterranean sponge Axinella damicornis

Immunomodulatory properties of frondoside A, a major triterpene glycoside from the North Atlantic commercially harvested sea cucumber Cucumaria frondosa

Isolation and structures of erylosides from the Caribbean sponge Erylus formosus

Anti-HIV-1 activity of phloroglucinol derivative, 6, 6′-bieckol, from Ecklonia cava

Biological effects of a sulfated-polysaccharide isolated from the marine red alga Champia feldmannii

The value of natural products to future pharmaceutical discovery

Renaissance in antibacterial discovery from actinomycetes

Natural products as aromatase inhibitors

The marine sponge Plakortis zyggompha: a source of original bioactive polyketides

Disturbance of voltage-induced cellular calcium entry by marine dimeric and tetrameric pyrrole-imidazole alkaloids

Antinociceptive and antiinflammatory effects of a mucin-binding agglutinin isolated from the red marine alga Hypnea cervicornis

Marine natural products

Marine natural products

Eurysterols A and B, cytotoxic and antifungal steroidal sulfates from a marine sponge of the genus Euryspongia

Actinomycetes from sediments in the Trondheim fjord, Norway: diversity and biological activity

The crosslinking and antimicrobial properties of tunichrome

β-Carboline alkaloids: biochemical and pharmacological functions

New advances in fatty acids as antimalarial, antimycobacterial and antifungal agents

Protein phosphatase inhibitors isolated from Spongia irregularis collected in Papua New Guinea

Monoglycerides from the brown alga Sargassum sagamianum: Isolation, synthesis, and biological activity

Cytotoxic and anti-inflammatory cembranoids from the soft coral Lobophytum crassum

Polysaccharides from Gracilaria corticata: sulfation, chemical characterization and anti-HSV activities

Durumolides A-E, anti-inflammatory and antibacterial cembranolides from the soft coral Lobophytum durum

Anticholinesterase activity of plastoquinones from Sargassum sagamianum: lead compounds for Alzheimer's disease therapy

Studies on puupehenone-metabolites of a Dysidea sp.: structure and biological activity

The dolabellane diterpene dolabelladienetriol is a typical noncompetitive inhibitor of HIV-1 reverse transcriptase enzyme

Natural products chemistry and taxonomy of the marine cyanobacterium Blennothrix cantharidosmum

Natural product growth inhibitors of Mycobacterium tuberculosis

Floridoside extracted from the red alga Mastocarpus stellatus is a potent activator of the classical complement pathway

19-epi-okadaic acid, a novel protein phosphatase inhibitor with enhanced selectivity

Isolation and structural elucidation of callipeltins J-M: antifungal peptides from the marine sponge Latrunculia sp

Anti-inflammatory constituents of the red alga Gracilaria verrucosa and their synthetic analogues

Antimicrobial potential of a lipopeptide biosurfactant derived from a marine Bacillus circulans

A SARS-coronovirus 3CL protease inhibitor isolated from the marine sponge Axinella cf. corrugata: structure elucidation and synthesis

Isolation and structural characterization of two antibacterial free fatty acids from the marine diatom, Phaeodactylum tricornutum

Tauramamide, a lipopeptide antibiotic produced in culture by Brevibacillus laterosporus isolated from a marine habitat: structure elucidation and synthesis

Bioprotective properties of seaweeds: in vitro evaluation of antioxidant activity and antimicrobial activity against food borne bacteria in relation to polyphenolic content

Three new antimicrobial metabolites of Phomopsis sp

Highly brominated mono-and bis-phenols from the marine red alga Symphyocladia latiuscula with radical-scavenging activity

Biomedicinals from the phytosymbionts of marine invertebrates: a molecular approach

Semisynthetic studies on the manzamine alkaloids

CYP3A4 inhibitors isolated from a marine derived fungus Penicillium species

Essramycin: a first triazolopyrimidine antibiotic isolated from nature

Novel bioactive metabolites from a marine derived bacterium Nocardia sp. ALAA

Chemistry and biology of the aeruginosin family of serine protease inhibitors

Antibiotics for emerging pathogens

Biomedical research tools from the seabed

Marine natural products as targeted modulators of the transcription factor NF-κB

Depsipeptides from microorganisms: a new class of antimalarials

Antileishmanial properties of tropical marine algae extracts

Secondary metabolites from cyanobacteria: complex structures and powerful bioactivities

Isomeric furanosesquiterpenes from the Portuguese marine sponge Fasciospongia sp

T-antigen binding lectin with antibacterial activity from marine invertebrate, sea cucumber (Holothuria scabra): possible involvement in differential recognition of bacteria

New iantherans from the marine sponge Ianthella quadrangulata: novel agonists of the P2Y(11) receptor

Bioactive metabolites from the Caribbean sponge Aka coralliphagum

Chemical transformation and biological studies of marine sesquiterpene (S)-(+)-curcuphenol and its analogs

Bis-and tris-indole alkaloids from marine organisms: new leads for drug discovery

The manzamines as an example of the unique structural classes available for the discovery and optimization of infectious disease controls based on marine natural products

Linckosides M-Q: neuritogenic steroid glycosides from the Okinawan starfish Linckia laevigata

Polybrominated diphenyl ethers from the Indonesian sponge Lamellodysidea herbacea

Isolation and structural characterization of a novel polysaccharide prepared from Arca subcrenata Lischke

Biologically active gangliosides from echinoderms

Antibacterial quinone metabolite from the brown alga, Sargassum sagamianum

Batzelladine alkaloids from the Caribbean sponge Monanchora unguifera and the significant activities against HIV-1 and AIDS opportunistic infectious pathogens

Three different hepcidins from tilapia, Oreochromis mossambicus: analysis of their expressions and biological functions

The marinopyrroles, antibiotics of an unprecedented structure class from a marine Streptomyces sp

Prodigiosin isolated from Hahella chejuensis suppresses lipopolysaccharide-induced NO production by inhibiting p38 MAPK, JNK and NF-kappaB activation in murine peritoneal macrophages

Sulfated polymannuroguluronate, a novel anti-acquired immune deficiency syndrome drug candidate, decreased vulnerability of PC12 cells to human immunodeficiency virus tat protein through attenuating calcium overload

Pheophytin a, a low molecular weight compound found in the marine brown alga Sargassum fulvellum, promotes the differentiation of PC12 cells

Tenacibactins A-D, hydroxamate siderophores from a marine-derived bacterium, Tenacibaculum sp. A4K-17

Pseudoceratins A and B, antifungal bicyclic bromotyrosine-derived metabolites from the marine sponge Pseudoceratina purpurea

Aaptamines as sortase A inhibitors from the tropical sponge Aaptos aaptos

Structures and absolute configurations of sulfateconjugated triterpenoids including an antifungal chemical defense of the green macroalga Tydemania expeditionis

Sulfated polysaccharide purified from Ecklonia cava accelerates antithrombin III-mediated plasma proteinase inhibition

A novel anticoagulant protein with high affinity to blood coagulation factor Va from Tegillarca granosa

Meroditerpenoids from the brown alga Sargassum siliquastrum

New Sulfoalkylresorcinol from marine-derived fungus, Zygosporium sp. KNC52

Ascochytatin, a novel bioactive spirodioxynaphthalene metabolite produced by the marine-derived fungus, Ascochyta sp. NGB4

Antimicrobial activity of volatile components and various extracts of the red alga Jania rubens

Cytotoxic and antiplasmodial substances from marine-derived fungi, Nodulisporium sp. and CRI247-01

Suppression of AP-1 activity by cycloprodigiosin hydrochloride

Isolation of two anti-inflammatory and one pro-inflammatory polyunsaturated fatty acids from the brown seaweed Undaria pinnatifida

Sulfated steroid glycosides from the Vietnamese starfish Linckia laevigata

New neuritogenic teroid glycosides from the Vietnamese starfish Linckia laevigata

Symbiodinolide, a novel polyol macrolide that activates N-type Ca 2+ channel, from the symbiotic marine dinoflagellate Symbiodinium sp

Identification of an antibacterial protein as l-amino acid oxidase in the skin mucus of rockfish Sebastes schlegeli

Antibacterial action of l-amino acid oxidase from the skin mucus of rockfish Sebastes schlegelii

Lamellarin alkaloids: structure and pharmacological properties

Carteramine A, an inhibitor of neutrophil chemotaxis, from the marine sponge Stylissa carteri

Complete structure elucidation of shishididemniols, complex lipids with tyramine-derived tether and two serinol units, from a marine tunicate of the family Didemnidae

New metabolites with antibacterial activity from the marine angiosperm Cymodocea nodosa

Antiparasitic, antineuroinflammatory, and cytotoxic polyketides from the marine sponge Plakortis angulospiculatus collected in Brazil

Potential cancer chemopreventive in vitro activities of monomeric xanthone derivatives from the marine algicolous fungus Monodictys putredinis

Nagelamides M and N, new bromopyrrole alkaloids from sponge Agelas species

Antifungal activity in triterpene glycosides from the sea cucumber Actinopyga lecanora

Pedein A and B: production, isolation, structure elucidation and biological properties of new antifungal cyclopeptides from Chondromyces pediculatus (Myxobacteria)

Structure, biological activity, and enzymatic transformation of fucoidans from the brown seaweeds

PF1270A, B and C, novel histamine H3 receptor ligands produced by Penicillium waksmanii PF1270

Structure and functional properties of ulvan, a polysaccharide from green seaweeds

Callophycoic acids and callophycols from the Fijian red alga Callophycus serratus

Acetylcholinesterase-inhibiting steroidal alkaloid from the sponge Corticium sp

Inhibition of the pathogenicity of Magnaporthe grisea by bromophenols, isocitrate lyase inhibitors, from the red alga Odonthalia corymbifera

Solution structures and biological functions of the antimicrobial peptide, arenicin-1, and its linear derivative

Inhibition of Candida albicans isocitrate lyase activity by sesterterpene sulfates from the tropical sponge Dysidea sp

Natural bromophenols from the marine red alga Polysiphonia urceolata (Rhodomelaceae): structural elucidation and DPPH radical-scavenging activity

Cephalosporolides H and I, Two Novel Lactones from a Marine-Derived Fungus, Penicillium sp

Fucoidan: structure and bioactivity

Bromophenols from the marine red alga Polysiphonia urceolata with DPPH radical scavenging activity

Cathepsin B inhibitory activities of three new phthalate derivatives isolated from seahorse

Venturamides A and B: antimalarial constituents of the Panamanian marine cyanobacterium Oscillatoria sp

Two new steroidal compounds from starfish Asterias amurensis Lutken

Antioxidant alkaloid from the South China Sea marine sponge Iotrochota sp

Sulfated polymannuroguluronate, a novel anti-AIDS drug candidate, inhibits HIV-1 Tatinduced angiogenesis in Kaposi's sarcoma cells

Anti-inflammatory cembranoids from the soft corals Sinularia querciformis and Sinularia granosa

Lipoxazolidinones A, B, and C: antibacterial 4-oxazolidinones from a marine actinomycete isolated from a Guam marine sediment

Anti-herpetic activity of a sulfated xylomannan from Scinaia hatei

New bioactive hydrogenated linderazulene-derivatives from the gorgonian Echinogorgia complexa

Heparinoid-active two sulfated polysaccharides isolated from marine green algae Monostroma nitidum

Marine-derived drugs in neurology

Antimicrobial and cytotoxic assessment of marine cyanobacteria -Synechocystis and Synechococcus

Lyngbyastatin 4, a dolastatin 13 analogue with elastase and chymotrypsin inhibitory activity from the marine cyanobacterium Lyngbya confervoides

Pompanopeptins A and B, new cyclic peptides from the marine cyanobacterium Lyngbya confervoides

Molecular insights into azumamide E histone deacetylases inhibitory activity

Marine Pharmacology in 1998 Antitumor and Cytotoxic Compounds

Marine pharmacology in 2000: antitumor and cytotoxic compounds

Marine pharmacology in 2001-2: antitumour and cytotoxic compounds

Marine pharmacology in 2003-2004: anti-tumour and cytotoxic compounds

Marine pharmacology in 2005-2006: antitumour and cytotoxic compounds

Marine pharmacology in 1999: compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, anthelmintic, antiinflammatory, antiplatelet, antiprotozoal and antiviral activities;affecting the cardiovascular, endocrine, immune, and nervous systems; and other miscellaneous mechanisms of action

Marine pharmacology in 2000: marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antituberculosis, and antiviral activities; affecting the cardiovascular, immune, and nervous systems and other miscellaneous mechanisms of action

Marine pharmacology in 2001-2002: marine compounds with anthelmintic, antibacterial, anticoagulant, antidiabetic, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems and other miscellaneous mechanisms of action

Marine pharmacology in 1998: marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, anthelmintic, antiplatelet, antiprotozoal, and antiviral activities; with actions on the cardiovascular, endocrine, immune, and nervous systems; and other miscellaneous mechanisms of action

Marine pharmacology in 1999: antitumor and cytotoxic compounds

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

Marine pharmacology in 2005-6: Marine compounds with anthelmintic, antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems, and other miscellaneous mechanisms of action

The odyssey of marine pharmaceuticals: a current pipeline perspective

Lynamicins A-E, chlorinated bisindole pyrrole antibiotics from a novel marine actinomycete

Antimalarial linear lipopeptides from a Panamanian strain of the marine cyanobacterium Lyngbya majuscula

Evaluation of selected tropical seaweeds for in vitro anti-trichomonal activity

A new antimalarial polyether from a marine Streptomyces sp. H668

1-deoxyrubralactone, a novel specific inhibitor of families X and Y of eukaryotic DNA polymerases from a fungal strain derived from sea algae

Marine algae: screening for a potent antibacterial agent

Enzyme inhibitors from marine invertebrates

Scalarane sesterterpenes from a marine sponge of the genus Spongia and their FXR antagonistic activity

Dehydroxychlorofusarielin B, an antibacterial polyoxygenated decalin derivative from the marine-derived fungus Aspergillus sp

Promotion of IL-8 production in PMA-stimulated HL-60 cells by sesquiterpene quinones from a marine sponge, Hippospongia sp

Thalassospiramides A and B, immunosuppressive peptides from the marine bacterium Thalassospira sp

Salinipyrones and pacificanones, mixed-precursor polyketides from the marine actinomycete Salinispora pacifica

Ariakemicins A and B, novel polyketide-peptide antibiotics from a marine gliding bacterium of the genus Rapidithrix

Bipinnapterolide B, a bioactive oxapolycyclic diterpene from the Colombian gorgonian coral Pseudopterogorgia bipinnata

Review of bioactive compounds from fungi in the South China Sea

Anti-inflammatory thiazine alkaloids isolated from the New Zealand ascidian Aplidium sp.: inhibitors of the neutrophil respiratory burst in a model of gouty arthritis

E/Z-rubrolide O, an anti-inflammatory halogenated furanone from the New Zealand ascidian Synoicum n. sp

alpha4/ 7-conotoxin Lp1.1 is a novel antagonist of neuronal nicotinic acetylcholine receptors

Mirabamides A-D, depsipeptides from the sponge Siliquariaspongia mirabilis that inhibit HIV-1 fusion

Structure, biology, evolution, and medical importance of sulfated fucans and galactans

Spongian diterpenoids from the sponge Spongia (Heterofibria) sp

Antiprotozoal activities of heterocyclic-substituted xanthones from the marine-derived fungus Chaetomium sp

Monodictyochromes A and B, dimeric xanthone derivatives from the marine algicolous fungus Monodictys putredinis

Isolation and purification of an anticoagulant from fermented red seaweed Lomentaria catenata

Lipid extract of Nostoc commune Var. sphaeroides Kutzing, a blue-green alga, inhibits the activation of sterol regulatory element binding proteins in HepG2 cells

Antimicrobial ambiguines from the cyanobacterium Fischerella sp. collected in Israel

New C-secosteroids from the gorgonian Tripalea clavaria

Extending the record of meroditerpenes from Cacospongia marine sponges

Radical scavenging and singlet oxygen quenching activity of marine carotenoid fucoxanthin and its metabolites

cDNA sequence and tissue expression of an antimicrobial peptide, dicentracin; a new component of the moronecidin family isolated from head kidney leukocytes of sea bass, Dicentrarchus labrax

An antiproliferative bis-prenylated quinone from the New Zealand brown alga Perithalia capillaris

Antimycobacterial activity of the red alga Polysiphonia virgata

Antitumor and cytotoxic compounds from marine organisms

Biosynthesis and structures of cyclomarins and cyclomarazines, prenylated cyclic peptides of marine actinobacterial origin

Four new briarane diterpenoids from the gorgonian coral Junceella fragilis

Diapolycopenedioic acid xylosyl ester, a novel glyco-C 30 -carotenoic acid produced by a new marine bacterium Rubritalea squalenifaciens

Viridamides A and B, lipodepsipeptides with antiprotozoal activity from the marine cyanobacterium Oscillatoria nigro-viridis

Anti-allergic phlorotannins from the edible brown alga, Eisenia arborea

Isolation and characterization of okadaic acid binding proteins from the marine sponge Halichondria okadai

Screening for antibacterial and antifungal activities in marine benthic invertebrates from northern Norway

An algalderived DL-galactan hybrid is an efficient preventing agent for in vitro dengue virus infection

Bioactive natural products from marine cyanobacteria for drug discovery

Lyngbyastatins 5-7, potent elastase inhibitors from Floridian marine cyanobacteria, Lyngbya spp

Kempopeptins A and B, serine protease inhibitors with different selectivity profiles from a marine cyanobacterium, Lyngbya sp

Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli

Novel anti-inflammatory omega-3 PUFAs from the New Zealand greenlipped mussel, Perna canaliculus

The isolation, purification and biological activity of a novel antibacterial compound produced by Pseudomonas stutzeri

Antibacterial activity of halogenated sesquiterpenes from Malaysian Laurencia spp

A new 9, 11-secosterol from the Vietnamese sea soft coral, Sarcophyton mililatensis, increases the function of osteoblastic MC3T3-E1 cells

A malespecific expression gene, encodes a novel anionic antimicrobial peptide, scygonadin, in Scylla serrata

Structural features and anti-HIV-1 activity of novel polysaccharides from red algae Grateloupia longifolia and Grateloupia filicina

Antifungal activity evaluation of the constituents of Haliclona baeri and Haliclona cymaeformis, collected from the Gulf of Thailand

Caribenols A and B, sea whip derived norditerpenes with novel tricarbocyclic skeletons

Novel ring B abeo-sterols as growth inhibitors of Mycobacterium tuberculosis isolated from a Caribbean Sea sponge, Svenzea zeai

Paeciloxanthone, a new cytotoxic xanthone from the marine mangrove fungus Paecilomyces sp

Spirastrellolides C to G: macrolides obtained from the marine sponge Spirastrella coccinea

Saliniketals A and B, bicyclic polyketides from the marine actinomycete Salinispora arenicola

Ziconotide: an update and review

Neopeltolide, a macrolide from a lithistid sponge of the family Neopeltidae

Glycolipids as immunostimulating agents

Antibacterial and antilarval activity of deep-sea bacteria from sediments of the West Pacific Ocean

Cell-adhesion inhibitors produced by sea hare-derived Periconia sp. III. Absolute stereostructures of peribysins J and macrosphelide M

A sulfated fucan from the brown alga Laminaria cichorioides has mainly heparin cofactor II-dependent anticoagulant activity

A new α-pyrone derivative, 6-[(E)-hept-1-enyl]-α-pyrone, with tyrosinase inhibitory activity from a marine isolate of the fungus Botrytis

Circumdatin I, a new ultraviolet-A protecting benzodiazepine alkaloid from a marine isolate of the fungus Exophiala

Isolation, structure elucidation, and antimycobacterial properties of dimeric naphtho-γ-pyrones from the marine-derived fungus Aspergillus carbonarius

This review was made possible with financial support from Midwestern University to AMSM; NIH-SC1 Award (grant 1SC1GM086271-01A1) of the University of Puerto Rico to ADR; and FAPESP grant 05/60175-2 (São Paulo, Brazil) to RGSB. The content of this review is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Assistance with extensive searches of the 2007-8 marine pharmacology literature in PubMed, Marinlit, Current Contents® and Chemical Abstracts®, as well as article retrieval by library staff members, and students from the Chicago College of Pharmacy, Midwestern University, are gratefully acknowledged. The authors are especially thankful to Ms. Mary Hall for the careful review of the manuscript.