Marine Pharmacology in 2009–2011: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action

1The current article presents a systematic review of the preclinical pharmacology of the marine natural products literature in 2009–2011, with a similar format to previous reviews, and which resulted from extensive searches of several databases, including Marinlit, PubMed, Current Contents® and Chemical Abstracts®. We have limited this review to the peer-reviewed literature that reported bioactivity or pharmacology of structurally characterized marine chemicals, and have continued to use a modification of Schmitz’s chemical classification to assign marine structures to six major chemical classes, namely, polyketides, terpenes, peptides, alkaloids, shikimates, and sugars. The preclinical antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral pharmacology of marine chemicals is presented in Table 1, with the corresponding structures shown in Figure 1. Marine compounds that affect the immune and nervous systems, as well as those with antidiabetic and anti-inflammatory effects are shown in Table 2, with their corresponding structures presented in Figure 2. Finally, marine compounds that have been demonstrated to affect a wide variety of cellular and molecular targets are exhibited in Table 3, and their structures presented in Figure 3. Several publications during 2009–2011 described extracts or as yet structurally uncharacterized marine compounds, and although they have been excluded from the current review, they certainly deserve further investigation because they report novel and interesting in vitro or in vivo preclinical pharmacology: antimicrobial and antistaphylococcal biofilm activity of three 5-kDa peptides isolated from coelomocyte effector cells of the sea urchin Paracentrotus lividus that could benefit patients with medical device-associated infections; an antibacterial polyunsaturated fatty acid, eicosapentanoic acid, isolated from extracts of the marine diatom Phaeodactylum tricornutum with activity against a range of Gram-positive and Gram-negative bacteria, including multidrug-resistant Staphyloccus aureus; potent anticoagulant activity of sulfated polysaccharides isolated from the Brazilian brown seaweed Dictyota cervicornis, which was close to that of clinically used low molecular weight heparin; potent anticoagulant activity of a sulfated polysaccharide isolated from the Chinese green seaweed Monostroma latissimum by a mechanism involving thrombin inhibition in the presence of heparin cofactor II; in vitro antileishmanial activity of dichloromethane extracts of a Tunisian sponge Sarcotragus sp., which demonstrated concomitant morphological alterations of Leishmania major promastigotes in vitro; in vivo and in vitro antifilarial activity of the marine sponge Haliclona exigua extracts against adult nematode Brugia malayi, a parasite that may cause lymphatic filariasis; significant nontoxic and anti-herpes simplex virus HSV-1 and HSV-2 activity in sulfated polysaccharide extracts isolated from four species of red and brown marine algae from New Zealand; anti-herpes simplex virus HSV-1 activity in high molecular weight exopolysaccharides purified from the French marine sponge Celtodoryx girardae and its symbiotic bacteria; anti-inflammatory activity of the crude extracts and fractions of the Mediterranean sponge Spongia officinalis in the in vivo rat carrageenan-induced paw edema assay; in vivo anti-inflammatory activity in polyphenolic extracts from the red alga Laurencia undulata resulting in significant inhibition of asthmatic reactions; in vitro anti-inflammatory effect in an ethanolic extract from the brown alga Ishige okamurae via inhibition of NF-κB transcription factor; induction of oxidative death in a human glioma cell line through a caspase-9 apoptotic pathway by extracts from the marine sponge Polymastia janeirensis; apoptotic activity in extracts from the marine diatom Cocconeis scutellum associated with activation of caspases-8 and -3 in human breast cancer lines; human neutrophil anti-elastase activity of purified sulfated polysaccharides from the red alga Delesseria sanguinea; high antioxidant activity in methanolic extracts of the Korean red alga Polysiphonia morrowii that protected against hydroxyl radical-induced DNA damage in vitro; antioxidant activity in phenolic compounds from the marine alga Halimeda monile that protected against chemically induced rat liver injury in vivo; significant antioxidant properties of polysaccharides from a marine fungus Penicillium sp. F23-2 against superoxide and hydroxyl radicals; in vitro antioxidant activities of acetylated, phosphorylated and benzoylated derivatives of the marine red alga Porphyra haitanensis phorphyran; acceleration of skin wound healing by amino acids isolated from the mollusc Rapana venosa suggesting a possible therapeutic use in skin burns; neuroprotective effects in extracts of the South Indian green seaweed Ulva reticulata that inhibited both acetyl-and butyryl-cholinesterases, and was comparable to agents currently approved for Alzheimer’s disease treatment.

2Table 1 presents the 2009–2011 preclinical pharmacological research on the antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities of the marine natural products (1–102) shown in Figure 1.

3During 2009–2011, 35 studies reported antibacterial marine natural products isolated from a diverse group of marine bacteria, ascidians, bryozoans, sponges, soft corals and algae, a persistent effort on which we have reported previously, and which continues to contribute to the global health challenge posed by drug-resistant bacteria.

4Only four papers reported molecular mechanism of action studies with marine antimicrobial compounds. Plaza and colleagues investigated bisdiarylbutene macrocycle chrysophaentin A (1) from the chrysophyte alga Chrysophaeum taylori that potently inhibited Gram positive methicillin-resistant Staphylococus aureus (minimum inhibitory concentration [MIC]50 = 1.5 μg/mL) and vancomycin-resistant Enterococcus faecium (MIC50 = 2.9 μg/mL) by binding and inhibiting GTPase activity of the essential bacterial cell division protein FtsZ. Two studies contributed to the ongoing search of quorum sensing antagonists as potentially novel antimicrobial drugs: Teasdale and colleagues extended the pharmacology of two previously described phenethylamide metabolites isolated from a marine Gram positive Halobacillus salinus strain. One of these compounds, 3-methyl-N-(2′-phenylethyl)-butyramide (2) interfered with quorum sensing-regulated activities (e.g., bioluminescence inhibition IC50 = 9 μg/mL) in several Gram negative species. Kwan and colleagues isolated a small cyclopropane-containing fatty acid, lyngbyoic acid (3) from the marine cyanobacterium Lyngbya cf. majuscula that affected both quorum sensing pathways (acylhomoserine lactone receptor LAsR (IC50 = 100 µM) as well as gene expression in Pseudomonas aeruginosa. Jeon and colleagues extended the pharmacology of the pyrroloiminoquinone alkaloids of the discorhabdin class isolated from the Korean marine sponge Sceptrella sp.. A new alkaloid (−)-discorhabdin Z (4), possessing a unique hemiaminal group, inhibited sortase A (IC50 = 6.5 μM), a bacterial transpeptidase that has been shown to covalently attach proteins to the bacterial cell wall and has become an important antimicrobial target.

5As shown in Table 1 and Figure 1, several marine chemicals, some of them novel, were reported to exhibit antibacterial activity with MICs < 10 μg/mL or 10 μM against several bacterial strains, although no mechanism of action studies were reported for these compounds: a new alkaloid agelasine D (5) isolated from the marine sponge Agelas nakamurai collected in Bali, Indonesia; the maleimide mixture aqabamycin E (6) discovered in a marine Vibrio sp. growing on the surface of the Red Sea soft coral Sinularia polydactyla; two new cyclodepsipeptides, bacillistatins 1 and 2 (7,8) purified from cultures of the Chilean bacterium Bacillus silvestris obtained from a crab; new diterpene–benzoate macrolides bromophycolides J–Q (9–14) from the Fijian red alga Callophycus serratus; a novel benzoxazole antibiotic caboxamycin (15) produced by the deep-sea Streptomyces sp. NTK 937 isolated in the Canary Basin; a brominated polyphenyl ether crossbyanol B (16) isolated from the Hawai’ian marine cyanobacterium Leptolyngbya crossbyana; three novel pyridoacridine alkaloids (17–19) characterized from the Mediterranean ascidian Cystodytes dellechiajei; the previously-described Fijian Cymbastela hooperi diterpene isonitrile (20) recently re-evaluated; a novel alkaloid eusynstyelamide F (21), isolated from an Arctic bryozoan Tegella cf. spitzbergensis; a novel cembranoid diterpene, knightol (22), found in the Colombian gorgonian octocoral Eunicea knighti; the novel antibiotic MC21-B (23) produced by the marine bacterium Pseudoalteromonas phenolica O-BC-30T; a novel long-chain 2H-azirine 2-carboxylic acid, motualevic acid F (24), described from a Fijian marine sponge Siliquariaspongia sp.; the thiopeptide TP-1161 (25), identified in a Norwegian marine-sediment derived Gram positive Nocardiopsis sp. bacterium; two novel α-pyrone macrolides neurymenolides A and B (26, 27) isolated from the Fijian red alga Neurymenia fraxinifolia; two polybrominated metabolites (28, 29) from a Hawai’ian marine bacterium Pseudoalteromonas sp. found on the surface of a nudibranch; pseudopterosin U (30) discovered in the Caribbean octocoral Pseudopterogorgia elisabethae; 5-bromo-8-methoxy-1-methyl-β-carboline (31), an alkaloid isolated from the New Zealand marine bryozoan Pterocella vesiculosa; a new rifamycin antibiotic, salinisporamycin (32), purified from a culture of the Micronesian marine actinomycete Salinispora arenicora YM23-082; a novel bioactive alkaloid, synoxazolidinone A (33), discovered in the sub-Arctic Norwegian ascidian Synoicum pulmonaria.

6Furthermore, during 2009–2011, several marine natural products were noted to have MIC or IC50 ranging from 10 to 50 μg/mL, or 10–50 μM, respectively, and thus because of their lower antibacterial potency were excluded from Table 1 and Figure 1: a novel casbane diterpenoid 10-hydroxydepressin (MIC = 17 μg/mL) from the Hainan soft coral Sinularia depressa; a novel guai-2-en-10α-methyl methanoate from the marine alga Ulva fasciata (MIC = 25–30 μg/mL); a novel gymnochrome F (MIC = 12.5 μg/mL) from the deep-water crinoid Holopus rangii; several novel fatty acids, ieodomycins (MIC = 32–64 μg/mL), from a marine Bacillus sp.; a novel sulfated sesterterpene alkaloid 19-oxofasciospongine A from a marine sponge Fasciospongia sp. (MIC = 20 μg/disk); a novel phenalenone derivative (MIC = 24 μM) from the marine-derived fungus Coniothyrium cereale; a novel 4,4′-oxybis[3-phenylpropionic acid] from the marine bacterium Bacillus licheniformis (IC50 = 50 μg/disk); a novel sargafuran (MIC = 15 μg/mL) from the marine brown alga Sargassum macrocarpum; a novel tetracyclic brominated diterpene (MIC = 32 μg/mL) from the red alga Sphaerococcus coronopifolius; and a new bromotyrosine alkaloid tyrokeradine B (MIC = 25 μg/mL) from a Verongid marine sponge.

7Finally, during 2009–2011, several publications described novel marine antimicrobial peptides: centrocins 1 and 2, two novel dimeric peptides (MIC = 1.3–2.5 μM) from the Norwegian green sea urchin Strongylocentrotus droebachiensis; halocyntin and papillosin, two new peptides (MIC = 0.75–25 μM) isolated from hemocytes of the Mediterranean ascidian Halocynthia papillosa; and hyastatin, a glycine-rich multi-domain peptide (MIC = 0.4–12.5 μM) from hemocytes of the Norwegian spider crab Hyas araneus.

8Ten studies during 2009–2011 reported on the antifungal activity of several novel marine natural products isolated from marine bacteria, sponges and bryozoa, a slight decrease from our last review, and previous reviews of this series.

9As shown in Table 1, only two reports described antifungal marine chemicals with novel mechanisms of action. DiGirolamo and colleagues identified two new sulfated sterols, geodisterol-3-O-sulfate (34) and 29-demethylgeodisterol-3-O-sulfate (35), in a marine sponge Topsentia sp., which enhanced the activity of the clinically used triazole antifungal agent fluconazole by reversing efflux pump-mediated fluconazole resistance in Candida albicans. Nishimura and colleagues extended the pharmacology of the bicyclic antifungal dodecapeptide theonellamide F (36) previously isolated from a sponge Theonella sp.. Chemical-genomic profiling analysis together with detailed subcellular localization studies determined that the antifungal theonellamides represent a new class of sterol-binding molecules that induce membrane damage and activate Rho1-mediated 1,3-β-d-glucan synthesis.

10Furthermore, as shown in Table 1 and Figure 1 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), although no mechanism of action studies were reported in the published articles: the antibacterial alkaloid 5-bromo-8-methoxy-1-methyl-β-carboline (31) isolated from the New Zealand marine bryozoan Pterocella vesiculosa; a novel linear tetrapeptide citronamide A (37) from the Australian sponge Citronia astra; two holostan-type triterpenoid glycosides, marmoratoside A (38) and 17α-hydroxy impatienside A (39), from the Chinese sea cucumber Bohadschia marmorata; the polyketide saadamycin (40) from an endophytic Streptomyces sp. strain Hedaya 48 isolated from the Egyptian sponge Aplysina fistularis, and two novel depsipeptides, theopapuamides B & C (41,42), isolated from the Indonesian marine sponge Siliquariaspongia mirabilis. Future mechanism of action studies with these potent compounds will hopefully characterize their molecular pharmacology.

11Finally, several novel structurally-characterized marine molecules demonstrated MICs or IC50s greater than 10 μg/mL or 10 μM, and therefore, because of the reported weaker antifungal activity, have been excluded from Table 1 and Figure 1: the maleimide mixture aqabamycin E (6) (MIC = 50 μg/mL); the novel antibacterial alkaloid synoxazolidinone A (33) (MIC = 12.5 μg/mL), and the new bromotyrosine tyrokeradine B (MIC = 12.5 μg/mL).

12These marine compounds may provide novel pharmacological leads thus contributing to the global search for clinically useful antifungal agents.

13As shown in Table 1, during 2009–2011 thirty two studies contributed to novel findings on the antiprotozoal and antituberculosis pharmacology of structurally characterized marine natural products, a considerable increase from previous 1998–2008 reviews.

14Malaria, which is caused by protozoa from the genus Plasmodium (P. falciparum, P. ovale, P. vivax and P. malariae), affects millions of people worldwide. Contributing to the global search for novel antimalarial drugs, and as presented in Table 1, twenty six novel marine molecules were shown during 2009–2011 to possess antimalarial activity, although mechanism of action studies were reported for only two compounds. Taglialatela-Scafati and colleagues extended the molecular pharmacology of plakortin (43), isolated from the Caribbean marine sponge Plakortis simplex, which potently inhibited CQ-resistant strains of Plasmodium falciparum. Plakortin was observed to give rise to toxic carbon radicals which were ultimately “responsible for subsequent reactions leading to Plasmodium death”. Lebouvier and colleagues reported that the homogentisic acid derivative 44 from a Vanuatu marine sponge Pseudoceratina sp. was moderately active in vitro against FcB1 P. falciparum strain, while concomitantly inhibiting the specific protein kinase pfnek-1 of the parasite (IC50 = 1.8 μM). Thus, compound 44 “could serve as a model for the development of new pfnek-1 inhibitors”.

15Potent (<2 µM) to moderate (>2–10 µM) antimalarial activity was reported for 24 marine natural products. Laville and colleagues isolated several novel guanidine batzelladine alkaloids (45–48) from the Caribbean marine sponge Monanchora arbuscula, which showed potent antimalarial activity against the human malaria parasite Plasmodium falciparum strain FcB1 (IC50 = 0.2–0.9 μM). Lane and colleagues characterized new diterpene–benzoate macrolides bromophycolides J, M, N, O, P and Q (9–14) from the Fijian red alga Callophycus serratus with potent antimalarial activity against P. falciparum (IC50 = 0.5–2.9 μM). Furthermore, Lin and colleagues isolated bromophycolides R, S and U (49–51) from the same Fijian red alga Callophycus serratus with potent antimalarial activity (IC50 = 0.9–2.1 μM) against P. falciparum. Davis and colleagues identified a novel β-carboline alkaloid, (+)-7-bromotrypargine (52), from an Australian marine sponge Ancorina sp. with moderate antimalarial activity (IC50 = 3.5–5.4 μM) against both chloroquine resistant (Dd2) and chloroquine-sensistive (3D7) P. falciparum strains. Wright and colleagues reported a diterpene formamide (53) from the tropical marine sponge Cyambastela hooperi that had moderate to potent activity (IC50 = 4.3 ng/mL and 0.5 μg/mL) against P. falciparum strains FCR3F86, W2 and D6. Jiménez-Romero and colleagues contributed a novel five-membered-ring polyketide endoperoxide epiplakinidioic acid (54) from the Puerto Rican sponge Plakortis halichondrioides that was potent (IC50 = 0.3 μg/mL) against the W2 chloroquinone-resistant strain of P. falciparum. Linington and colleagues purified a novel linear peptide, gallinamide A (55), from a cyanobacterium Schizothrix sp. with moderate antimalarial activity (IC50 = 8.4 μM) against chloroquine-resistant P. falciparum, yet with a structure that might become an “attractive foundation for further SAR investigations”. Ueoka and colleagues investigated a new polyketide, gracilioether B (56), from the Japanese marine sponge Agelas gracilis that was potent (IC50 = 0.5 µg/mL) against P. falciparum strain ItG. Wattanapiromsakul and colleagues isolated a new isocyanoditerpene, 8-isocyanoamphilecta-11 (20), 15-diene (57), from a Thai sponge Ciocalapata sp. with potent antimalarial activity (IC50 = 0.98 μM) against P. falciparum chloroquine-resistant strain K1. Tripathi and colleagues found two new cyclic depsipeptides, lagunamides A (58) and B (59), from the Singaporean marine cyanobacterium Lyngbya majuscula with potent antimalarial activity (IC50 = 0.19–0.91 μM) against the drug-sensitive NF54 P. falciparum strain. Fattorusso and colleagues discovered that a new endoperoxyketal, manadoperoxide C (60), from the Indonesian sponge Plakortis cf. simplex, had moderate in vitro antiplasmodial activity (IC50 = 2.3 μM) against the W2 chloroquinone-resistant strain of P. falciparum as well as provided further insight into “the structure activity relationships of simple 1,2-dioxane antimalarials”. Yamada and colleagues identified a novel alkaloid 3,4-dihydro-manzamine J N-oxide (61) from an Okinawan marine sponge Amphimedon sp. with potent in vitro antiplasmodial activity (IC50 = 0.58 μg/mL) against the K1 strain of P. falciparum. Wei and colleagues extracted a new tetracyclic bis-piperidine alkaloid, neopetrosiamine A (62), from the Puerto Rican marine sponge Neopetrosia proxima with moderate antiplasmodial activity (IC50 = 2.3 μM) against P. falciparum and low concomitant cytotoxicity to Vero cells. Yang and colleagues extended the pharmacology of the known bromotyrosine alkaloid psammaplysin F (63) from an Australian marine sponge Hyattella sp. by reporting potent inhibition (IC50 = 0.87–1.4 μM) of P. falciparum 3D7 and Dd2 strains.

16Eighteen marine compounds were reported to possess activity against other protozoa thus contributing to the ongoing global search for novel agents for the so-called neglected diseases, namely leishmaniasis (caused by several species of the genus Leishmania), amebiasis, trichomoniasis, African sleeping sickness (caused by Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense) and American sleeping sickness or Chagas disease (caused by Trypanosoma cruzi). Dos Santos and colleagues reported that a 4-acetoxydolastane diterpene (64) isolated from the Brazilian brown alga Canistrocarpus cervicornis dose-dependently inhibited promastigote, axenic amastigote and intracellular amastigote forms of Leishmania amazonensis (IC50 = 2.0, 12.0 and 4.0 μg/mL, respectively) by extensive mitochondrial damage and lipid peroxidation.

17As shown in Table 1 and Figure 1, several marine natural products were characterized to exhibit antiprotozoal activity, although the mechanism of action of these compounds remains undetermined. Vik and colleagues completed a comprehensive screening of agelasine terpene analogs from a marine sponge Agelas sp. and reported that four agelasine analogs (65–68) potently inhibited Leishmania infantum, T. brucei brucei and T. cruzi (IC50 = 0.093–0.11; 0.11–0.23; 0.11–0.43 μg/mL, respectively) with low concomitant cytotoxicity, suggesting they could become novel leads for design of “potent and selective drugs”. Sanchez and colleagues found two novel linear lipopeptides, almiramides B and C (69,70), from the marine cyanobacterium Lyngbya majuscula that inhibited the protozoan parasite Leishmania donovani (IC50 = 1.9–2.4 μM) with minimal cytotoxicity towards Vero cells (IC50 = 33.1–52.3 μM). Davis and colleagues investigated a new brominated alkaloid, convolutamine I (71), from the bryozoan Amathia tortusa that was highly active towards the parasite Trypanosoma brucei brucei (IC50 = 1.1 μM), yet presenting low cytotoxicity in human embryonic kidney cells (IC50 = 22.0 μM). Scala and colleagues completed the first antiprotozoal screening of marine bromopyrrole alkaloids isolated from the marine sponges Axinella verrucosa and Agelas dispar and determined that longamide B (72) and dibromopalau’amine (73) inhibited Trypanosoma brucei rhodesiense (IC50 = 1.53 & 0.46 μg/mL, respectively), and Leishmania donovani (IC50 = 3.85 & 1.09 μg/mL, respectively), with low cytotoxicity. Cantillo-Ciau and colleagues isolated two known and one novel sulfoquinovosyl diacylglycerols (74–76) from the Mexican tropical brown alga Lobophora variegata with high antiprotozoal activity against E. histolytica (IC50 = 3.9 μg/mL) and moderate activity towards Trichomonas vaginalis trophozoites (IC50 = 8.0 μg/mL), and with a good selectivity index (SI > 10). Yamada and colleagues characterized a novel alkaloid 3,4-dihydro-manzamine J N-oxide (61) from an Okinawan marine sponge Amphimedon sp. which displayed moderate in vitro activity against Trypanosoma brucei brucei (IC50 = 0.27 μg/mL). Rubio and colleagues evaluated several known peroxiterpenes as well as a novel (+)-muqubilone B (77) from the Papua New Guinea marine sponge Diacarnus bismarckensis shown to inhibit Trypanosoma brucei brucei (IC50 = 2 μg/mL), concluding that these marine chemicals could become “therapeutic leads” against T. brucei. Ma and colleagues identified novel highly oxidized steroids norselic acids A–E (78–82) isolated from an Antarctic marine sponge Crella sp. which moderately inhibited Leishmania sp. (IC50 = 2.0–3.6 μM). Regalado and colleagues reinvestigated the Caribbean sponge Pandaros acanthifolium and discovered that among several new steroidal glycosides, both pandaroside G (83) and pandaroside G methyl ester (84) potently inhibited the growth of Trypanosoma brucei rhodesiense (IC50 = 0.8 and 0.038 μM, respectively), and Leishmania donovani (IC50 = 1.3 and 0.051 μM, respectively) but with rather high concomitant cytotoxicity. Feng and colleagues isolated a novel cyclic polyketide peroxide, 11,12-didehydro-13-oxo-plakortide Q (85), from an Australian marine sponge Plakortis sp. with significant activity (IC50 = 0.049 μM) against Trypanosoma brucei brucei. Pimentel-Elardo and colleagues reported the isolation of the known cyclic depsipeptide valinomycin (86) from marine Streptomyces sp. strains associated with several Croatian marine sponges, and observed significant activity against both Trypanosoma brucei brucei (IC50 = 0.0032 μM) and Leishmania major (IC50 < 0.11 μM).

18As shown in Table 1, four novel marine natural products contributed to the global search for novel antituberculosis agents, a decrease from our previous reviews.

19Vicente and colleagues extended the pharmacology of the known compound hymenidin (87) from the Puerto Rican marine sponge Prosuberites laughlini by demonstrating its antimycobacterial activity (MIC = 6.1 μg/mL) against M. tuberculosis H37Rv. Pruksakorn and colleagues isolated three new aminolipopeptides, trichoderins A (88), A1 (89) and B (90) from a marine sponge-derived fungus Trichoderma sp. that potently inhibited (MIC = 0.02–2.0 μg/mL) the M. tuberculosis strain H37Rv under both aerobic and dormancy-inducing conditions. Wei and colleagues isolated tetracyclic bis-piperidine alkaloid neopetrosiamine A (62) from the Puerto Rican marine sponge Neopetrosia proxima which inhibited growth (MIC = 7.5 μg/mL) of the pathogenic strain Mycobacterium tuberculosis H37Rv. Although all of these studies demonstrate that marine alkaloids and peptides may potentially become novel antituberculosis leads, further studies are required to determine the molecular pharmacology of these compounds.

20As shown in Table 1, three reports were published during 2009–2011 on the antiviral pharmacology of novel marine natural products against human cytomegalovirus and herpes simplex virus. Cheng and colleagues purified two new diterpenoids, gyrosanols A and B (91,92), and two novel cembranoids, lobophynin C and ehrenberoxide B (93,94), from the Taiwanese soft corals Sinularia capillosa and Sarcophyton ehrenbergi, respectively, which inhibited the herpes virus-5 or cytomegalovirus (HCMV) (IC50 = 2.6–5.8 μM), an interesting preclinical contribution because HCMV infections may be life-threatening in immunocompromised patients. Palem and colleagues extended the pharmacology of the known β-carboline alkaloid manzamine A (95), isolated from an Indo-Pacific sponge Acanthostrongylophora sp., by demonstrating the compound inhibited HSV-1 infection (apparent IC50 = 1 μM) in rabbit corneal cells by affecting viral immediate-early gene transcription.

21Three articles reported 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), a decrease from our previous review. Ding and colleagues investigated the novel pentacyclic indolosesquiterpene xiamycin (96) isolated from the Streptomyces sp. GT2002/1503 bacterium and demonstrated selective inhibition against macrophage and T cell β-chemokine receptor CCR5 (5) tropic HIV-infection (estimated IC50 = 7.2 μg/mL), with no effect against α-chemokine receptor CXCR4 (X4) tropic HIV. Fan and colleagues isolated several DOPA-derived pyrrole alkaloids, baculiferins I, J, L and M (97–100), from the Chinese marine sponge Iotrochota baculifera, which were found to be potent inhibitors of HIV-1 IIIB (IC50 = 0.2–7.0 μM) by binding to the HIV target proteins Vif, APOBEC3G, and gp41 in an as yet undetermined mechanism. Plaza and colleagues isolated several new cyclic depsipeptides from the Indonesian marine sponge Siliquariaspongia mirabilis including celebesides A and C (101–102), which inhibited HIV-1 in an infectivity assay (IC50 = 1.9 ± 0.4 μg/mL), thus correlating the anti-HIV activity of these compounds with the presence of phosphoserine.

22Table 2 presents the preclinical pharmacology of marine chemicals (103–162) which demonstrated antidiabetic and anti-inflammatory activity, as well as affected the immune and nervous system, and whose structures are shown in Figure 2.

23Heo and colleagues extended the pharmacology of diphlorethohydroxycarmalol [DPHC] (103), previously isolated from the marine brown alga Ishige okamurae, by showing that DPHC alleviated postprandial hyperglycemia in diabetic mice by potent inhibition of both α-glucosidase and α-amylase enzymes (IC50 = 0.16 and 0.53 nM, respectively) suggesting a possible use of DPHC “as a nutraceutical or functional food for diabetes”. Li and colleagues evaluated the known sesquiterpene dysidine (104) from the Hainan marine sponge Dysidea villosa, and revealed that it activated the insulin pathway by inhibition of human protein phosphatase 1B (IC50 = 6.70 µM), a well characterized drug target for type-II diabetes and obesity treatment, as well as glucose uptake and glucose transporter 4 translocation in vitro.

24There was a remarkable increase in marine anti-inflammatory pharmacology research during 2009–2011. The molecular mechanism of action of several marine natural products, which were shown in preclinical pharmacological studies to target neutrophils and macrophages both in vitro and in vivo, was reported in several publications. Asolkar and colleagues described two new cyclohexadepsipeptides arenamides A and B (105,106), isolated from the Fijian bacterium Salinispora arenicola, that inhibited LPS-induced murine macrophage RAW 264.7 cells PGE2 and NO production in vitro, by affecting NFκB signaling activity (IC50 = 3.7 and 1.7 μM, respectively), thus highlighting their “anti-inflammatory characteristics”. Three publications yielded potentially novel compounds targeting proinflammatory mediators released by activated brain microglia, a macrophage involved in neuroinflammation and neurodegeneration: Youssef and colleagues described a new steroid callysterol (107) from the Red Sea sponge Callyspongia siphonella, which potently inhibited rat hind paw edema with an activity close to cortisone, and also reduced TXB2 release from LPS-activated rat brain microglia (apparent IC50 > 10 μM). Jean and colleagues observed that the sesquiterpene capnellene (108) isolated from the Indonesian soft coral Capnella imbricate, attenuated expression of inducible cyclooxygenase-2 both in activated microglia in vitro and in vivo, suggesting it might contribute to “the search for new therapeutic agents for treatment of neuroinflammatory diseases”. Shi and colleagues isolated a new terpene, elisabethin H (109) from the Caribbean gorgonian octocoral Pseudopterogorgia elisabethae, which significantly inhibited superoxide anion (O2–) generation from E. coli LPS activated rat neonatal microglia in vitro (IC50 = 7 μM). Li and colleagues reported that the floridosides (110,111), isolated from the South Korean marine red alga Laurencia undulata, possessed significant antioxidant capacity and inhibited the proinflammatory matrix metalloproteinases MMP-2 and MMP-9, thus suggesting they might be candidates for further development as natural marine antioxidants. Three publications investigated inhibition of pro-inflammatory mediators released by activated macrophage cell lines: Malloy and colleagues reported that the lipopeptide malyngamide 2 (112) from the Papua New Guinea marine cyanobacterium Lyngbya sordida inhibited nitric oxide production in LPS-primed RAW 264.7 macrophage cells (IC50 = 8.0 μM). In a detailed mechanistic study Villa and colleagues investigated the lipopeptide malyngamide F (113) from the marine cyanobacterium Lyngbya majuscula showing that it inhibited nitric oxide production in LPS-primed RAW 264.7 macrophage cells (IC50 = 7.1 μM) by selectively inhibiting the MyD88-dependent pathway of TLR4 and 9, thus potentially becoming a “useful tool” in cellular biology. Kim and colleagues extended previous studies with the phlorotannin phlorofucofuroeckol A (PFF-A) (114), isolated from the Korean brown alga Ecklonia stolonifera, by demonstrating its antioxidant activity was of similar potency to vitamin C, and that it inhibited nitric oxide and PGE2 production (apparent IC50 = 5–10 μM) by downregulation of iNOS and COX-2 protein expression in LPS-primed RAW 264.7 macrophage cells. Using an in vivo rat colitis model, Belmiro and colleagues provided a detailed molecular characterization of the anti-inflammatory properties of a dermatan sulfate (115), analog of mammalian heparin, purified from the Brazilian ascidian Styela plicata, which at 8 mg/kg per day significantly decreased lymphocyte and macrophage recruitment as well as TNF-α, TGF-β, and VEGF production in the inflamed rat colon. Hanif and colleagues reported that the highly hydroxylated long-chain sulfate symbiopolyol (116), isolated from a symbiotic dinoflagellate of the jellyfish Mastigias papua significantly inhibited (K50 = 6.6 μM) the expression of the inducible adhesion vascular cell adhesion molecule-1 which binds to leukocytes present in early stages of inflammation, and thus might become a “potential anti-inflammatory agent”. Costantino and colleagues reported that tedanol (117), a new brominated and sulfated pimarane diterpene isolated from the Caribbean sponge Tedania ignis, significantly reduced both the acute and subchronic phases of carrageenan-induced inflammation at 1 mg/kg with concomitant inhibition of both COX-2, iNOS expression and cellular infiltration.

25As shown in Table 2 and in contrast to the marine anti-inflammatory compounds previously discussed, while an anti-inflammatory activity and IC50 were reported, the molecular mechanism of action remained undetermined for the following marine compounds: carijoside A (118); chabrosterol (119); coscinolactams (120–122); durumhemiketalolide C (123); durumolide F (124); gyrosanolides B and C (125,126); klysimplexin sulfoxide C (127); L. crassum diterpenes (128,129); perthamides C and D (130,131); rossinones A and B (132,133); nebrosteroid I (134); sarcoehrenosides A and B (135,136); sarcocrassocolides A & B (137,138); simplexin E (139); and terpioside B (140).

26In 2009–2011, immune system pharmacology of marine compounds showed a considerable decrease from our previous review.

27Kwan and colleagues isolated the linear peptides grassystatins A–C (141–143) from a marine cyanobacterium identified as Lyngbya cf. confervoides, demonstrating that the compounds selectively inhibited aspartic protease cathepsin E (IC50 = 0.3–0.8 nM) versus cathepsin D, as well as antigen-stimulated T cell proliferation, with a concomitant reduction of IL-17 and interferon γ. Takei and colleagues reported that the known compounds callyspongidiol (144) and 14,15-dihydrosiphonodiol (145), isolated from a marine sponge Callyspongia sp., activated both functional and phenotypic maturation of human monocyte-derived dendritic cells, as well as higher interleukin-10 production by T cells, thus revealing potential use in autoimmune diseases and cancer. Shim and colleagues observed that the phloroglucinol derivative phlorofucofuroeckol A (PFF-A) (114), purified from the Korean marine seaweed Ecklonia stolonifera, reduced the expression of the human basophil FcεR1 receptor (apparent IC50 = 25 µM), as well as intracellular [Ca2+]i and histamine release, findings which may be relevant for regulation of IgE-mediated allergic reactions. Strangman and colleagues discovered novel splenocin B (146) isolated from the marine bacterium Streptomyces species strain CNQ431 that displayed potent inhibition of murine splenocyte-derived TH2 cytokines interleukin 5 and 13 (IC50 = 1.6–1.8 nM), thus contributing to the development of a “splenocin-derived drug” for allergic inflammation. Dai and colleagues isolated a water soluble polysaccharide HCLPS-1 (147) from the Chinese pearl-producing mollusc Hyriopsis cumingii Lea, which stimulated murine spleen lymphocyte proliferation in vitro and in vivo in a concentration-dependent manner (apparent IC50 less than 20 mg/kg), suggesting HCLPS-1 might become a “potential natural immunomodulator” upon further pharmacological study. Orsi and colleagues contributed to the immunopharmacology of the sulfated dinoflagellate polyether yessotoxin (148), by demonstrating that it decreased macrophage phagocytic activity against the fungus Candida albicans (apparent IC50 = 1 nM), affected the cytoskeleton by inducing F-actin re-organization, and enhanced release of the cytokine TNF-α and chemokines MIP-1α and MIP-2.

28As shown in Table 2, the nervous system pharmacology of marine natural products in 2009–2011 involved some areas of neuropharmacology, namely neuronal neurite retraction, neurotransmission inhibition, neuronal Ca2+ oscillations and free radical inhibition.

29Marine natural products have previously been reported to affect neuritogenesis, a process required by neurons to respond to the extracellular environment to form synaptic connections. Inutsuka and colleagues contributed novel molecular studies on the effect of calyculin A (149) on neurons, demonstrating that rapid rat hippocampal neuron neurite retraction (apparent IC50 = 100 mM) induced by the toxin was dependent on actin filament polymerization or myosin II motor, yet independent of the microtubule polymerization status, and perhaps resulted from dephosphorylation of myosin light chain kinase. Sakurada and colleagues reported that the novel Palauan sponge Cribrochalina olemda purine (150), which elicited convulsions upon intracerebroventricular injections in mice (4 nM/mouse), inhibited GABAergic transmission in hippocampal neurons. Noteworthy was the author’s observation that this marine purine was “closely related in structure to endogenous neurosignaling molecules and commonly used CNS stimulants”.

30As shown in Table 2, two marine compounds (151,152) identified as part of a drug discovery screening program, were shown to inhibit neuronal Ca2+ oscillations, a network phenomenon that appears to depend on voltage-gated sodium channel activation. Choi and colleagues reported that a cyclic depsipeptide hoiamide B (151), isolated from a Papua New Guinean cyanobacteria assemblage of Symploca sp. and Oscillatoria cf. sp., stimulated sodium influx (IC50 = 3.9 µM) in murine neuronal cells in vitro by putative activation of site 2 on the sodium channel, while suppressing spontaneous Ca2+ (IC50 = 79.8 nM) with greater potency, thus revealing that hoiamide B may have more than one molecular target. Pereira and colleagues contributed a novel marine macrolide palmyrolide A (152) isolated from Northern Pacific Palmyra Atoll cyanobacteria assemblages of Leptolyngbya cf. and Oscillatoria sp. that inhibited both sodium influx (IC50 = 5.2 µM) in mouse neuroblastoma cells and spontaneous Ca2+ oscillations (IC50 = 3.7 µM) in primary cultures of murine cerebrocortical neurons, “making it an intriguing candidate for further pharmacological exploration”. Zhao and colleagues reported that the known compound xyloketal B (153), isolated from the marine mangrove fungus Xylaria sp., inhibited ischemia-induced PC12 cell injury (IC50 = 100 µM) by a neuroprotective mechanism involving free radical scavenging and reduction of mitochondrial membrane potential and superoxide generation, suggesting further development for effective stroke therapy.

31Finally, and as presented in Table 2, during 2009–2011, several other marine compounds were reported to affect the nervous system by demonstrating pharmacological activity on Ca2+ oscillations, several receptors, and neuronal nitric oxide synthase, yet the mechanism of action of these compounds remained undetermined: alotamide A (154), (−)-dibromophakellin (155), dysideamine (156), ircinialactams (157,158), eusynstyelamides B and C (159,160), nanolobatolide (161), and pulicatin A (162).

32Table 3 presents the 2009–2011 preclinical pharmacology of 68 marine compounds (163–226) with miscellaneous mechanisms of action, with their respective structures shown in Figure 3. Because additional in vitro and in vivo pharmacological data for these compounds remained unpublished, assignment of these marine compounds to a particular drug class was not possible.

33As shown in Table 3, the peer-reviewed literature reported a pharmacological activity, an IC50, and a molecular mechanism of action for 21 marine natural products: bisebromoamide (163); botryllamides I and J (164,165); dysidine (104); Ecklonia cava phlorotannins (166,167); fucophlorethols (168,169); gonad-stimulating substance (GSS) (170); halichlorine (171); hoiamide A (172); hypochromins A and B (173,174); mycothiazole (175); Mycale sp. pyrroles (176,177); neocomplanines A and B (178,179); pateamine A (180); polytheonamide B (181); and zampanolide (182).

34In contrast, although a pharmacological activity was described, and an IC50 for inhibition of an enzyme or receptor determined, detailed molecular mechanism of action studies were unavailable at the time of publication for the following 47 marine compounds included in Table 3: alotaketals A and B (183,184); aquastatin A (185); australin E (186); lyngbyastatins 9 & 10 (187,188); brunsvicamides A, B and C (189–191); carteriosulfonic acids A, B and C (192–194); Carteriospongia foliascens sesterterpenoids (195,196); clavatadines D and E (197,198); fibrosterol sulfates A and B (199,200); gracilin L (201); grassystatins A, B and C (141–143); 2-hydroxycircumdatin C (202); jaspaquinol (203); largamides A, B and C (204–206); largamide D oxazolidine (207); Laurencia similis brominated metabolites (208,209); molassamide (210); myrothenone A (211); 42-hydroxy-palytoxin (212); plectosphaeroic acids A, B and C (213–215); puupehenone (216); Sinularia numerosa oxylipin (217); sipholenone E (218); spartinoxide (219); 23-nor-spiculoic acid B (220); tanikolide dimer (221); tamulamides A and B (222,223); terretonins E and F (224,225); and tetrangulol methyl ether (226).

35Several reviews covering both general and specific areas of marine preclinical pharmacology were published during 2009–2011: (a) marine pharmacology and marine pharmaceuticals: a renaissance in marine pharmacology: from preclinical curiosity to clinical reality; biologically active marine natural products; drug development from marine natural products; biotechnological potential of marine natural products; pharmaceuticals from marine natural products: surge or ebb?; marine pharmacology in Australia: the Roche Research Institute; the global marine pharmaceutical pipeline in 2010: U.S. Food and Drug Administration-approved compounds and those in Phase I, II and III of clinical development; marine drugs from sponge-microbe associations; cyanobacteria as an emerging source for drug discovery; marine invertebrates as a future therapeutic treasure; biodiversity conservation and marine natural products drug discovery; marine invertebrates as a source of guanidines with chemical and pharmacological significance; innovations in the field of marine natural products and a new wave of drugs; (b) antimicrobial marine pharmacology: antibacterial marine natural products; marine microbes and pharmaceutical development; marine microbe-derived antibacterial agents; antimicrobial peptides from marine invertebrates; novel anti-infective compounds from marine bacteria; conventional and unconventional antimicrobials from fish, marine invertebrates and microalgae; (c) antiviral marine pharmacology: antiviral lead compounds from marine sponges; potential anti-HIV agents from marine resources; marine compounds and their antiviral activities; marine organisms as a therapeutic source against herpes simplex virus infection; (d) antiparasitic,antituberculosis, antimalarial and antifungal marine pharmacology: antiparasitic marine invertebrate-derived small molecules; marine antileishmanial natural products; antituberculosis leads from marine microbial metabolites; antimalarial drug discovery from marine sources between January 2003 and December 2008; antimalarial marine natural products from 2006 to 2008; antimalarial marine compounds; (e) immuno- and anti-inflammatory marine pharmacology: marine natural product leads for treatment of inflammation; marine natural products targeting phospholipase A2; marine diterpene glycosides as anti-inflammatory agents; anti-inflammatory compounds from marine algae; (f) cardiovascular marine pharmacology: marine-derived angiotensin-I-converting enzyme inhibitors; (g) nervous system marine pharmacology: conotoxins as natural products drug leads; marine indole alkaloids as new drug leads for depression and anxiety; marine natural products and ion channel pharmacology; neuroprotective effects of marine algae; conopeptides as novel options for pain management; structure-activity studies with α-conotoxins as selective antagonists of nicotinic acetylcholine receptors; (h) miscellaneous molecular targets: calyculins and related marine natural products as serine threonine protein phosphatase inhibitors; NF-κB inhibition by marine natural products; protein kinase inhibitors from marine sponges.

36The global marine preclinical and clinical pharmaceutical pipelines remain remarkably active one year after U.S. Food and Drug Administration approval of brentuximab vedotin (Adcetris®), a conjugate between a monoclonal antibody that targets the cell-membrane protein CD30, an antigen which is highly expressed in lymphoid tumors, and several units of the potent antimitotic agent monomethyl auristatin E, a synthetic analog of the marine compound dolastatin 10.

37This review aims to continue contributing to the marine preclinical pipeline review series that was initiated in 1998 and reveals the breadth of preclinical pharmacological research during 2009–2011, resulting from the global research effort of chemists and pharmacologists from Australia, Belgium, Brazil, Canada, China, Colombia, Cuba, Egypt, Fiji, France, Germany, Indonesia, Israel, Italy, Japan, Luxemburg, Malaysia, Mexico, the Netherlands, New Caledonia, New Zealand, Norway, Panama, Papua New Guinea, Philippines, South Africa, South Korea, Singapore, Spain, Switzerland, Taiwan, Thailand, United Kingdom, Venezuela, Vietnam, and the United States. Thus, we feel confident to predict that the marine preclinical pharmaceutical pipeline will most probably continue to provide novel pharmacological lead compounds that will enrich the marine clinical pharmaceutical pipeline, which currently consists of 6 U.S. Food and Drug Administration-approved pharmaceuticals and 11 compounds in Phase I, II and III of clinical development and which may be viewed at.