Biochimica et Biophysica Acta - Marine Pharmacologymarinepharmacology.midwestern.edu/docs/Mayer et...

Biochimica et Biophysica Acta 1790 (2009) 283–308

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Biochimica et Biophysica Acta

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Review

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

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

a Department of Pharmacology, Chicago College of Osteopathic Medicine, Midwestern University, 555 31st Street, Downers Grove, IL 60515, USAb Department of Chemistry, University of Puerto Rico, San Juan, PR 00931, USAc Instituto de Química de São Carlos, Universidade de São Paulo, CP 780, CEP 13560-970, São Carlos, Brazild School of Pharmacy, Chemistry and Biochemistry, The University of Mississippi, Faser Hall, University, MS 38677, USA

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

0304-4165/$ – see front matter © 2009 Elsevier B.V. Adoi:10.1016/j.bbagen.2009.03.011

a b s t r a c t
a r t i c l e i n f o
Article history:
Received 16 December 2008Received in revised form 9 March 2009Accepted 12 March 2009Available online 19 March 2009
Keywords:DrugMarineMetaboliteNatural productPharmacologyReviewToxicology

Background: The review presents the 2005–2006 peer-reviewed marine pharmacology literature, and followsa similar format to the authors' 1998–2004 reviews. The preclinical pharmacology of chemicallycharacterized marine compounds isolated from marine animals, algae, fungi and bacteria is systematicallypresented.Results: Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosisand antiviral activities were reported for 78 marine chemicals. Additionally 47 marine compounds werereported to affect the cardiovascular, immune and nervous system as well as possess anti-inflammatoryeffects. Finally, 58 marine compounds were shown to bind to a variety of molecular targets, and thus couldpotentially contribute to several pharmacological classes.Conclusions: Marine pharmacology research during 2005–2006 was truly global in nature, involvinginvestigators from 32 countries, and the United States, and contributed 183 marine chemical leads to theresearch pipeline aimed at the discovery of novel therapeutic agents.General significance: Continued preclinical and clinical research with marine natural products demonstrating
a broad spectrum of pharmacological activity will probably result in novel therapeutic agents for thetreatment of multiple disease categories.
© 2009 Elsevier B.V. All rights reserved.

1. Introduction

The current article reviews the 2005–6 preclinical pharmacologyof marine natural products using a similar format to the previousreviews on pharmacological research [1–5]. The review of theliterature on the pharmacology of antitumor and cytotoxic marinecompounds has been reported elsewhere [6–11]. Only those articlesreporting on the bioactivity or pharmacology of marine chemicals thatwere structurally characterized are included in the current article. Asin our previous reviews, we used a modification of Schmitz's chemicalclassification [12] to assign structures to four major chemical classes,namely, polyketides, terpenes, nitrogen-containing compounds orpolysaccharides. Those articles that reported anthelmintic, antibac-terial, anticoagulant, antifungal, antimalarial, antiprotozoal, antitu-berculosis and antiviral properties of marine chemicals have beenpresented in Table 1 with the corresponding structures shown in Fig.1.The publications describing marine compounds affecting the cardio-

1 630 971 6414.ayer).

ll rights reserved.

vascular, immune and nervous systems, as well as those with anti-inflammatory effects are grouped in Table 2, and their structuresshown in Fig. 2. Finally, marine compounds with activity towards aseries of cellular and molecular targets are exhibited in Table 3, andtheir structures depicted in Fig. 3. Publications regarding thebioactivity of marine extracts or as yet structurally uncharacterizedmarine compounds have been excluded from the present review,although several promising reports were published during 2005–6:anti-inflammatory and analgesic effects of Egyptian Red Sea spongeextracts [13]; proangiogenic effects of 15–20 kDa fucoidans onendothelial cells [14]; antioxidative and anti-inflammatory effects ofphlorotannin-containing extracts with potential for osteoarthritisfrom the brown alga Ecklonia cava [15]; immunostimulating activityin vivo of a novel sulfated exopolysaccharide derived from a red-tidemicroalga Gyrodinium impudicum [16]; antiherpetic activity in vitro ofsulfated fucans from the marine brown alga Stoechospermum margin-atum [17]; in vitro bioactivity of Brazilian marine sponge extractsagainst herpes, adenovirus and rotaviruses [18]; antifungal activity ofglycolipid fractions from the red alga Chondria armata [19]; antiviraland immunoregulatory activity of an exopolysaccharide from the

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Table 1Marine pharmacology in 2005–6: marine compounds with anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis, and antiviral activities.

Drug class Compound/organisma Chemistry Pharmacologic activity IC50b MMOAb Countryc References

Anthelmintic (−)-echinobetaine A and(+)-B (1,2)/sponge

Alkaloidf Activity against nematodeHaemonchus contortus

8.3–83 μg/mL++ Undetermined AUS [27,28]

Anthelmintic Laurencia scoparia terpene(3)/alga

Sesquiterpenee Activity against nematodeNippostrongylus brasiliensis

0.11 mM Undetermined URY,BRA

[29]

Antibacterial Caminosides B and D(4,5)/sponge

Polysaccharideg Methicillin-resistant S. aureusand vancomicin-resistantEnterococcus inhibition

3.1–6.3 μg/disk+ E. coli Type IIIsecretion inhibition

CAN,NLD,USA

[30]

Antibacterial Spongosorites sp. alkaloids(6,7)/sponge

Alkaloidf S. aureus inhibition 3.12–6.25 μg/mL+ Sortase A inhibition S.KOR [31]

Antibacterial Aurelin (8)/jellyfish Peptidef E. Coli inhibition 7.7 μg/mL+ Undetermined RUS [32]Antibacterial Batzellaside A (9)/sponge Alkaloidf S. epidermidis inhibition ≤6.3 μg/mL+ Undetermined USA [33]Antibacterial Dendridine A (10)/sponge Alkaloidf B. subtilis and M. luteus inhibition 4.2–8.3 μg/mL+ Undetermined AUS, JPN [34]Antibacterial 6-oxo-de-O-methyllasiodiplodin

(11)/fungusPolyketided B. subtilis, S. aureus and

S. enteritidis inhibition6.25–12.5 μg/mL+ Undetermined CHN [35]

Antibacterial Grammistins (12)/fish Peptidef B. subtilis, S. aureus andE. coli inhibition

3.13–12.5 μg/mL+ Undetermined JPN [36]

Antibacterial Halichonadin C (13)/sponge Sesquiterpenee M. luteus inhibition 0.52 μg/mL+ Undetermined JPN [37]Antibacterial Lajollamycin (14)/bacterium Polyketided S. aureus and S. pneumoniae

inhibition1.5–4 μg/mL+ Undetermined USA [38]

Antibacterial Marinomycins A–D(15–18)/bacterium

Polyketided S. aureus and E. faceiuminhibition

0.1–0.6 μM Undetermined USA [39]

Antibacterial Resistoflavin methyl ether(19)/bacteria

Polyketided B. subtilis inhibition 3.1 μg/mL+ Undetermined DEU [40]

Antibacterial Streptomyces anthraquinones(20,21)/bacterium

Polyketided Methicillin-resistant S. aureusinhibition


Antibacterial Streptomycetaceae quinone(22)/bacterium

Polyketided Methicillin-resistantS. aureus and vancomicin-resistant Enterococcus inhibition

1.95–3.90 μg/mL+ Undetermined USA [42]

Antibacterial Xeniolide I (23)/soft coral Terpenee E. coli and B. subtilis inhibition 1.2 μg/mL+ Undetermined ISR [43]Anticoagulant Limandra aspera protein/fish Peptidef Factor XIIa and platelet integrins

inhibitionb1 μM Formation of inactive

complex with XIIaKOR [57]

Anticoagulant Fucoidans (24)/alga Polysaccharideg Thrombin and factor Xa inhibitionin vitro and in vivo

ND RUS [58]

Anticoagulant Heparin (25)/clam Polysaccharideg Activated partial thromboplastintime and Xa inhibition in vitro

52–97 IU/mg Lower activity thanbovine mucosalheparin

ITA [59]

Anticoagulant Sulfated galactans(26,27)/alga

Polysaccharideg Thrombin and factor Xa inhibitionin vitro

ND 2,3-disulfatedα-galactose units criticalmotif

BRA [60]

Anticoagulant Sulfated galactofucan(28)/alga

Polysaccharideg Endothelial cell heparan sulfatesynthesis stimulation

ND Factor Xa inhibitionin vitro

BRA [61]

Antifungal Capisterones A and B(29,30)/alga

Steroide Enhancement of fluconazoleactivity

ND CDR1 and MDR1 effluxpump reversal activity

USA [62]

Antifungal Dysidea herbacea phenol(31)/sponge

Polyketided C. albicans and A. niger inhibition 1.95–7.8 μg/mL+ Leakage of K+ fromfungal cells

ISR [63]

Antifungal Spongistatin (32)/sponge Polyketided Broad panel of yeasts andfilamentous fungi

1–32 μg/mL+ Disruption ofmicrotubule network

USA [64]

Antifungal Halocidin (33)/ascidian Peptidef C. albicans inhibition 1–4 μg/mL+ Membrane poreformation

KOR [66]

Antifungal Hassallidin A (34)/bacterium Lipopeptidef C. albicans and A. fumigatusinhibition

4.8 μM+ Undetermined DEU [67]

Antifungal Latrunculins (35–42)/sponge Polyketided C. albicans inhibition comparableto clotrimazole

2.5–19 μM+ Undetermined EGY,USA

[49]

Antifungal Majusculoic acid (43)/bacterium

Polyketided C. albicans inhibition, less potentthan fluconazole

8 μM+ Undetermined USA [68]

Antimalarial Pycnidione (44)/fungus Polyketided P. falciparum W2 and D6 straininhibition

0.2–0.4 ng/mL Undetermined AUS,USA

[77]

Antimalarial Plakortide Q (45)/sponge Polyketided P. falciparum D10 and W2strain inhibition

0.5–1 μM Undetermined ITA [78]

Antimalarial Xestospongia sp. xestoquinone(46)/sponge

Polyketided FCB1 P. falciparum inhibition 3 μM Pfnek-1 kinaseinhibition

FRA [79]

Antimalarial Manzamine Y (47)/sponge Alkaloidf P. falciparum D6 and W2 straininhibition

0.4–0.85 μg/mL Undetermined IDN, ESP,USA

[80]

Antimalarial Caucanolides A and D(48,49)/soft coral

Diterpenee P. falciparum W2 inhibition 17 μg/mL Undetermined COL,PAN,USA

[81]

Antimalarial Eunicea sp. sesquiterpenoids(50–54)/coral

Sesquiterpenee P. falciparum W2 strain inhibition 10–18 μg/mL Undetermined COL,PAN,USA

[82]

Antimalarial Kallolide D (55)/sea whip Diterpenee P. falciparum inhibition 30.6 μM Undetermined PAN,USA

[83]

Antimalarial Leptolide anddeoxypseudopterolide(56,57)/coral

Diterpenee P. falciparum W2 strain inhibition 50 and 74 μM Undetermined ESP, PAN [84]

284 A.M.S. Mayer et al. / Biochimica et Biophysica Acta 1790 (2009) 283–308

Table 1 (continued).

Drug class Compound/organisma Chemistry Pharmacologic activity IC50b MMOAb Countryc References

Antimalarial Muricea austera tyramine(58)/coral

Tyraminederivativef

P. falciparum W2 strain inhibition 36 μM Undetermined ESP, PAN [85]

Antiprotozoal Ent-plakortide P (59)/sponge Polyketided Leishmania mexicana inhibition 1 μg/mL Undetermined KOR [86]Antiprotozoal Karatungiol A (60)/alga Polyketided Trichomonas foetus inhibition 1 μg/mL+ Undetermined JPN [87]Antiprotozoal Isoakaterpin (61)/sponge Meroterpenoide Leishmania spp. adenosine

phosphoribosyl transferaseinhibition

1.05 μM Undetermined CAN,BRA

[88]

Antituberculosis Fistularin-3 and 11-deoxy-fistularin-3 (62,63)/sponge

Tyrosinederivativef

M. tuberculosis inhibition 7.1–7.3 μM+ Undetermined BRA [89]

Antituberculosis Ileabethoxazole (64)/soft coral Diterpenee M. tuberculosis inhibition 61 μg/mL+ Undetermined USA [91]Antituberculosis Manzamine alkaloid

(65–73)/spongeAlkaloidsf M. tuberculosis inhibition 0.4–5.2 μg/mL+ Undetermined IDN, ESP,

USA[80]

Antiviral Callophylis variegatagalactans/alga

Polysaccharideg Herpes simplex and denguetype 2 inhibition

0.1–2.2 μg/mL Undetermined ARG [92]

Antiviral Naviculan/diatom Polysaccharideg Herpes simplex 1 and 2 inhibition 7.4–14 μM Undetermined JPN [93]Antiviral Schizymenia binderi sulfated

galactan/algaPolysaccharideg Herpes simplex 1 and 2 inhibition 0.18–0.76 μg/mL Interference with

HSV-heparan sulfatecellular residues

ARG,CHL

[94]

Antiviral Sargassum plastoquinones(74–76)/alga

Terpenoide Measles and cytomegalovirusinhibition

0.49–3.1 μM Lipid peroxidationobserved

JPN [95]

Antiviral Dictyota diterpenes (77,78)/alga Diterpenee Inhibition of HIV-1 reversetranscriptase

10–35 μM⁎⁎ RNA-dependentDNA-polymerase activityinhibition

BRA [96]

Antiviral Griffithsin/alga Proteinf T- and M-tropic HIV-1 inhibition 0.043–0.63 nM Inhibition of CD4-dependent gp120 binding

USA [97]

aOrganism, Kingdom Animalia: fish and ascidian (Phylum Chordata); sea star (Phylum Echinodermata), clam (Phylum Mollusca), sponges (Phylum Porifera); corals, sea whips andjellyfish (Phylum Cnidaria); KingdomMonera: bacteria (Phylum Cyanobacteria); Kingdom Fungi: fungus; Kingdom Plantae: diatom, alga; bIC50: concentration of a compound requiredfor 50% inhibition in vitro; ⁎estimated IC50; ⁎⁎Ki: inhibition constant for a drug; ⁎⁎⁎Kd: concentration at which 50% of ligand binding sites are occupied; ND: not determined; +MIC:minimum inhibitory concentration; ++LD99: dose required to kill 99% of test population; bMMOA: molecular mechanism of action; cCountry: ARG: Argentina; AUS: Australia; BRA:Brazil; CAN: Canada; CHN: China; CHL: Chile; COL: Colombia; DEU: Germany; EGY: Egypt; ESP: Spain; FRA: France; IDN: Indonesia; IND: India; ISR: Israel; ITA: Italy; JPN: Japan; NLD:The Netherlands; NZL: New Zealand; PAN: Panama; PRT: Portugal; RUS: Russia; SVN: Slovenia; URY: Uruguay; dPolyketide; eTerpene; fNitrogen-containing compound;gPolysaccharide.

285A.M.S. Mayer et al. / Biochimica et Biophysica Acta 1790 (2009) 283–308

marine Bacillus licheniformis [20]; potent anticoagulant activity of asulfated polysaccharide from the brown alga E. cava [21]; antimicro-bial activity of Red Sea coral extracts [22]; a novel broad-spectrumantibacterial protein produced by the bacterium Marinomonasmediterranea [23]; antiviral activity of polysaccharide fractionsisolated from the cyanobacterium Arthrospira platensis (formerlySpirulina platensis) [24]; antiangiogenic and antimicrobial activity ofsponge-associated bacterial extracts [25], and a β-galactose-specificlectin with anti-HIV-1 activity isolated from the marine worm Chae-topterus variopedatus [26].

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

Table 1 presents new pharmacological findings reported during2005–6 on the anthelmintic, antibacterial, anticoagulant, antifungal,antimalarial, antiprotozoal, antituberculosis, and antiviral pharmacol-ogy of the 78 marine natural products shown in Fig. 1.

2.1. Anthelmintic and antibacterial activity

Three studies contributed to the search of novel anthelminticmarine natural products during 2005–6. Capon et al. [27,28] describedtwo novel betaines (−)-echinobetaine A (1) and (+)-echinobetaine B(2), from the Australian sponge Echinodictyum sp. which werenematocidal (LD99=83 and 8.3 μg/mL, respectively) to the commer-cial livestock parasiteHaemonchus contortus. Although themechanismof action of these compounds remains undetermined, (+)-echinobe-taine B's nematocidal activity was comparable to that of “twocommercially available synthetic anthelmintics, closantel and leva-misole”. Davyt et al. [29] reported a novel halogenated β-bisabolenesesquiterpenoid (3) from the red alga Laurencia scoparia that showedanthelmintic activity (EC50=0.11 mM) against the parasitant stage(L4) of Nippostrongilus brasiliensis, a rat gastrointestinal parasite thathas a similar lifestyle and morphology to human hookworms.

As part of an ongoing global effort to discover novel antimicrobialsto treat infections caused by resistant pathogenic bacteria, during2005–6, 27 studies contributed novel antibacterial marine naturalproducts isolated from marine fungi, bacteria, sponges, soft corals,jellyfish and fish, a considerable increase from our previous reviews[1–5]. Only two reports provided detailed mechanism of actionstudies. Linington et al. [30] discovered that the novel caminosides B(4) and D (5) glycolipids, isolated from the Caribbean marine spongeCaminus sphaeoroconia, were inhibitors of pathogenic E. coli type IIIsecretion system. Both caminosides were observed to “possess anumber of structural features not found in sponge glycolipids” andwere also noted to be effective against Gram-positive methicillin-resistant S. aureus and vancomycin-resistant Enteroccocus (MIC=3.1–6.3 μg/disk). Oh et al. [31] reported that the bis(indole) alkaloidsdeoxytopsentin (6) and hamacanthin A (7) isolated from the marinesponge Spongosorites sp. exhibited potent antibacterial activity againstS. aureus (MIC=3.12–6.35 μg/mL). Interestingly, both alkaloidsinhibited the enzyme sortase A (IC50=15.7 and 86.3 μg/mL,respectively), a membrane-associated transpeptidase that plays akey role in Gram-positive pathogenic bacterial invasion of host cells.

As shown in Table 1, several potent marine antibacterials were alsoreported in 2005–6 (Fig. 1), with MICs less than 10 μg/mL againstseveral antibiotic-resistant bacterial strains, but unfortunately thearticles did not include data on putative mechanisms of action: aurelin(8) [32]; batzellaside A (9) [33]; dendridine A (10) [34]; 6-oxo-de-O-methyllasiodiplodin (11) [35]; grammistins (12) [36]; halichonadin C(13) [37]; lajollamycin (14) [38]; marinomycins A (15), B (16), C (17)and D (18) [39]; resistoflavin methyl ether (19) [40]; Streptomycesanthraquinones (20–21) [41]; Streptomycetaceae quinone (22) [42]and, xeniolide I (23) [43].

Furthermore, novel structurally-characterized marine moleculeswithMICs greater than 10 μg/mLwere also isolated during this period,but are not included in Table 1 or Fig. 1 because of their weakerantibacterial activity: agelasidine A (MIC=50 μg/mL) [44]; alkylpyr-idinium (MICb25 μg/mL) [45]; diaporthelactone (MIC=50 μg/mL)[46]; Geniculosporium sp. botryanes [47]; guangomide A and B


(MIC=100 μg/mL) [48]; latrunculins (MIC=14.7–17.8 μg/mL) [49];norresistomycin (MIC=16 μg/mL) [50]; perinadine A (MIC=33–66.7 μg/mL) [51]; Pseudomonas aeruginosa quinoline (MIC=50–100 μg/mL) [52]; rifamycin B and SV [53]; sarasinoside A1 and J [54];scalusamide A (MIC=33 μg/mL) [55], and Thorectandra sp. alkaloid(MIC=12.5 μg/mL) [56]. Although these marine compounds demon-strated weaker antimicrobial activity, they highlight the fact thatnovel antimicrobial leads may result from further research into thechemical biodiversity present in marine bacteria, fungi and sponges.

2.2. Anticoagulant activity

As shown in Table 1, during 2005–6, 5 articles reported anticoagu-lant marine natural products isolated from algae, fish and clams, anincrease from our previous reviews [1–5]. Rajapakse et al. [57]characterized a 12.01 kDa single-chain monomeric protein from themarine yellowfin sole (Limanda aspera) which inhibited the blood

Fig. 1. Marine compounds with anthelmintic, antibacterial, anticoagulant, antif

coagulation serine endopeptidase factor XII (IC50b1 μM)by forming aninactive complex, and also triggered platelet aggregation by binding toa membrane glycoprotein integrin. Drozd et al. [58] extended thepharmacology of the fucoidans (24) from the marine algae Fucusevanescens and Laminaria cichorioides, showing that these sulfatedpolysaccharides inhibited both thrombin and factor Xa with potencycomparable to non-fractioned and low-molecular weight heparins,although with considerable variability attributed to the “degree ofsulfation and various types of glycoside bonds”. Luppi et al. [59]reported the purification and structural characterization of an unusuallow-sulfated heparin (25) from the marine Italian bivalve molluskCallista chione that decreased anti-factor Xa and activated partialthromboplastin time activity (IC50=52–97 IU/mg), probably as theresult of a specific decrease in sulfation at position 2 of the uronic acidunits. Pereira et al. [60] using an approach that combined structuralanalysis with specific biological assays, investigated the anticoagulantpharmacology of sulfated galactans (26,27) isolated from the red

ungal, antimalarial, antiprotozoal, antituberculosis, and antiviral activities.

Fig. 1 (continued).


marine alga Gelidium crinale. Their detailed mechanistic studiesdemonstrated that 2,3-disulfatedα-galactose units along the galactanchain were of major significance for the sulfated galactan’s anti-coagulant activity, because the chains modulated interactions of thepolysaccharides with “target proteases and coagulation inhibitors”.Rocha et al. [61] described a novel sulfated galactofucan (28) isolatedfrom the marine brown alga Spatoglossum schroederi with a uniquestructure composed of a central core of 4-linked, partially 3-sulfated β-galactose units. Remarkably, the polysaccharide had no anticoagulantactivity, yet showed potent antithrombotic activity resulting from thesynthesis of heparan sulfate by vascular endothelial cells.

2.3. Antifungal activity

As shown in Table 1, sixteen studies during 2005–6 reported on theantifungal activity of several novel marine natural products isolated

frommarine algae, fungi, bacteria, sponges and sea stars, a substantialincrease from our 1998–2004 reviews [1–5].

Four reports extended the molecular pharmacology of novelantifungal marine chemicals. Li et al. [62] discovered that thecapisterones A and B (29,30) from the green alga Penicillus capitatusreversed drug resistance to clinically relevant azole-resistant fungalstrains. Interestingly, although both compounds had no inherentantifungal activity, they enhanced fluconazole activity in efflux pump-overexpressing Candida albicans strains, suggesting their utility inprotocols for resistant fungal infections. Sionov et al. [63] observedthat a phenol compound (31) from the marine sponge Dysideaherbacea had significant activity against the human fungal pathogensC. albicans and Aspergillus fumigatus (MIC=1.95–7.8 μg/mL) whichcompared well with the clinically used antifungal amphotericin B(MIC=1–2 μg/mL). The phenol compound caused significant con-centration-dependent changes in fungal cell morphology and cell

Fig. 1 (continued).


membrane, resulting in K+ ion leakage. Pettit et al. [64] extended thein vitro and in vivo pharmacology of the marine spongistatin 1 (32)isolated from the marine sponge Hyrios erecta, a previously describedanticancer agent [65]. The macrocyclic lactone polyether was shownto be fungicidal to 74 reference strains and clinical isolates (MIC=1–32 μg/mL), including several fungal strains resistant to the clinicallyused drugs flucytosine, ketoconazole and fluconazole. Furthermore,mechanism of action studies revealed that spongistatin 1 disruptedcytoplasmatic and spindlemicrotubules in Cryptococcus neoformans ina time- and concentration-dependent manner, preventing nuclearmigration, and both nuclear and cellular cell division. Jang et al. [66]found that a synthetic analogue of halocidin (33), a previouslyreported antimicrobial peptide isolated from the hemocytes of amarine ascidian, had potent antifungal activity (MIC=1–4 μg/mL).The synthetic Di-K19Hc peptide derivative of 33 was shown to bind toC. albicans very rapidly (30 s) via an interaction with β-1,3-glucan, acomponent of the fungal cell wall, and concomitantly inducing ionchannel formation, K+ efflux, and death of the fungal cell.

Additionally, and as shown in Table 1, several marine chemicalsshowed significant antifungal activity (i.e. MICs that were less than10 μg/mL; Fig. 1; 34–43), but unfortunately mechanism of actionstudies were lacking at the time of publication: the lipopeptidehassallidin A (34), (MIC=4.8 μM) [67], the polyketide latrunculins(35–42), (MIC=2.5–19 μM) [49], and the fatty acid majusculoic acid(43), (MIC=8 μM) [68]. Further investigation of the molecularpharmacology of these compounds will be required to determine theirmechanism of action.

Finally, additional novel structurally-characterized marine mole-cules demonstrated MICs greater than 10 μg/mL, and thereforebecause of the weaker antifungal activity they have been excludedfrom Table 1 and Fig. 1: amphidinols (IC50=10–58 μM) [69,70],callipeltins F-I (IC50=100 μM) [71], Lamellodysidea herbacea sterols[72], minutosides A and B [73], oceanalin A (IC50=30 μM) [74],sokodoside A and B [75], and sterigmatocyn [76]. Although thesemarine chemicals showed weaker antifungal activity, they representpotential pharmacological leads perhaps possessing novel and

Fig. 1 (continued).


uncharacterized mechanisms of action that might ultimately benefitthe ongoing global search for clinically useful antifungal agents.

2.4. Antimalarial, antiprotozoal, and antituberculosis activity

As shown in Table 1, in 2005–6 nine studies were reported in thearea of antimalarial, antiprotozoal and antituberculosis pharmacologyof structurally-characterized marine natural products, a significantincrease from our previous 1998–2004 reviews [1–5].

Wright and Lang-Unnasch [77] reported that pycnidione (44)isolated from the marine fungus Phoma sp., had significant anti-plasmodial activity against three strains of Plasmodium falciparum(IC50=0.15–0.4 μM). Because of structural similarities betweenpycnidione and atovaquone, an ingredient of the antimalarialmedication Malarone®, the investigators proposed that the antiplas-modial activity of pycnidione was “significant in terms of leadstructure development”. Campagnuolo et al. [78] identified anti-malarial activity in novel polyketide cycloperoxides isolated from themarine sponge Plakortis simplex. The known plakortide Q (45)demonstrated the highest inhibition of P. falciparum chloroquine-sensitive and chloroquine-resistant strains (IC50=0.52–1 μM),

suggesting that the configuration at C-3 exerted a significant effecton antimalarial activity of these compounds. Laurent et al. [79] provedthat the known xestoquinone (46) isolated from the Pacific Oceansponge Xestospongia sp. had significant in vitro antiplasmodial activity(IC50=3 μM), and inhibited Pfnek-1(IC50=1 μM), a protein kinase ofP. falciparum that plays a yet undetermined role in its biochemistry.Rao et al. [80] highlighted the bioactivity of four newmanzamine-typealkaloids, as well as that of 13 known manzamine alkaloids isolatedfrom Indonesian sponges of the genus Acanthostrongylophora againstthe chloroquine-sensitive and chloroquine-resistant strains ofP. falciparum. Although less potent than artemisinin, used as a controlin these studies (IC50=10 and 6.3 ng/mL, respectively), the higherbioactivity of manzamine Y (47) against P. falciparum (IC50=0.42–0.85 μg/mL) demonstrated the importance of the hydroxy group andthe 8-membered ring in the aliphatic region of this molecule for theantimalarial activity.

Several additional marine chemicals were reported in 2005–6 topossess antimalarial activity, but their bioactivity appeared to be lesssignificant, i.e.MICN10 μM: thediterpenes caucanolidesA andD(48,49)from the Colombian gorgonian coral Pseudopterogorgia bipinnata,(IC50=17 μg/mL) [81], sesquiterpenoid metabolites (50–54) from a

Fig. 1 (continued).


Caribbean gorgonian coral Eunicea sp., (IC50=10–18 μg/mL) [82], thediterpene kallolide D (55) from a Colombian Pseudopterogorgia species,(IC50=30.6 μM) [83], the furanocembranolide diterpenes leptolide(56) and deoxypseudopterolide (57) from the Panamanian octocoralsLeptogorgia alba and Leptogorgia rigida, (IC50=50 and 74 μM, respec-tively)[84], and a tyramine derivative (58) from the PanamanianoctocoralMuricea austera (IC50=36 μM) [85].

Three marine compounds were reported to possess antiprotozoalactivity. Lim et al. [86] found that ent-plakortide P (59), a newnatural product from the sponge Plakortis sp., inhibited Leishmaniamexicana proliferation (IC50=1 μg/mL), although it appeared to beless potent than ketoconazole (IC50=0.06 μg/mL). Washida et al.[87] examined a novel polyol compound karatungiol A (60) isolatedfrom the symbiotic Indonesian marine dinoflagellate Amphidiniumsp., and observed antiprotozoal activity against Trichomonas foetus(IC50=1 μg/mL). This constitutes an important observation in view

of the fact that this flagellated protozoan parasite of both the bovineand feline reproductive tract appears to show increasing resistanceto the anthelmintics fenbendazole and metronidazole. Gray et al.[88] discovered a new disulfated meroterpenoid, isoakaterpin (61),from extracts of the Brazilian marine sponge Callyspongia sp. thatinhibited Leishmania spp. adenine phosphoribosyl transferase(IC50=1.05 μM), an enzyme that is part of the purine salvagepathway in the parasite, and “should compromise parasite but notmammal metabolism”.

Three novel marine compounds were contributed to the globalsearch for novel antituberculosis agents. De Oliveira et al. [89] reportedthat (+)-fistularin-3 (62) and 11-deoxy-fistularin-3 (63) isolatedfrom the Brazilian sponge Aplysina cauliformis inhibited growth ofMycobacterium tuberculosis H37Rv (MIC=7.1–7.3 μM, respectively),thus extending previous observations on the antituberculosis activityof fistularin-3 (62) [90]. Because these compounds evidenced very

Fig. 1 (continued).


low toxicity to macrophages (IC50=200 and 630 μM, respectively),there is definite potential for these compounds to become leads forantituberculosis drug development. As part of the investigation of theextensive chemodiversity of the Caribbean seawhip Pseudopterogorgiaelisabethae, Rodriguez et al. [91] noted that at the concentration rangeof 128–64 µg/mL the novel benzoxazole alkaloid ileabethoxazole (64)inhibitedM. tuberculosis (H37Rv, MIC=61 μg/mL), with a potency that“lies within the same range as that of the very active rifampin”. As aresult of an ongoing investigation to identify new manzamines fromthe Indo-Pacific sponge, Acanthostrongylophora sp., Rao et al. [80]identified two of the alkaloids, namely (+)-8-hydroxymanzamine A(66) and manzamine F (73), that inhibited M. tuberculosis (H37Rv,MIC=0.9 and 0.4 μg/mL, respectively), results which compared veryfavorably with rifampicin (MIC=0.5 μg/mL), a first-line antitubercu-losis drug.

2.5. Antiviral activity

As shown in Table 1, interest in the antiviral pharmacology of novelmarine natural products remained high during 2005–6. Four studiesreported novel marine chemicals with antiviral activity against herpes

simplex, measles and cytomegalovirus. Rodriguez et al. [92] isolatedthree galactan polysaccharide fractions from the Argentinian marinealgae Callophyllis variegata which showed potent antiviral activityagainst herpes simplex types 1 (HSV-1) and 2 (HSV-2) (IC50=0.16–2.19 μg/mL) and dengue type 2 (IC50=0.1–0.41 μg/mL), togetherwithlow cytotoxicity, suggesting that these compounds might become“promising antiviral agents”. Lee et al. [93] described a sulfatedpolysaccharide naviculan from Navicula directa, a diatom collectedfrom deep-seawater in Toyama Bay, Japan, which inhibited HSV-1 andHSV-2 (IC50=7–14 μg/mL) by interfering with early stages of viralreplication, probably affecting viral binding, adsorption and penetra-tion into host cells. Matsuhiro et al. [94] reported the structuralanalysis and antiviral activity of a sulfated galactan isolated from themarine red seaweed Schizymenia binderi. The sulfated galactanexhibited highly selective antiviral activity against HSV-1 and HSV-2(IC50=0.18–0.76 μg/mL), very low cytotoxicity, appeared to inhibitviral adsorption to host cells andwas thus considered to be superior to“other previously reported sulfated galactans of algal origin”.Iwashima et al. [95] discovered that three plastoquinones (74–76)isolated from the marine alga Sargassum micracanthum inhibitedcytomegalovirus (IC50=0.49–2.6 μM) and measles virus (IC50=2.7–

Fig. 1 (continued).


3.1 μM), suggesting that the compounds could become “leadcompounds in an anti-human cytomegalovirus drug” development.

Two reports contributed additional pharmacology against humanimmunodeficiency virus type-1 (HIV-1), the causative agent of theacquired immunodeficiency disease syndrome (AIDS), a disease thatinfects more than 40 million people worldwide. In a detailedmechanistic study De Souza et al. [96] described the biochemicalpharmacology of two diterpenes (77–78) isolated from a Brazilianmarine alga Dictyota menstrualis on HIV-1 reverse transcriptaseenzyme. Both diterpenes were shown to behave as classical non-competitive reversible inhibitors of the RNA-dependent DNA-poly-merase activity of HIV-1 reverse transcriptase (Ki=10 and 35 μM,respectively). Mori et al. [97] contributed the characterization of anovel and potent HIV-inactivating protein griffithsin from the red algaGriffithsia sp. Griffithsin, a new type of lectin, displayed potent antiviralactivity against laboratory strains and primary isolates of HIV-1(IC50=0.043–0.63 nM), by a mechanism that required binding to

viral glycoproteins (e.g. gp120, gp41 and gp160) in a monosaccharide-dependent manner. Furthermore, the authors noted griffithsin was apotential “candidate microbicide to prevent the sexual transmission ofHIV and AIDS”.

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

Table 2 summarizes the preclinical pharmacological researchcompleted during 2005–2006 with the 47 marine secondarymetabolites shown in Fig. 2.

3.1. Anti-inflammatory compounds

The anti-inflammatory pharmacology of marine compoundsreported during 2005–6 showed a considerable increase from ourprevious reviews [1–5].

Table 2Marine pharmacology in 2005–6: marine compounds with anti-inflammatory activity, and affecting the cardiovascular, immune and nervous system.

Drug class Compound/organisma+ Chemistry Pharmacological activity IC50b MMOAc Countryd References

Anti-inflammatory Bolinaquinone (79) andpetrosiaspongiolide M(80)/sponge

Merosesquiterpenef

and SesterterpenefInhibition of colonicinflammation in vivo

ND iNOS, NO, IL-1β andPGE2 inhibition

ESP, ITA [98]

Anti-inflammatory Cladocorans A and B(81,82)/coral

Sesterterpenef Secretory phospholipaseA2 inhibition

0.8–1.95 μM Undetermined JPN [99]

Anti-inflammatory Dysidea quinones (83,84)/sponge

Sesquiterpene-quinonef

Human neutrophil free radicalrelease inhibition in vitro

3–11 μM Superoxide anioninhibition

NZL [100]

Anti-inflammatory Manzamines A–F(65,69,71,73,85,86)/sponge

Indole-derivedalkaloidg

Modulation of LPS-activatedbrain microglia in vitro

0.016–10 μM TXB2 and superoxideanion inhibition

USA [101]

Anti-inflammatory Sarcophines (87,88)/softcoral

Diterpenef Modulation of LPS-activatedbrain microglia in vitro

1 μM TXB2 and superoxideanion inhibition

EGY, USA [102]

Anti-inflammatory Euryspongia n. sp. sterol(89)/sponge

Steroidf HU keratinocyte 6-keto-PGF1α inhibition

10 μg/mL⁎ Undetermined FRA [104]

Anti-inflammatory Gibberoketosterol (90)/soft coral

Steroidf iNOS and COX-2 proteininhibition

10 μM⁎ Undetermined EGY,TAIW

[105]

Anti-inflammatory Ircinia spinosula chromenol(91)/sponge

Triterpene-polyketidee

Porcine leukocyte LTB4

inhibition1.9 μM Undetermined GRC, DEU [106]

Anti-inflammatory Isoparalemnone (92)/softcoral

Sesquiterpenef Inhibition of iNOS protein 10 μM⁎ Undetermined EGY,TAIW

[107]

Anti-inflammatory PFF-B (93)/alga Shikimate-derivativee

Inhibition of histamine releasein vitro

7.8 μM Undetermined JPN [108]

Anti-inflammatory Symbioimine (94)/dinoflagellate

Alkaloidg COX-2 protein inhibition N10 μM⁎ Undetermined JPN [109]

Cardiovascular Lepadiformines A and B(95,96)/ascidian

Alkaloidg Cardiac inward rectifying K+

current inhibition1.4–1.6 μM⁎⁎⁎ Voltage-dependent

blockFRA [110]

Cardiovascular Zooxanthellamide Cs (97)/alga

Polyketidee Vasoconstriction of rat bloodvessels

0.39 μM Undetermined JPN [111]

Immune system Annulins A–C (98–100)/hydroid

Polyketidee Indoleamine 2,3-dioxygenaseinhibition

0.1-1.1 μM ⁎⁎ Undetermined CAN [112]

Immune system Cucumariosides (101)/sea cucumber

Triterpene-oligoglycosidef

Stimulation of lymphocytesand neutrophils

ND IL-6 and TNF-α increase RUS [113]

Immune system Damicoside (102)/sponge Glycosphingolipid Stimulation of spleen cellproliferation

1.0 ng/mL⁎ Free galactose grouprequired for activity

ITA [114]

Immune system Laminarin/alga Polysaccharideh Inhibition of lymphocyteapoptosis

1–4 mg/mL Induction of 33 immuneresponse genes

S.KOR [115]

Immune system Sulfated SPMG (103)/alga Polysaccharideh In vivo activation of T cells 10 mg/kg IL-2, IFN-γ increase;TNF-α decrease

CHN [116]

Immune system Verrucarin A (104)/fungus Polyketidee Interleukin-8 inhibition N10 ng/mL⁎ p38 and JNK MAP kinaseinhibition

JPN [117]

Nervous system CEG-3 ganglioside (105)/sea cucumber

Glycolipid Induction of neurite outgrowth 10 μM⁎ Undetermined JPN [120]

Nervous system CEG-6 ganglioside (106)/sea cucumber

Glycolipid Induction of neurite outgrowth b10 μM⁎ Undetermined JPN [121]

Nervous system LLG-5 ganglioside (107)/sea star

Ganglioside Induction of neurite outgrowth b10 μM⁎ Undetermined JPN [122]

Nervous system GP-3 ganglioside (108)/seastar

Ganglioside Induction of neurite outgrowth N10 μM⁎ Undetermined JPN [123]

Nervous system Linckosides F, I, K (109–111)/sea star

Steroidf Induction of neurite outgrowth ND Dependent on pentosemodified C branch

JPN [124]

Nervous system Shimalactone A (112)/fungus Polyketidee Induction of neuritogenesis 10 μg/mL⁎ Undetermined JPN [125]Nervous system Sargachromenol (113)/alga Diterpene-

polyketideePromotion of NGF-stimulatedneurite outgrowth

9 μM cAMP and MAP kinasepathways required

JPN [118]

Nervous system Conus vexillum conotoxins(114–116)/snail

Peptideg Non-competitive nicotinicreceptor antagonists

0.4–8.4 nM Slow block of α7 andα3β2 nicotinic receptor

AUS, DEU [126]

Nervous system SO-3 conopeptide (117)/snail Peptideg N-type neuronal Ca2+

current inhibition0.16 μM Selective N-type voltage-

sensitive Ca channel blockerCHN [127]

Nervous system Dysiherbaines (118,119)/sponge

Aminoacidg Ionotropic glutamate receptorbinding

0.5–4.3 nM⁎⁎ GluR5, GluR6 and KA2receptor binding

FIN, JPN,GBR, USA

[128,129]

Nervous system (−)-pictamine (120)/ascidian

Quinolizidinealkaloidg

Nicotinic acetylcholinereceptor block

1.5 μM α4β2 receptor irreversibleinhibition

JPN, USA [130]

Nervous system Bromopyrrole alkaloid(121)/sponge

Bromopyrrolealkaloidg

Glutamate and serotoninantagonist

10 μg/mL⁎ Inhibition of neuronalCa2+ entry

ITA, DEU [131]

Nervous system Daminin (122)/sponge Pyrrole alkaloidg Inhibition of neuronal Ca2+

levels1 μg/mL⁎ Undetermined ITA, DEU [132]

Nervous system Gephyromycin (123)/bacterium

Polyketidee Increase of neuronal Ca2+

levelsND Undetermined GBR, DEU [133]

Nervous system Motuporamine C (124)/sponge

Alkaloidg Neuronal growth collapse 5 μM⁎ Upregulation of Rhopathway

CAN [134]

Nervous system Trigonelline (125)/soft coral Pyridinium alkaloidg Voltage-activated K+

current inhibitionN0.1 mM⁎ Enhanced Ca2+ influx EGY, GBR [135]

aOrganism: Kingdom Animalia: hydroid, corals (Phylum Cnidaria); ascidian, blue shark (Phylum Chordata), sea star, cucumber (Phylum Echinodermata); snail (Phylum Mollusca);sponge (Phylum Porifera); Kingdom Fungi: fungus; Kingdom Plantae: alga; KingdomMonera: bacterium (Phylum Cyanobacteria); bIC50: concentration of a compound required for 50%inhibition in vitro; ⁎estimated IC50; ⁎⁎Ki: inhibition constant for a drug; ⁎⁎⁎Kd: concentration at which 50% of ligand binding sites are occupied; ND: not determined; cMMOA:molecular mechanism of action; NO: nitric oxide; dCountry: AUS: Australia; CHN: China; DEU: Germany; EGY: Egypt; FIN: Finland; FRA: France; GBR: United Kingdom; GRC: Greece;ITA: Italy; JPN: Japan; NZL: New Zealand; S.KOR: South Korea; TAIW: Taiwan; ePolyketide; fTerpene; gNitrogen-containing compound; hPolysaccharide.


Fig. 2. Marine compounds with anti-inflammatory activity, and affecting the cardiovascular, immune and nervous system.


Busserolles et al. [98] tested the hypothesis that oral administra-tion of bolinaquinone (79) and petrosiaspongiolide M (80), twomarine terpenes isolated from the sponges Dysidea sp. and Petrosas-pongia nigra, could inhibit inflammation and oxidative stress in an invivo murine model of inflammatory bowel disease in humans. Theobservation that both compounds inhibited neutrophilic infiltration,interleukin-1β, prostaglandin E2 levels and cyclooxygenase 2 proteinexpression in vivo, supports further development of these compoundsfor “protective strategies” against intestinal inflammatory diseases.Miyaoka et al. [99] contributed to the pharmacology of phospholipaseA2 inhibitors by investigating two sesterterpenoids, cladocorans A(81) and B (82) from the coral Cladocora cespitosa, which possess a γ-hydroxy-butenolide moiety. Cladocorans A and B were observed topotently inhibit secretory phospholipase A2 (IC50=0.8–1.9 μM), witha potency similar to manoalide (IC50=0.6 μM). McNamara et al. [100]

reported the isolation of a novel isozonarone derivative (83) and ofisozonarol (84) from the New Zealand sponge Dysidea cf. cristagalli. Invitro studies with human neutrophils demonstrated a concentration-dependent reduction of superoxide anion release (IC50=3–11 μM) bya mechanism hypothesized to involve the accumulation of thelipophilic sesquiterpene moiety in cell membranes, where it couldinterfere with superoxide production. Mayer et al. [101] conducted astructure–activity relationship (SAR) study to investigate the anti-neuroinflammatory properties of the indole-derived alkaloids man-zamines A (65), B (69), C (85), D (86), E (71) and F (73), isolated fromthe marine sponges Haliclona sp., Amphimedon sp., and Xestospongiasp. Manzamine A's potent inhibition of both superoxide anion(IC50=0.1 μM) and thromboxane B2 (IC50=0.016 μM) release byactivated brain microglia cells, suggested that the “solubility or ionicforms of manzamine A as well as changes such as saturation or

Fig. 2 (continued).


oxidation of the β carboline or 8-membered amine ring” played acritical role in the observed SAR results. Sawant et al. [102]investigated both the marine cembranoid diterpene sarcophine (87)and a semisynthetic sulfur-containing derivative (88) in an in vitroanti-neuroinflammatory assay [103]. Only compound (87) signifi-cantly inhibited both generation of superoxide anion and throm-boxane B2 (IC50=1 μM) from activated rat brain macrophages,demonstrating that “targeting the epoxide ring of sarcophine”enhanced sarcophine's anti-inflammatory activity. Mandeau et al.[104] showed that a new steroid, 3β-hydroxy-26-norcampest-5-en-25-oic acid (89) from the sponge Euryspongia n. sp. reduced 6KPGF1αproduction by human keratinocytes by 41% at 10 μg/mL. Interestingly,Ahmed et al. [105] reported that the known steroid gibberoketosterol(90), isolated from the Formosan soft coral Sinularia gibberosa,significantly reduced proinflammatory iNOS and COX-2 proteins inlipopolysaccharide-stimulated murine macrophages at a concentra-tion of 10 μM to 44.5% and 68.3% of control values, respectively.Tziveleka et al. [106] submitted anti-inflammatory studies with theknown chromenol (91) isolated from the Greek marine spongeIrcinia spinosula. The authors noted that the compound's potentinhibition of leukotriene B4 generation by stimulated porcineleukocytes (IC50=1.9 μM), was related to the “absence of a sidechain OH group as well as the reduced number of prenyl moieties”on the sponge metabolite. Huang et al. [107] described a novel

sesquiterpenoid isoparalemnone (92) from the Formosan soft coralParalemnalia thyrsoides that significantly inhibited inflammatoryiNOS protein expression (70% at 10 μM) in activated RAW 264.7cells. Sugiura et al. [108] reported that a phlorofucofuroeckol-B (93)from an edible Japanese marine brown alga, Eisenia arborea,inhibited histamine release (IC50=7.8 μM) from a rat basophilicleukemia in a concentration-dependent manner, an observationwhich compared favorably with a clinically used antihistamineTranilast (IC50=46.6 μM). Kita et al. [109] discovered a novelamphoteric iminium metabolite, symbioimine (94) in a dinoflagel-late Symbiodinium sp. isolated from the marine flatworm Amphis-colops sp., and showed that it inhibited the cyclooxygenase 2 enzymeby 32% at 10 μM. The authors suggested that symbioimine mightbecome a useful lead to develop new nonsteroidal anti-inflammatorydrugs.

3.2. Cardiovascular compounds

Sauviate et al. [110] reported novel studies on the mechanism ofaction of lepadiformines A and B (95,96), previously describedmarine alkaloids from the tunicate Clavelina moluccensis. Lepadifor-mines A and B dose-dependently inhibited the background inwardrectifying K+ current (IC50=1.42 μM) by blocking the cardiacmuscle Kir channel, and putatively interacting with “one of the

Fig. 2 (continued).


negatively charged aminoacids located in the inner vicinity of thenarrow K+ selectivity filter, candidates being residues D172, E224 orE229". Onodera et al. [111] isolated zooxanthellamide Cs (97) fromcultures of the marine dinoflagellate Symbiodinium sp., and showedthey were vasoconstrictive to rat blood vessels (EC50=0.39 μM).The structure–activity relationship study suggested that the “hugemacrolactone structure” played an as yet undetermined but criticalrole in the vasoconstrictive activity.

3.3. Compounds affecting the immune system

As a significant contribution to the discovery of novel indolea-mine 2,3-dioxygenase (INDO) inhibitors, agents shown to preventimmunological rejection of tumors, Pereira et al. [112], reported thatthe polyketides annulins A, B, and C (98–100) purified from themarine Northeastern Pacific hydroid Garveia annulata, potentlyinhibited INDO in vitro (Ki=0.12–0.68 μM). Interestingly, theannulins were more potent than 1-methyltryptophan (Ki=6.6 μM),one of the most potent agents currently available. Aminin et al. [113]

investigated the immunomodulatory properties of a “medical lead”named cumaside, which consisted of a complex of cholesterol withmonosulfated cucumariosides (101), triterpene oligoglycosides fromthe Far-Eastern edible sea cucumber Cucumaria japonica. Theinvestigators observed that cumaside, while lowering the membra-nolytic activity of the cucumariosides, appeared to significantlyenhance their immunomodulatory properties on both human andmurine macrophages and lymphocytes. Costantino et al. [114]contributed a new α-galactoglycosphingolipid, damicoside (102),isolated from the marine sponge Axinella damicornis. Damicosideexhibited concentration-dependent stimulatory activity in a murinespleen proliferation assay, showing that a free galactose 2-OH and 3-OH are critical for activity, while in contrast, a free galactose 4-OH isnot required for the immunostimulatory activity of these bioactiveglycosphingolipids compounds. Kim et al. [115] investigated theantiapoptotic activity of laminarin polysaccharides isolated from thealga Laminaria japonica. A detailed pharmacological investigationrevealed that the laminarin polysaccharides suppressed mousethymocyte apoptosis, while also significantly inducing the

Fig. 2 (continued).


upregulation of 33 immunomodulatory genes from a total of 7410genes which were examined using a cDNA microarray. Xia et al. [116]extended the pharmacology of a sulfated polymannuroguluronate(SPMG) (103), a polysaccharide with an average molecular weight of8.0 kDa isolated from the brown alga Laminaria japonica, whichrecently entered Phase II clinical trials in China as an anti-AIDS drugcandidate. Although SPMG appeared to exert immunopotentiation bydirect activation of T cell proliferation, and the concomitantmodulation of cytokines, namely enhancement of interleukin-2 andinterferon-γ generation and inhibition of tumor necrosis factor-αrelease, the authors concluded that “much remains, however,unknown about the immunomodulation mechanism of SPMG”. Odaet al. [117] described the pharmacology of verrucarin A (104), acompound isolated from the culture broth of the Palauan marinefungus Myrothecium roridum. Verrucarin A significantly inhibitedinterleukin-8 production from human promyelocytic leukemia cells,by a mechanism that involved inhibition of the activation of themitogen-activated kinases c-JUN and p38.

3.4. Compounds affecting the nervous system

Pharmacological studies with marine compounds affecting thenervous system during 2005–6 focused on three main areas ofneuropharmacology: the stimulation of neurogenesis, the targetingof receptors, and other miscellaneous activities on the nervoussystem.

Biologically active molecules which stimulate neurogenesis andrescue damaged neuronal cells are potentially promising therapeuticstrategies to treat neurodegenerative diseases [118]. As shown inTable 2, the enhancement of the neuritogenic properties of nervegrowth factor (NGF), a chemical that has a critical role indifferentiation, survival and neuronal regeneration, was reportedfor several marine natural compounds isolated from sea cucumbers,sea stars, brown algae and a fungus, respectively.

Nandini et al. [119] isolated a novel 70-kDa chondroitin sulfate/dermatan sulfate hybrid chain from the skin of the blue sharkPrionace glauca which exhibited neuritogenic activity of both anaxonic and a dendritic nature, as well as binding activities forvarious growth factors and two neurotrophic factors. The uniquestructure and biological activity of the proteoglycans demonstratedthat shark skin has “immense potential to be exploited forpharmaceutical purposes”. Although it is clear that the harvest ofsharks for either food or pharmaceutical purposes is highlyquestionable, from a sustainability point of view the characteriza-tion of biological metabolites from these animals is extremelyinteresting and significant. Kisa et al. [120,121] contributed twonew monosialo- and disialo-gangliosides CEG-3 (105) and CEG-6(106) from the Japanese sea cucumber Cucumaria echinata.Although the molecular mechanism of action remains undeter-mined, both gangliosides induced neurite outgrowth in 42–50%of rat pheochromocytoma PC12 cells at 10 μM in the presenceof NGF, suggesting the “isolation and characterization of such

Fig. 2 (continued).


neuritogenically active ganglosides” will require considerablefurther study. Inagaki et al. [122] contributed the first isolationand characterization of a trisialo-ganglioside LLG-5 (107) from thesea star Linckia laevigata. LLG-5 proved to be more neuritogenic(59.3% at 10 μM) to rat pheochromocytoma PC12 cells than CEG-3

and CEG-6. Higuchi et al. [123] isolated a biologically activeglycoside GP-3 (108) from the starfish Asterina pectinifera whichproved to be slightly less neuritogenic (38.2% at 10 μM) to ratpheochromocytoma PC12 cells than CEG-3, CEG-6 and LLG-5. Hanet al. [124] reported a structure–activity relationship with new


steroid glycosides, namely linckosides (109–111) isolated from theOkinawan sea star Linckia laevigata. All linckosides enhanced theneuritogenic activity of NGF by 40–98%, with a SAR study revealingthe “importance of the carbon branch modified by a pentose at theside chain” in the neuritogenic activity. Wei et al. [125] investigateda novel polyketide shimalactone A (112) isolated from the culturedmarine-derived fungus Emericella variecolor GF10. Shimalactone Ainduced neuritogenesis in a neuroblastoma Neuro 2A cell line at10 μg/mL by an as yet undetermined mechanism. Tsang et al. [118]described sargachromenol (113) from the marine brown alga Sar-gassum macrocarpum. Sargachromenol was shown to “markedly”promote NGF-dependent neurogenesis in PC12D cells(ED50=9 μM). Interestingly, mechanistic studies demonstratedthat both the cyclic AMP-mediated protein kinase and mitogen-activated protein kinase 1/2 signal transduction pathways wererequired for neurite growth stimulated by sargachromenol. Tsang'sdetailed molecular studies clearly suggests that additional mechan-ism of action investigations with the gangliosides, linckosides andshimalactones might possibly help develop these chemicals aspotentially new medicines for the treatment of neurodegenerativediseases.

As shown in Table 2, the conotoxins αD-VxXIIA, αD-VxXIIB, andαD-VxXIIC, conopeptide SO-3 and dysiherbaine, were shown to targetreceptors present in the nervous system.

Loughnan et al. [126] reported three novel conotoxins αD-VxXIIA,αD-VxXIIB, and αD-VxXIIC (114–116), purified from the venom of themarine snail Conus vexillum. A detailed series of mechanistic studiesrevealed that the three post-translationally modified conotoxins werenon-competitive inhibitors of nicotinic acetylcholine receptors withselectivity towards α7 and β-containing neuronal receptor subtypes,and with αD-VxXIIB conotoxin being the most potent (IC50=0.4 nMfor α7). Wen et al. [127] described a new O-superfamily conopeptideSO-3 (117), derived from the marine snail Conus striatus. Because thenew conopeptide was shown to selectively target N-type voltage-sensitive calcium currents in cultured hippocampal neurons(IC50=0.16 μM), the authors suggested that it may have “therapeuticpotential as a novel analgesic agent”. Sanders et al. [128,129] extendedthe pharmacology of dysiherbaines (118,119), potent kainate receptoragonists derived from the marine sponge Dysidea herbacea. Detailedmolecular studies revealed the site residues responsible for subunitselectivity of the two compounds on kainate receptors, observationswhich could aid in the rational design of “selective ligands withdistinct pharmacological properties”. Tsuneki et al. [130] investigatedthe preclinical pharmacology of the marine quinolizidine alkaloid (−)pictamine (120), isolated from the ascidian Clavelina picta. Pictamineirreversibly blocked α4β2 and α7 nicotinic acetylcholine receptors(IC50=1.5 μM), and thus could become a valuable tool to studyneuronal activity mediated by these two major types of nicotinicreceptors.

As shown in Table 2, during 2005–6, additional marinecompounds were reported to exhibit pharmacological effects onthe nervous system. Aiello et al. [131] established the molecularpharmacology of a novel bromopyrrole alkaloid (121), isolated fromthe Mediterranean sponge Axinella verrucosa. In a series of in vitrostudies, the alkaloid was observed to display potent neuroprotectiveactivity against the agonists serotonin and glutamate. Aiello et al.[132] also reported another marine natural product, namely thealkaloid daminin (122) isolated from the Mediterranean spongeAxinella damicornis. Daminin was observed to reduce Ca2+ levels inneuronal cells in vitro stimulated with either glutamic acid or n-methyl-D-aspartate, agents that cause a strong rise in Ca2+ in thesecells. Bringmann et al. [133] isolated a novel angucyclinonegephyromycin (123) from the bacterium Streptomyces griseus.Gephyromcyin appeared to “represent a new potent glutamateagonist” towards neuronal cells, and at 3 μg/mL caused significantincrease in intracellular Ca2+ concentration, a response comparable

to the potent glutamate agonist DCG-IV. To et al. [134] whilestudying the mechanisms involved in neuronal outgrowth observedthat the alkaloid motuporamine C (124), isolated from the PapuaNew Guinea marine sponge Xestospongia exigua, stimulated con-centration-dependent neuronal growth cone collapse. The intra-cellular signaling mechanisms involved significant upregulation ofthe Rho–Rho–kinase collapse pathway, suggesting this compoundmight be useful to examine mechanisms “utilized by neurons foroutgrowth”. Temraz et al. [135] noted that Red Sea soft coralsSarcophyton glaucum and Lobophyton crassum contained naturalproducts which include trigonelline (125), that increased theelectrophysiological excitability of rat cultured dorsal root ganglionneurons. The increased excitability was associated with enhancedKCl-evoked Ca2+ influx consistent with an increase in actionpotential firing, perhaps contributing to “chemical defenses”.

4. Marine compounds with miscellaneous mechanisms of action

Table 3 lists 58 marine compounds with miscellaneous pharma-cological mechanisms of action, and with their respective structurespresented in Fig. 3. Because during 2005–2006 additional pharmaco-logical data were unavailable, it was not possible to assign thesecompounds to a particular drug class as was the case for thecompounds included in Tables 1 and 2.

As shown in Table 3, the pharmacological activity, respectiveIC50, and a molecular mechanism of action have been reported for23 marine natural products: Agelas sp. dibromopyrrole (126),adociaquinone B (127), barettins (128 and 129), bromoageliferins(130 and 131), chlorolissoclimide (132), fascaplysin analogue CA224(133), hippuristanol (134), liphagal (135), lukianol B (136),rubrolide (137), micropeptins (138 and 139), pateamine (140),phlorofucofuroeckol A (141), purealin (142), Spongia sesterterpe-noids (143–145), squalamine analog (146), and xestospongin B(147) and C (148).

In 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 unavailablefor the following 35 marine compounds included in Table 3:actiniarin B (149), amphezonol A (150), ascochitine (151), briaex-cavatin E and G (152 and 153), brunsvicamides B and C (154 and155), caulerpin (156), cortistatin A (157), cyanopeptolin 954 (158),dehydroluffariellolide diacid (159), O-methyl nakafuran-8-lactone(160), 2β,3α-epitaondiol (161), fascaplysin (162), gorgosterols(163–165), hexylitaconic acid (166), himeic acid A (167), kalihinolA (168), largamides D–G (169–172), peribysins E–G (173–175),petrosamine B (176), phrygiasterol (177), Portieria hornemanniimonoterpenes (178 and 179), S. micracanthum plastoquinone(180), scalaradial (181), secomycalolide A (182), and Symphyocla-dia latiuscula bromophenol (183).

5. Reviews on marine pharmacology

Several reviews covering both general and specific subject areas ofmarine pharmacology were published during 2005–6: (a) generalmarine pharmacology: biodiversity as a continuing source of noveldrug leads [136]; international collaboration in drug discovery anddevelopment [137]; indole alkaloid marine natural products as apromising source of new drug leads for multiple disease categories[138]; the biopotential of marine actinomycete diversity and naturalproduct discovery [139]; the renaissance of natural products as drugcandidates [140]; bioactive compounds from cyanobacteria andmicroalgae [141]; drug discovery from natural sources [142]; a newresource for drug discovery: marine actinomycete bacteria [143];bioactive compounds from marine processing byproducts [144];implications of marine biotechnology on drug discovery [145]; (b)antimicrobial marine pharmacology: advances in antimicrobial and

Table 3Marine pharmacology in 2005–6: marine compounds with miscellaneous mechanisms of action.

Compound/organisma Chemistry Pharmacological activity IC50b MMOAc Countryd References

Agelas sp. dibromopyrrole(126)/sponge

Alkaloidg Reduction in Ca2+ elevationinduced by K+ depolarization

b0.3 mM Voltage-gated calcium channelinhibition

DEU [169]

Adociaquinone B (127)/sponge Alkaloidg Cdc25B phosphataseinhibition

0.07 μM Selective oxidation of catalytic cysteine USA [170]

Barettin (128) and8,9-dihydrobarettin (129)/sponge

Diketopiperazineg Serotonin uptake inhibition 0.34–4.63 μM Binding to 5-HT2A, 5-HT2C, 5-HT4and 5-HT2C

SWE [171]

Bromoageliferin (130) anddibromoageliferin (131)/sponge

Alkaloidg Inhibition of Ca2+ entry 4–6.6 μM Reduction of voltage-dependentcalcium entry

DEU [172]

Chlorolissoclimide (132)/marine slug

Alkaloidal diterpenef Reversible protein synthesisinhibition

0.7 μM Blocked elongation and ribosomerelease from polysomes

CAN, USA [173]

Fascaplysin analogue CA224(133)/synthetic

Alkaloidg Cyclin-dependent kinase 4inhibition

5.5 μM No Cdk2-cyclin A inhibition; no DNAintercalation

GBR [174]

Hippuristanol (134)/coral Steroidf Translation inhibition in vitroand in vivo

0.4–2 μM Translation initiation factor eIF4ARNA-binding inhibition

JPN, CAN, USA [175]

Liphagal (135)/sponge Meroterpenef Phosphatidylinositol-3-kinaseinhibition

0.1 μM More selectivity to PI3Kα than PI3Kγ CAN, NLD, USA [176]

Lukianol B (136) and rubrolide(137)/ascidian

Tyrosine derivativeg Antidiabetic activity 0.6–0.8 μM Aldose reductase inhibition ESP [177]

Micropeptin 88N (138) and88-Y (139)/bacterium

Depsipeptideg Chemotrypsin inhibition 1.3–15 μM Attachment to active site of enzyme,no hydrolysis

JPN [178]

Pateamine (140)/sponge Polyketidee Protein synthesis inhibition 5 nM Translation initiation factor eIF4A I/IIand III inhibition

CAN, NZL, USA [179]

Phlorofucofuroeckol A(141)/alga Shikimate-derivative Angiotensin-convertingenzyme 1 inhibition

12.7 μM Reactive oxygen species/peroxynitritescavenger

S.KOR [180]

Purealin (142)/sponge Dibromotyrosinederivativeg

Cytoplasmatic dynein heavychain inhibitor

35 μM Uncompetitive inhibition, no bindingto ATP site

USA [181]

Spongia sesterterpenoid(143–145)/sponge

Sesterterpenef Hypercholesterolemiaantagonist

8.1–64.5 μM Farnesoid X-activated receptorinhibition

S. KOR [182]

Squalamine analog (146)/shark Sterol derivativef Activation of bidirectionalCl− transport

Undetermined Cl− transport dependent on IP3-insensitive stores and unidentifiedreceptor

USA [183]

Xestospongin B (147)/sponge Alkaloidg IP3-induced Ca2+ signallinginhibition

27–44 μM Competitive to IP3 receptor binding CHL, FRA, NCL [184]

Xestospongin C (148)/sponge Alkaloidg IP3-induced Ca2+ releaseinhibition

458 nM Enhanced rayanodyne receptor activity USA [185]

Actiniarin B (149)/anemone Polyketidee Cdc25B phosphataseinhibition

1.6 μg/mL Undetermined USA [186]

Amphezonol A (150)/alga Polyketidee DNA-polymerase α inhibition 15 μM Undetermined JPN [187]Ascochitine (151)/fungus Polyketidee M. tuberculosis tyrosine

phosphatase inhibition11.5 μM Undetermined DEU [188]

Briaexcavatin E (152)/coral Diterpenef Neutrophil elastase inhibition 5–10 μM Undetermined TAIW [189]Briaexcavatin G (153)/coral Diterpenef Neutrophil elastase inhibition ND Undetermined TAIW [190]Brunsvicamides B and C(154, 155)/bacterium

Peptidesg M. tuberculosis tyrosinephosphatase inhibition

7.3–8 μM Undetermined GBR, DEU [191]

Caulerpin (156)/alga Alkaloidg HU protein tyrosinephosphatase 1 B inhibition

3.77 μM Undetermined CHN [192]

Cortistatin A (157)/sponge Alkaloidg Antiangiogenic 2 nM Undetermined IDN, JPN [193]Cyanopeptolin 954(158)/bacterium

Depsipeptideg α-chymotrypsin inhibition 45 nM Undetermined DEU, CHE [194]

Dehydroluffariellolide diacid(159)/sponge

Sesterterpenef Cdc25B phosphataseinhibition

1.6 μg/mL Undetermined USA [195]

O-methyl nakafuran-8-lactone(160)/sponge

Sesquiterpenef Protein tyrosine phosphatase1B inhibition

1.58 μM Undetermined CHN, S. KOR [196]

2β,3α-epitaondiol (161)/alga Meroterpenef Sodium channel inhibition 0.7 μM Undetermined USA [197]Fascaplysin (162)/sponge Alkaloidg Cdc25B phosphatase

inhibition1.0 μg/mL Undetermined USA [195]

Gorgosterols (163–165)/coral Sterolf Binding to liver X receptor α 0.07–1.3 μM Undetermined CRI, USA [198]Hexylitaconic acid (166)/fungus Polyketidee Inhibition of p53-HDM2

ubiquitin–protein ligase50 μg/mL Undetermined JPN [199]

Himeic acid A (167)/fungus Polyketidee/peptide Ubiquitin-activating enzymeinhibition

b50 μM Undetermined JPN [200]

Kalihinol A (168)/sponge Diterpenef Cyclooxygenase 2 inhibition 1.07 μM Undetermined CHN, ITA [201]Largamides D–G (169–172)/bacterium

Depsipeptideg α-chymotrypsin type IIinhibition


Peribysins E–G (173–175)/fungus Sesquiterpenef Cell adhesion inhibition 15–20.1 μM Undetermined JPN [203,204]Petrosamine B (176)/sponge Alkaloidg Aspartyl semialdehyde

dehydrogenase inhibition306 μM Undetermined AUS [205]

Phrygiasterol (177)/starfish Sterolf Inhibition of Ca2+ influx 20 μg/mL Undetermined RUS [206]Portieria hornemanniimonoterpenes (178,179)/alga

Monoterpenef DNA methyl transferase-1inhibition


Sargassum micracanthumplastoquinone (180)/alga

Meroterpenef Lipid peroxidation inhibition 0.95 μg/mL Undetermined JPN [208]

Scalaradial (181)/sponge Sesterterpenef PI3K/Akt signaling inhibition 2.9 μM Undetermined,but independentof sPLA2

CHN [209]


Table 3 (continued).

Compound/organisma Chemistry Pharmacological activity IC50b MMOAc Countryd References

Secomycalolide A(182)/sponge Polyketidee/peptide Rat proteasome activityinhibition

11 μg/mL Undetermined JPN [210]

Symphyocladia latiusculabromophenol (183)/alga

Polyketide Aldose reductase inhibition 0.11–1.15 μg/mL Undetermined CHN [211]

a Organism, Kingdom Animalia: ascidians, shark (Phylum Chordata), anemone, corals (Phylum Cnidaria), starfish (Phylum Echinodermata), sea slug (Phylum Mollusca), sponge(Phylum Porifera); Kingdom Fungi: fungus; Kingdom Plantae: alga.

b IC50: concentration of a compound required for 50% inhibition in vitro.c MMOA: molecular mechanism of action.d Country: CAN: Canada; CHE: Switzerland; CHL: Chile; CHN: China; CRI: Costa Rica; DEU: Germany; ESP: Spain; FRA: France; GBR: United Kingdom; IDN: Indonesia; ITA: Italy;

JPN: Japan; NCL: New Caledonia; NZL: New Zealand; RUS: Russia; S. KOR: South Korea; SWE: Sweden; TAIW: Taiwan.e Polyketide.f Terpene.g Nitrogen-containing compound.h Polysaccharide.


antiangiogenic pharmacology of squalamine [146]; marine naturalproducts as anti-infective agents [147]; chemotyping/metabolomicsuse for metabolite profiling in microbial drug discovery [148]; the

Fig. 3. Marine Compounds with Misc

status of natural products from fungi and their potential as anti-infective agents [149]; (c) cardiovascular pharmacology: dietary long-chain omega-3 fatty acids of marine origin and their protective

ellaneous Mechanisms of Action.

Fig. 3 (continued).


cardiovascular effects [150]; (d) antituberculosis, antimalarial and an-tifungal marine pharmacology: compounds for infectious diseases[151]; marine natural products against tuberculosis [152]; (e) antiviralmarine pharmacology: antiviral activities of polysaccharides fromnatural sources [153]; antiplasmodial marine natural products in theperspective of current chemotherapy and prevention of malaria [154];(f) anti-inflammatory marine pharmacology: therapeutic potential ofthe antioxidative properties of coelenterazine, a marine biolumines-cent substrate [155]; chemistry and biology of anti-inflammatorymarine phospholipase A2 inhibitors [156]; the structures, biosynthesisand pharmacology of the marine natural products of Pseudopterogoriaelisabethae [157]; chemistry and biology of anti-inflammatory marinenatural products [158]; marine sponge metabolites for the control ofinflammatory diseases [159]; antioxidant metabolites from marine-derived fungi [160]; (g) nervous system marine pharmacology: marinecompounds for the treatment of neurological disorders [161];potential candidates for Alzheimer's disease [151]; novel pain reliefvia marine snails [162]; bryostatin-1: pharmacology and therapeuticpotential as a CNS drug [163], and (h)miscellaneous molecular targets:V-ATPases as drug targets [164]; topoisomerase inhibitors of marineorigin [165]; enzyme inhibitors from marine actinomycetes [166];

marine compounds as a new source for glycogen kinase 3 inhibitors[167].

6. Conclusion

Four years after the approval of the marine compound ziconotide(Prialt®) by the U.S. Food and Drug Administration [168], globalresearch focused on the therapeutic potential of marine naturalproducts remains very active and sustained. The latest update on theclinical pipeline of marine-derived agents is available at http://marinepharmacology.midwestern.edu/clinPipeline.htm.

The current contribution to themarine pharmacology reviews serieswhich was begun in 1998 [1–5], demonstrates that marine pharmacol-ogy research continued to proceed at a sustained pace in 2005–2006, asa result of the active participation of natural product chemists andpharmacologists from Argentina, Australia, Brazil, Canada, Chile, China,Colombia, Costa Rica, Egypt, Finland, France, Germany, Greece, India,Indonesia, Israel, Italy, Japan, The Netherlands, New Caledonia, NewZealand, Panama, Portugal, Russia, Slovenia, SouthKorea, Spain, Sweden,Switzerland, Taiwan, United Kingdom, Uruguay, and the United States.Thus, if the rate of preclinical and clinical pharmacological research

http://marinepharmacology.midwestern.edu/clinPipeline.htm

http://marinepharmacology.midwestern.edu/clinPipeline.htm

Fig. 3 (continued).


continues, we anticipate that more marine natural products willprobably become potential leads for clinical development as noveltherapeutic agents for the treatment of multiple disease categories.

Acknowledgements

This review was made possible with financial support fromMidwestern University to AMSM; grant number 1R01A136596, fromthe National Institute of Allergy and Infectious Diseases, NIH, and theMedicines for Malaria Venture to MTH; NIH-SCORE Program (GrantS06GM08102) of the University of Puerto Rico to ADR; and FAPESPgrant 05/60175-2 (São Paulo, Brazil) to RGSB. The content of thisreview is solely the responsibility of the authors and does notnecessarily represent the official views of the NIH. Assistance withextensive searches of the 2005–2006 marine pharmacology literature

in PubMed, Marinlit, Current Contents® and Chemical Abstracts®, aswell as article retrieval by library staff members, medical andpharmacy students of Midwestern University, is most gratefullyacknowledged. The authors especially wish to thank Ms. Bin Wangfor assistance with the preparation of figures, and Ms. Mary Hall forcarefully reviewing the manuscript.

References

[1] A.M.S. Mayer, V.K.B. Lehmann, Marine pharmacology in 1998: marinecompounds with antibacterial, anticoagulant, antifungal, anti-inflammatory,anthelmintic, antiplatelet, antiprotozoal, and antiviral activities;with actions onthe cardiovascular, endocrine, immune, and nervous systems; and othermiscellaneous mechanisms of action, The Pharmacologist 42 (2000) 62–69.

[2] A.M.S. Mayer, M.T. Hamann, Marine pharmacology in 1999: compounds withantibacterial, anticoagulant, antifungal, anti-inflammatory, anthelmintic, anti-inflammatory, antiplatelet, antiprotozoal and antiviral activities;affecting the

Fig. 3 (continued).



cardiovascular, endocrine, immune, andnervous systems; andothermiscellaneousmechanismsof action, Comp. Biochem. Physiol. C: Pharmacol.132 (2002) 315–339.

[3] A.M.S. Mayer, M.T. Hamann, Marine pharmacology in 2001–2002: marinecompounds with anthelmintic, antibacterial, anticoagulant, antidiabetic, anti-fungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antitubercu-losis, and antiviral activities; affecting the cardiovascular, immune and nervoussystems and othermiscellaneousmechanisms of action, Comp. Biochem. Physiol.C: Pharmacol. 140 (2005) 265–286.

[4] A.M.S. Mayer, A.D. Rodriguez, R.G.S. Berlinck, M.T. Hamann, Marine pharmacol-ogy in 2003–4: marine compounds with anthelmintic antibacterial, antic-oagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal,antituberculosis, and antiviral activities; affecting the cardiovascular, immuneand nervous systems, and other miscellaneous mechanisms of action, Comp.Biochem. Physiol. C: Pharmacol. 145 (2007) 553–581.

[5] A.M.S. Mayer, M.T. Hamann, Marine pharmacology in 2000: marine compoundswith antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial,antiplatelet, antituberculosis, and antiviral activities; affecting the cardiovas-cular, immune, and nervous systems and other miscellaneous mechanisms ofaction, Mar. Biotechnol. (NY) 6 (2004) 37–52.

[6] A.M.S. Mayer, Marine Pharmacology in 1998: antitumor and cytotoxic com-pounds, The Pharmacologist 41 (1999) 159–164.

[7] A.M.S. Mayer, V.K.B. Lehmann, Marine pharmacology in 1999: antitumor andcytotoxic compounds, Anticancer Res. 21 (2001) 2489–2500.

[8] A.M.S. Mayer, K.R. Gustafson, Marine pharmacology in 2000: antitumor andcytotoxic compounds, Int. J. Cancer 105 (2003) 291–299.

[9] A.M.S. Mayer, K.R. Gustafson, Marine pharmacology in 2001–2: antitumor andcytotoxic compounds, Eur. J. Cancer 40 (2004) 2676–2704.

[10] A.M.S. Mayer, K.R. Gustafson, Marine pharmacology in 2003–2004: anti-tumourand cytotoxic compounds, Eur. J. Cancer 42 (2006) 2241–2270.

[11] A.M.S. Mayer, K.R. Gustafson, Marine pharmacology in 2005–2006: antitumourand cytotoxic compounds, Eur. J. Cancer 44 (2008) 2357–2387.

[12] F.J. Schmitz, B.F. Bowden, S.I. Toth, Antitumor and cytotoxic compounds frommarine organisms, in: D.H. Attaway, O.R. Zaborsky (Eds.), Marine Biotechnology,Pharmaceutical and Bioactive Natural Products, vol. 1, Plenum Press, New York,1993, pp. 197–308.

[13] I. Fakhr, N. Hamdy, M. Radwan, S. El-Batran, O. El Shabrawy, Studies on the anti-inflammatory and analgesic effects of extracts from marine sponges, Nat. Prod.Sci. 12 (2006) 74–78.

[14] K. Matsubara, C. Xue, X. Zhao, M. Mori, T. Sugawara, T. Hirata, Effects of middlemolecular weight fucoidans on in vitro and ex vivo angiogenesis of endothelialcells, Int. J. Mol. Med. 15 (2005) 695–699.

[15] H.C. Shin, H.J. Hwang, K.J. Kang, B.H. Lee, An antioxidative and antiinflammatoryagent for potential treatment of osteoarthritis from Ecklonia cava, Arch.Pharmacol. Res. 29 (2006) 165–171.

[16] J.H. Yim, E. Son, S. Pyo, H.K. Lee, Novel sulfated polysaccharide derived from red-tide microalga Gyrodinium impudicum strain KG03 with immunostimulatingactivity in vivo, Mar. Biotechnol. (NY) 7 (2005) 331–338.

[17] U. Adhikari, C.G.Mateu, K. Chattopadhyay, C.A. Pujol, E.B.Damonte, B. Ray, Structureand antiviral activity of sulfated fucans from Stoechospermum marginatum,Phytochemistry 67 (2006) 2474–2482.

[18] A.C. da Silva, J.M. Kratz, F.M. Farias, A.T. Henriques, S.J. Dos, R.M. Leonel, C. Lerner,B. Mothes, C.R. Barardi, C.M. Simoes, In vitro antiviral activity of marine spongescollected off Brazilian coast, Biol. Pharm. Bull. 29 (2006) 135–140.

[19] A. Al-Fadhli, S. Wahidulla, L. D'Souza, Glycolipids from the red alga Chondriaarmata (Kutz.) Okamura, Glycobiology 16 (2006) 902–915.

[20] A. Arena, T.L. Maugeri, B. Pavone, D. Iannello, C. Gugliandolo, G. Bisignano,Antiviral and immunoregulatory effect of a novel exopolysaccharide from amarine thermotolerant Bacillus licheniformis, Int. Immunopharmacol. 6 (2006)8–13.

[21] Y. Athukorala,W.K. Jung, T. Vasanthan, Y.J. Jeon, An anticoagulative polysaccharidefrom an enzymatic hydrolysate of Ecklonia cava, Carbohydr. Polym. 66 (2006)184–191.

[22] D. Kelman, Y. Kashman, E. Rosenberg, A. Kushmaro, Y. Loya, Antimicrobialactivity of red sea corals, Mar. Biol. 149 (2006) 357–363.

[23] P. Lucas-Elio, P. Hernandez, A. Sanchez-Amat, F. Solano, Purification and partialcharacterization of marinocine, a new broad-spectrum antibacterial proteinproduced by Marinomonas mediterranea, Biochim. Biophys. Acta 1721 (2005)193–203.

[24] S. Rechter, T. Konig, S. Auerochs, S. Thulke, H.Walter, H. Dornenburg, C.Walter, M.Marschall, Antiviral activity of Arthrospira-derived spirulan-like substances,Antiviral Res. 72 (2006) 197–206.

[25] A.N. Thakur, N.L. Thakur, M.M. Indap, R.A. Pandit, V.V. Datar, W.E. Muller,Antiangiogenic, antimicrobial, and cytotoxic potential of sponge-associatedbacteria, Mar. Biotechnol. (NY) 7 (2005) 245–252.

[26] J.H. Wang, J. Kong, W. Li, V. Molchanova, I. Chikalovets, N. Belogortseva, P.Luk'yanov, Y.T. Zheng, A beta-galactose-specific lectin isolated from the marineworm Chaetopterus variopedatus possesses anti-HIV-1 activity, Comp. Biochem.Physiol. C: Pharmacol. 142 (2006) 111–117.

[27] R.J. Capon, D. Vuong, E. Lacey, J.H. Gill, (−)-Echinobetaine A: isolation,structure elucidation, synthesis, and SAR studies on a new nematocide from asouthern Australian marine sponge, Echinodictyum sp, J. Nat. Prod. 68 (2005)179–182.

[28] R.J. Capon, D. Vuong, M. McNally, T. Peterle, N. Trotter, E. Lacey, J.H. Gill, (+)-Echinobetaine B: isolation, structure elucidation, synthesis and preliminary SARstudies on a newnematocidal betaine from a southern Australianmarine sponge,Echinodictyum sp, Org, Biomol. Chem. 3 (2005) 118–122.

[29] D. Davyt, R. Fernandez, L. Suescun, A.W. Mombru, J. Saldana, L. Dominguez, M.T.Fujii, E. Manta, Bisabolanes from the red alga Laurencia scoparia, J. Nat. Prod. 69(2006) 1113–1116.

[30] R.G. Linington, M. Robertson, A. Gauthier, B.B. Finlay, J.B. MacMillan, T.F. Molinski,S.R. Van, R.J. Andersen, Caminosides B–D, antimicrobial glycolipids isolated fromthe marine sponge Caminus sphaeroconia, J. Nat. Prod. 69 (2006) 173–177.

[31] K.B. Oh, W. Mar, S. Kim, J.Y. Kim, M.N. Oh, J.G. Kim, D. Shin, C.J. Sim, J. Shin, Bis(indole) alkaloids as sortase A inhibitors from the sponge Spongosorites sp,Bioorg. Med. Chem. Lett. 15 (2005) 4927–4931.

[32] T.V. Ovchinnikova, S.V. Balandin, G.M. Aleshina, A.A. Tagaev, Y.F. Leonova, E.D.Krasnodembsky, A.V. Men'shenin, V.N. Kokryakov, Aurelin, a novel antimicrobialpeptide from jellyfish Aurelia aurita with structural features of defensins andchannel-blocking toxins, Biochem. Biophys. Res. Commun. 348 (2006) 514–523.

[33] N.L. Segraves, P. Crews, A Madagascar sponge Batzella sp. as a source of alkylatediminosugars, J. Nat. Prod. 68 (2005) 118–121.

[34] M. Tsuda, Y. Takahashi, J. Fromont, Y. Mikami, J. Kobayashi, Dendridine A, a bis-indole alkaloid from a marine sponge Dictyodendrilla species, J. Nat. Prod. 68(2005) 1277–1278.

[35] R.Y. Yang, C.Y. Li, Y.C. Lin, G.T. Peng, Z.G. She, S.N. Zhou, Lactones from a brownalga endophytic fungus (No. ZZF36) from the South China Sea and theirantimicrobial activities, Bioorg. Med. Chem. Lett. 16 (2006) 4205–4208.

[36] N. Sugiyama, M. Araki, M. Ishida, Y. Nagashima, K. Shiomi, Further isolation andcharacterization of grammistins from the skin secretion of the soapfishGrammistes sexlineatus, Toxicon 45 (2005) 595–601.

[37] H. Ishiyama, A. Hashimoto, J. Fromont, Y. Hoshino, Y. Mikami, J. Kobayashi,Halichonadins A–D, new sesquiterpenoids from a sponge Halichondria sp,Tetrahedron 61 (2005) 1101–1105.

[38] R.R. Manam, S. Teisan, D.J. White, B. Nicholson, J. Grodberg, S.T. Neuteboom, K.S.Lam, D.A. Mosca, G.K. Lloyd, B.C. Potts, Lajollamycin, a nitro-tetraene spiro-beta-lactone-gamma-lactam antibiotic from the marine actinomycete Streptomycesnodosus, J. Nat. Prod. 68 (2005) 240–243.

[39] H.C. Kwon, C.A. Kauffman, P.R. Jensen, W. Fenical, Marinomycins A–D, antitumor-antibiotics of a new structure class from a marine actinomycete of the recentlydiscovered genus “Marinispora”, J. Am. Chem. Soc. 128 (2006) 1622–1632.

[40] I. Kock, R.P. Maskey, M.A. Biabani, E. Helmke, H. Laatsch, 1-Hydroxy-1-norresistomycin and resistoflavin methyl ether: new antibiotics from marine-derived streptomycetes, J. Antibiot. (Tokyo) 58 (2005) 530–534.

[41] A.M. Socha, D. Garcia, R. Sheffer, D.C. Rowley, Antibiotic bisanthraquinonesproduced by a streptomycete isolated from a cyanobacterium associated withEcteinascidia turbinata, J. Nat. Prod. 69 (2006) 1070–1073.

[42] I.E. Soria-Mercado, A. Prieto-Davo, P.R. Jensen, W. Fenical, Antibiotic terpenoidchloro-dihydroquinones from a new marine actinomycete, J. Nat. Prod. 68(2005) 904–910.

[43] A. Bishara, A. Rudi, I. Goldberg, Y. Benayahu, Y. Kashman, Novaxenicins A–D andxeniolides I–K, seven new diterpenes from the soft coral Xenia novaebrittanniae,Tetrahedron 62 (2006) 12092–12097.

[44] M.A. Medeiros, A. Lourenco, M.R. Tavares, M.J. Curto, S.S. Feio, J.C. Roseiro,(−)-Agelasidine A from Agelas clathrodes, Z. Naturforsch.,C: Biosci. 61 (2006)472–476.

[45] E. Chelossi, I. Mancini, K. Sepcic, T. Turk, M. Faimali, Comparative antibacterialactivity of polymeric 3-alkylpyridinium salts isolated from the Mediterraneansponge Reniera sarai and their synthetic analogues, Biomol. Eng. 23 (2006)317–323.

[46] X. Lin, Y. Huang, M. Fang, J. Wang, Z. Zheng, W. Su, Cytotoxic and antimicrobialmetabolites from marine lignicolous fungi, Diaporthe sp, FEMS Microbiol. Lett.251 (2005) 53–58.

[47] K. Krohn, J. Dai, U. Florke, H.J. Aust, S. Drager, B. Schulz, Botryanemetabolites fromthe fungus Geniculosporium sp. isolated from the marine red alga Polysiphonia,J. Nat. Prod. 68 (2005) 400–405.

[48] T. Amagata, B.I. Morinaka, A. Amagata, K. Tenney, F.A. Valeriote, E. Lobkovsky, J.Clardy, P. Crews, A chemical study of cyclic depsipeptides produced by a sponge-derived fungus, J. Nat. Prod. 69 (2006) 1560–1565.

[49] K.A. El Sayed, D.T. Youssef, D. Marchetti, Bioactive natural and semisyntheticlatrunculins, J. Nat. Prod. 69 (2006) 219–223.

[50] A. Gorajana, B.V. Kurada, S. Peela, P. Jangam, S. Vinjamuri, E. Poluri, A. Zeeck, 1-Hydroxy-1-norresistomycin, a new cytotoxic compound from a marine actino-mycete, Streptomyces chibaensis AUBN1/7, J. Antibiot. (Tokyo) 58 (2005)526–529.

[51] M. Sasaki, M. Tsuda, M. Sekiguchi, Y. Mikami, J. Kobayashi, Perinadine A a noveltetracyclic alkaloid from marine-derived fungus Penicillium citrinum, Org. Lett. 7(2005) 4261–4264.

[52] B. Uzair, N. Ahmed, V.U. Ahmad, F. Kousar, A new antibacterial compoundproduced by an indigenous marine bacteria-fermentation, isolation, andbiological activity, Nat. Prod. Res. 20 (2006) 1326–1331.

[53] T.K. Kim, A.K. Hewavitharana, P.N. Shaw, J.A. Fuerst, Discovery of a new source ofrifamycin antibiotics inmarine sponge actinobacteria by phylogenetic prediction,Appl. Environ. Microbiol. 72 (2006) 2118–2125.

[54] H.F. Dai, R.A. Edrada, R. Ebel, M. Nimtz, V. Wray, P. Proksch, Norlanostanetriterpenoidal saponins from the marine sponge melophlussarassinorum, J. Nat.Prod. 68 (2005) 1231–1237.

[55] M. Tsuda, M. Sasaki, T. Mugishima, K. Komatsu, T. Sone, M. Tanaka, Y. Mikami, J.Kobayashi, Scalusamides A–C, new pyrrolidine alkaloids from the marine-derived fungus Penicillium citrinum, J. Nat. Prod. 68 (2005) 273–276.

[56] N.L. Segraves, P. Crews, Investigation of brominated tryptophan alkaloids fromtwo thorectidae sponges: Thorectandra and Smenospongia, J. Nat. Prod. 68(2005) 1484–1488.


[57] N. Rajapakse, W.K. Jung, E. Mendis, S.H. Moon, S.K. Kim, A novel anticoagulantpurified from fish protein hydrolysate inhibits factor XIIa and plateletaggregation, Life Sci. 76 (2005) 2607–2619.

[58] N.N. Drozd, A.S. Tolstenkov, V.A. Makarov, T.A. Kuznetsova, N.N. Besednova, N.M.Shevchenko, T.N. Zvyagintseva, Pharmacodynamic parameters of anticoagulantsbased on sulfated polysaccharides from marine algae, Bull. Exp. Biol. Med. 142(2006) 591–593.

[59] E. Luppi, M. Cesaretti, N. Volpi, Purification and characterization of heparin fromthe Italian clam Callista chione, Biomacromolecules 6 (2005) 1672–1678.

[60] M.G. Pereira, N.M. Benevides, M.R. Melo, A.P. Valente, F.R. Melo, P.A. Mourao,Structure and anticoagulant activity of a sulfated galactan from the red alga,Gelidium crinale. Is there a specific structural requirement for the anticoagulantaction? Carbohydr. Res. 340 (2005) 2015–2023.

[61] H.A. Rocha, F.A. Moraes, E.S. Trindade, C.R. Franco, R.J. Torquato, S.S. Veiga, A.P.Valente, P.A.Mourao, E.L. Leite, H.B. Nader, C.P. Dietrich, Structural and hemostaticactivities of a sulfated galactofucan from the brown alga Spatoglossum schroederi.An ideal antithrombotic agent? J. Biol. Chem. 280 (2005) 41278–41288.

[62] X.C. Li, M.R. Jacob, Y. Ding, A.K. Agarwal, T.J. Smillie, S.I. Khan, D.G. Nagle, D.Ferreira, A.M. Clark, Capisterones A and B, which enhance fluconazole activity inSaccharomyces cerevisiae, from the marine green alga Penicillus capitatus, J. Nat.Prod. 69 (2006) 542–546.

[63] E. Sionov, D. Roth, H. Sandovsky-Losica, Y. Kashman, A. Rudi, L. Chill, I. Berdicevsky,E. Segal, Antifungal effect and possible mode of activity of a compound from themarine sponge Dysidea herbacea, J. Infect. 50 (2005) 453–460.

[64] R.K. Pettit, T. Woyke, S. Pon, Z.A. Cichacz, G.R. Pettit, C.L. Herald, In vitro and invivo antifungal activities of the marine sponge constituent spongistatin, Med.Mycol. 43 (2005) 453–463.

[65] F.M. Uckun, C. Mao, S.T. Jan, H. Huang, A.O. Vassilev, C.S. Navara, R.K. Narla,Spongistatins as tubulin targeting agents, Curr. Pharm. Des. 7 (2001) 1291–1296.

[66] W.S. Jang, H.K. Kim, K.Y. Lee, S.A. Kim, Y.S. Han, I.H. Lee, Antifungal activity ofsynthetic peptide derived from halocidin, antimicrobial peptide from thetunicate, Halocynthia aurantium, FEBS Lett. 580 (2006) 1490–1496.

[67] T. Neuhof, P. Schmieder, K. Preussel, R. Dieckmann, H. Pham, F. Bartl, H. vonDohren, Hassallidin A, a glycosylated lipopeptide with antifungal activity fromthe cyanobacterium Hassallia sp, J. Nat. Prod. 68 (2005) 695–700.

[68] J.B. MacMillan, T.F. Molinski, Majusculoic acid, a brominated cyclopropyl fattyacid from a marine cyanobacterial mat assemblage, J. Nat. Prod. 68 (2005)604–606.

[69] R. Echigoya, L. Rhodes, Y. Oshima, M. Satake, The structures of five new antifungaland hemolytic amphidinol analogs from Amphidinium carterae collected in NewZealand, Harmful Algae 4 (2005) 383–389.

[70] N. Morsy, S. Matsuoka, T. Houdai, N. Matsumori, S. Adachi, M. Murata, T. Iwashita,T. Fujita, Isolation and structure elucidation of a newamphidinol with a truncatedpolyhydroxyl chain from Amphidinium klebsii, Tetrahedron 61 (2005)8606–8610.

[71] V. Sepe, R. D'Orsi, N. Borbone, M.V. D'Auria, B.B.A. Giuseppe, M.C. Monti, A.Catania, A. Zampella, Callipeltins F–I: new antifungal peptides from the marinesponge Latrunculia sp, Tetrahedron 62 (2006) 833–840.

[72] P. Sauleau, M.L. Bourguet-Kondracki, Novel polyhydroxysterols from the Red Seamarine sponge Lamellodysidea herbacea, Steroids 70 (2005) 954–959.

[73] H.D. Chludil, M.S. Maier, Minutosides A and B, antifungal sulfated steroidxylosides from the patagonian starfish Anasterias minuta, J. Nat. Prod. 68 (2005)1279–1283.

[74] T.N. Makarieva, V.A. Denisenko, P.S. Dmitrenok, A.G. Guzii, E.A. Santalova, V.A.Stonik, J.B. MacMillan, T.F. Molinski, Oceanalin A, a hybrid alpha,omega-bifunctionalized sphingoid tetrahydroisoquinoline beta-glycoside from themarine sponge Oceanapia sp, Org. Lett. 7 (2005) 2897–2900.

[75] Y. Okada, S. Matsunaga, R.W. van Soest, N. Fusetani, Sokodosides, steroidglycosides with an isopropyl side chain, from the marine sponge Erylus placenta,J. Org. Chem. 71 (2006) 4884–4888.

[76] A. Kralj, S. Kehraus, A. Krick, E. Eguereva, G. Kelter, M. Maurer, A. Wortmann, H.H.Fiebig, G.M. Konig, Arugosins G and H: prenylated polyketides from the marine-derived fungus Emericellanidulans var. acristata, J. Nat. Prod. 69 (2006)995–1000.

[77] A.D. Wright, N. Lang-Unnasch, Potential antimalarial lead structures from fungiof marine origin, Planta Med 71 (2005) 964–966.

[78] C. Campagnuolo, E. Fattorusso, A. Romano, O. Taglialatela-Scafati, N. Basilico, S.Parapini, D. Taramelli, Antimalarial polyketide cycloperoxides from the marinesponge Plakortis simplex, Eur. J. Org. Chem. 23 (2005) 5077–5083.

[79] D. Laurent, V. Jullian, A. Parenty, M. Knibiehler, D. Dorin, S. Schmitt, O. Lozach, N.Lebouvier, M. Frostin, F. Alby, S. Maurel, C. Doerig, L. Meijer, M. Sauvain,Antimalarial potential of xestoquinone, a protein kinase inhibitor isolated from aVanuatu marine sponge Xestospongia sp, Bioorg. Med. Chem. 14 (2006)4477–4482.

[80] K.V. Rao, M.S. Donia, J. Peng, E. Garcia-Palomero, D. Alonso, A. Martinez, M.Medina, S.G. Franzblau, B.L. Tekwani, S.I. Khan, S. Wahyuono, K.L. Willett, M.T.Hamann, Manzamine B and E and ircinal A related alkaloids from an IndonesianAcanthostrongylophora sponge and their activity against infectious, tropicalparasitic, and Alzheimer's diseases, J. Nat. Prod. 69 (2006) 1034–1040.

[81] C.A. Ospina, A.D. Rodriguez, J.A. Sanchez, E. Ortega-Barria, T.L. Capson, A.M.Mayer, Caucanolides A–F, unusual antiplasmodial constituents from a colombiancollection of the gorgonian coral Pseudopterogorgia bipinnata, J. Nat. Prod. 68(2005) 1519–1526.

[82] S.P. Garzon, A.D. Rodriguez, J.A. Sanchez, E. Ortega-Barria, Sesquiterpenoidmetabolites with antiplasmodial activity from a Caribbean gorgonian coral,Eunicea sp,, J. Nat. Prod. 68 (2005) 1354–1359.

[83] J. Marrero, C.A. Ospina, A.D. Rodriguez, P. Baran, H. Zhao, S.G. Franzblau, E.Ortega-Barria, New diterpenes of the pseudopterane class from two closelyrelated Pseudopterogorgia species: isolation, structural elucidation, and biologi-cal evaluation, Tetrahedron 62 (2006) 6998–7008.

[84] M. Gutierrez, T.L. Capson, H.M. Guzman, J. Gonzalez, E. Ortega-Barria, E. Quinoa,R. Riguera, Leptolide, a new furanocembranolide diterpene from Leptogorgiaalba, J. Nat. Prod. 68 (2005) 614–616.

[85] M. Gutierrez, T.L. Capson, H.M. Guzman, J. Gonzalez, E. Ortega-Barria, E. Quinoa,R. Riguera, Antiplasmodial metabolites isolated from the marine octocoralMuricea austera, J. Nat. Prod. 69 (2006) 1379–1383.

[86] C.W. Lim, Y.K. Kim, H.D. Youn, H.Y. Park, Enantiomeric compounds withantileishimanial activities from a sponge, Plakortis sp. Agric. Chem. Biotechnol.49 (2006) 21–23.

[87] K. Washida, T. Koyama, K. Yamada, M. Kita, D. Uemura, Karatungiols A and B, twonovel antimicrobial polyol compounds, from the symbiotic marine dinoflagellateAmphidinium sp, Tetrahedron Lett. 47 (2006) 2521–2525.

[88] C.A. Gray, S.P. de Lira, M. Silva, E.F. Pimenta, O.H. Thiemann, G. Oliva, E. Hajdu, R.J.Andersen, R.G. Berlinck, Sulfated meroterpenoids from the Brazilian spongeCallyspongia sp. are inhibitors of the antileishmaniasis target adenosinephosphoribosyl transferase, J. Org. Chem. 71 (2006) 8685–8690.

[89] M.F. de Oliveira, J.H. de Oliveira, F.C. Galetti, A.O. de Souza, C.L. Silva, E. Hajdu, S.Peixinho, R.G. Berlinck, Antimycobacterial brominated metabolites from twospecies of marine sponges, Planta Med. 72 (2006) 437–441.

[90] H. Gao, M. Kelly, M.T. Hamann, Bromotyrosine-derived metabolites from thesponge Aiolochroia crassa, Tetrahedron 55 (1999) 9717–9726.

[91] I.I. Rodriguez, A.D. Rodriguez, Y.H. Wang, S.G. Franzblau, Ileabethoxazole: a novelbenzoxazole alkaloid with antimycobacterial activity, Tetrahedron Lett. 47(2006) 3229–3232.

[92] M.C. Rodriguez, E.R. Merino, C.A. Pujol, E.B. Damonte, A.S. Cerezo, M.C.Matulewicz, Galactans from cystocarpic plants of the red seaweed Callophyllisvariegata (Kallymeniaceae, Gigartinales), Carbohydr. Res. 340 (2005) 2742–2751.

[93] J.B. Lee, K. Hayashi, M. Hirata, E. Kuroda, E. Suzuki, Y. Kubo, T. Hayashi, Antiviralsulfated polysaccharide from Navicula directa, a diatom collected from deep-seawater in Toyama Bay, Biol. Pharm. Bull. 29 (2006) 2135–2139.

[94] B. Matsuhiro, A.F. Conte, E.B. Damonte, A.A. Kolender, M.C. Matulewicz, E.G.Mejias, C.A. Pujol, E.A. Zuniga, Structural analysis and antiviral activity of asulfated galactan from the red seaweed Schizymenia binderi (Gigartinales,Rhodophyta), Carbohydr. Res. 340 (2005) 2392–2402.

[95] M. Iwashima, J. Mori, X. Ting, T. Matsunaga, K. Hayashi, D. Shinoda, H. Saito, U.Sankawa, T. Hayashi, Antioxidant and antiviral activities of plastoquinones fromthe brown alga Sargassum micracanthum, and a new chromene derivativeconverted from the plastoquinones, Biol. Pharm. Bull. 28 (2005) 374–377.

[96] P.H. de Souza, L.R. Leao-Ferreira, N. Moussatche, V.L. Teixeira, D.N. Cavalcanti, L.J.da Costa, R. Diaz, I.C. Frugulhetti, Effects of diterpenes isolated from the Brazilianmarine alga Dictyota menstrualis on HIV-1 reverse transcriptase, Planta Med 71(2005) 1019–1024.

[97] T. Mori, B.R. O'Keefe, R.C. Sowder, S. Bringans, R. Gardella, S. Berg, P. Cochran, J.A.Turpin, R.W. Buckheit Jr., J.B. McMahon, M.R. Boyd, Isolation and characterizationof griffithsin, a novel HIV-inactivating protein, from the red alga Griffithsia sp, J.Biol. Chem. 280 (2005) 9345–9353.

[98] J. Busserolles, M. Paya, M.V. D'Auria, L. Gomez-Paloma, M.J. Alcaraz, Protectionagainst 2,4,6-trinitrobenzenesulphonic acid-induced colonic inflammation inmice by the marine products bolinaquinone and petrosaspongiolide M, Biochem.Pharmacol. 69 (2005) 1433–1440.

[99] H. Miyaoka, M. Yamanishi, H. Mitome, PLA2 inhibitory activity of marinesesterterpenoids cladocorans, their diastereomers and analogues, Chem. Pharm.Bull. (Tokyo) 54 (2006) 268–270.

[100] C.E. McNamara, L. Larsen, N.B. Perry, J.L. Harper, M.V. Berridge, E.W. Chia, M.Kelly, V.L. Webb, Anti-inflammatory sesquiterpene-quinones from the NewZealand sponge Dysidea cf. cristagalli, J. Nat. Prod. 68 (2005) 1431–1433.

[101] A.M.S. Mayer, M.L. Hall, S.M. Lynch, S.P. Gunasekera, S.H. Sennett, S.A. Pomponi,Differential modulation of microglia superoxide anion and thromboxane B2generation by the marine manzamines, BMC. Pharmacol 5 (2005) 6.

[102] S. Sawant, D. Youssef, A. Mayer, P. Sylvester, V. Wali, M. Arant, S.K. El, Anticancerand anti-inflammatory sulfur-containing semisynthetic derivatives of sarco-phine, Chem. Pharm. Bull. (Tokyo) 54 (2006) 1119–1123.

[103] A.M.S. Mayer, S. Oh, E. Presto, K.B. Glaser, P.B. Jacobson, LPS-primed rat brainmicroglia: a convenient in vitro model to search for anti-inflammatory marinenatural products, SHOCK 7 (1997) 49.

[104] A. Mandeau, C. Debitus, M.F. Aries, B. David, Isolation and absolute configurationof new bioactive marine steroids from Euryspongia n. sp, Steroids 70 (2005)873–878.

[105] A.F. Ahmed, Y.T. Hsieh, Z.H. Wen, Y.C. Wu, J.H. Sheu, Polyoxygenated sterols fromthe Formosan soft coral Sinularia gibberosa, J. Nat. Prod. 69 (2006) 1275–1279.

[106] L.A. Tziveleka, D. Abatis, K. Paulus, R. Bauer, C. Vagias, V. Roussis, Marinepolyprenylated hydroquinones, quinones, and chromenols with inhibitoryeffects on leukotriene formation, Chem. Biodivers. 2 (2005) 901–909.

[107] H.C. Huang, Z.H. Wen, C.H. Chao, A.F. Ahmed, M.Y. Chiang, Y.H. Kuo, C.H. Hsu, J.H.Sheu, Novel sesquiterpenoids from the Formosan soft coral Paralemnaliathyrsoides, Tetrahedron Lett. 47 (2006) 8751–8755.

[108] Y. Sugiura, K.Matsuda, Y. Yamada, M. Nishikawa, K. Shioya, H. Katsuzaki, K. Imai, H.Amano, Isolation of a new anti-allergic phlorotannin, phlorofucofuroeckol-B, froman edible brown alga, Eisenia arborea, Biosci. Biotechnol. Biochem. 70 (2006)2807–2811.

[109] M. Kita, N. Ohishi, K. Washida, M. Kondo, T. Koyama, K. Yamada, D. Uemura,Symbioimine and neosymbioimine, amphoteric iminium metabolites from the


symbiotic marine dinoflagellate Symbiodinium sp.⁎, Bioorg. Med. Chem. 13 (2005)5253–5258.

[110] M.P. Sauviat, J. Vercauteren, N. Grimaud, M. Juge, M. Nabil, J.Y. Petit, J.F. Biard,Sensitivity of cardiac background inward rectifying K+ outward current (IK1) tothe alkaloids lepadiformines A, B, and C, J. Nat. Prod. 69 (2006) 558–562.

[111] K. Onodera, H. Nakamura, Y. Oba, Y. Ohizumi, M. Ojika, Zooxanthellamide Cs:vasoconstrictive polyhydroxylated macrolides with the largest lactone ring sizefrom a marine dinoflagellate of Symbiodinium sp, J. Am. Chem. Soc. 127 (2005)10406–10411.

[112] A. Pereira, E. Vottero, M. Roberge, A.G. Mauk, R.J. Andersen, Indoleamine 2,3-dioxygenase inhibitors from the Northeastern Pacific Marine Hydroid Garveiaannulata, J. Nat. Prod. 69 (2006) 1496–1499.

[113] D.L. Aminin, B.V. Pinegin, L.V. Pichugina, T.S. Zaporozhets, I.G. Agafonova, V.M.Boguslavski, A.S. Silchenko, S.A. Avilov, V.A. Stonik, Immunomodulatory proper-ties of Cumaside, Int. Immunopharmacol. 6 (2006) 1070–1082.

[114] V. Costantino, M. D'Esposito, E. Fattorusso, A. Mangoni, N. Basilico, S. Parapini, D.Taramelli, Damicoside from Axinella damicornis: the influence of a glycosylatedgalactose 4-OH group on the immunostimulatory activity of alpha-galactoglyco-sphingolipids, J. Med. Chem. 48 (2005) 7411–7417.

[115] K.H. Kim, Y.W. Kim, H.B. Kim, B.J. Lee, D.S. Lee, Anti-apoptotic activity oflaminarin polysaccharides and their enzymatically hydrolyzed oligosaccharidesfrom Laminaria japonica, Biotechnol. Lett. 28 (2006) 439–446.

[116] W. Xia, J. Li, M. Geng, X. Xin, J. Ding, Potentiation of T cell function by a marinealgae-derived sulfated polymannuroguluronate: in vitro analysis of novelmechanisms, J. Pharm. Sci. 97 (2005) 107–115.

[117] T. Oda, M. Namikoshi, K. Akano, H. Kobayashi, Y. Honma, T. Kasahara, Verrucarin ainhibition of map kinase activation in a pma-stimulated promyelocytic leukemiacell line, Marine Drugs. 3 (2005) 64–73.

[118] C.K. Tsang, A. Ina, T. Goto, Y. Kamei, Sargachromenol, a novel nerve growth factor-potentiating substance isolated from Sargassum macrocarpum, promotes neuriteoutgrowth and survival via distinct signaling pathways in PC12D cells,Neuroscience 132 (2005) 633–643.

[119] C.D. Nandini, N. Itoh, K. Sugahara, Novel 70-kDa chondroitin sulfate/dermatansulfate hybrid chains with a unique heterogeneous sulfation pattern from sharkskin, which exhibit neuritogenic activity and binding activities for growth factorsand neurotrophic factors, J. Biol. Chem 280 (2005) 4058–4069.

[120] F. Kisa, K. Yamada, T. Miyamoto, M. Inagaki, R. Higuchi, Constituents ofHolothuroidea, 17. Isolation and structure of biologically active monosialo-gangliosides from the sea cucumber Cucumaria echinata, Chem. Pharm. Bull.(Tokyo) 54 (2006) 982–987.

[121] F. Kisa, K. Yamada, T. Miyamoto, M. Inagaki, R. Higuchi, Constituents ofHolothuroidea, 18. Isolation and structure of biologically active disialo- andtrisialo-gangliosides from the sea cucumber Cucumaria echinata, Chem. Pharm.Bull. (Tokyo) 54 (2006) 1293–1298.

[122] M. Inagaki, T. Miyamoto, R. Isobe, R. Higuchi, Biologically active glycosides fromasteroidea, 43. Isolation and structure of a new neuritogenic-active gangliosidemolecular species from the starfish Linckia laevigata, Chem. Pharm. Bull. (Tokyo)53 (2005) 1551–1554.

[123] R. Higuchi, S. Inoue, K. Inagaki, M. Sakai, T. Miyamoto, T. Komori, M. Inagaki, R.Isobe, Biologically active glycosides from asteroidea, 42. Isolation and structureof a new biologically active ganglioside molecular species from the starfishAsterina pectinifera, Chem. Pharm. Bull. (Tokyo) 54 (2006) 287–291.

[124] C. Han, J. Qi, M. Ojika, Structure–activity relationships of novel neuritogenicsteroid glycosides from the Okinawan starfish Linckia laevigata, Bioorg. Med.Chem. 14 (2006) 4458–4465.

[125] H. Wei, T. Itoh, M. Kinoshita, N. Kotoku, S. Aoki, M. Kobayashi, Shimalactone A, anovel polyketide, from marine-derived fungus Emericella variecolor GF10,Tetrahedron 61 (2005) 8054–8058.

[126] M. Loughnan, A. Nicke, A. Jones, C.I. Schroeder, S.T. Nevin, D.J. Adams, P.F.Alewood, R.J. Lewis, Identification of a novel class of nicotinic receptorantagonists: dimeric conotoxins VxXIIA, VxXIIB, and VxXIIC from Conus vexillum,J. Biol. Chem. 281 (2006) 24745–24755.

[127] L. Wen, S. Yang, H. Qiao, Z. Liu, W. Zhou, Y. Zhang, P. Huang, SO-3, a new O-superfamily conopeptide derived from Conus striatus, selectively inhibits N-typecalcium currents in cultured hippocampal neurons, Br. J. Pharmacol. 145 (2005)728–739.

[128] J.M. Sanders, K. Ito, L. Settimo, O.T. Pentikainen, M. Shoji, M. Sasaki, M.S. Johnson,R. Sakai, G.T. Swanson, Divergent pharmacological activity of novel marine-derived excitatory amino acids on glutamate receptors, J. Pharmacol. Exp. Ther.314 (2005) 1068–1078.

[129] J.M. Sanders, O.T. Pentikainen, L. Settimo, U. Pentikainen, M. Shoji, M. Sasaki, R.Sakai, M.S. Johnson, G.T. Swanson, Determination of binding site residuesresponsible for the subunit selectivity of novel marine-derived compounds onkainate receptors, Mol. Pharmacol. 69 (2006) 1849–1860.

[130] H. Tsuneki, Y. You, N. Toyooka, T. Sasaoka, H. Nemoto, J.A. Dani, I. Kimura, Marinealkaloids (−)-pictamine and (−)-lepadin B block neuronal nicotinic acetylcho-line receptors, Biol. Pharm. Bull. 28 (2005) 611–614.

[131] A. Aiello, M. D'Esposito, E. Fattorusso, M. Menna, W.E. Muller, S. Perovic-Ottstadt,H.C. Schroder, Novel bioactive bromopyrrole alkaloids from the Mediterraneansponge Axinella verrucosa, Bioorg. Med. Chem. 14 (2006) 17–24.

[132] A. Aiello, M. D'Esposito, E. Fattorusso, M. Menna, W.E.G. Muller, S. Perovic-Ottstadt, H. Tsuruta, T.A.M. Gulder, G. Bringmann, Daminin, a bioactive pyrrolealkaloid from the Mediterranean sponge Axinella damicornis, Tetrahedron 61(2005) 7266–7270.

[133] G. Bringmann, G. Lang, K. Maksimenka, A. Hamm, T.A. Gulder, A. Dieter, A.T. Bull,J.E. Stach, N. Kocher, W.E. Muller, H.P. Fiedler, Gephyromycin, the first bridged

angucyclinone, from Streptomyces griseus strain NTK 14, Phytochemistry 66(2005) 1366–1373.

[134] K.C. To, K.T. Loh, C.D. Roskelley, R.J. Andersen, T.P. O'Connor, The anti-invasivecompound motuporamine C is a robust stimulator of neuronal growth conecollapse, Neuroscience 139 (2006) 1263–1274.

[135] T.A. Temraz, W.E. Houssen, M. Jaspars, D.R. Woolley, K.N. Wease, S.N. Davies, R.H.Scott, A pyridinium derivative from Red Sea soft corals inhibited voltage-activated potassium conductances and increased excitability of rat culturedsensory neurones, BMC Pharmacol. 6 (2006) 10.

[136] G.M. Cragg, D.J. Newman, Biodiversity: a continuing source of novel drug leads,Pure and Applied Chemistry. 77(1):7–24, 77 (2005) 7–24.

[137] G.M. Cragg, D.J. Newman, International collaboration in drug discovery anddevelopment from natural sources, Pure Appl. Chem. 77 (2005) 1923–1942.

[138] W. Gul, M.T. Hamann, Indole alkaloid marine natural products: an establishedsource of cancer drug leads with considerable promise for the control ofparasitic, neurological and other diseases, Life Sci. 78 (2005) 442–453.

[139] P.R. Jensen, T.J. Mincer, P.G. Williams, W. Fenical, Marine actinomycete diversityand natural product discovery, Antonie Van Leeuwenhoek 87 (2005) 43–48.

[140] I. Paterson, E.A. Anderson, The renaissance of natural products as drugcandidates, Science 310 (2005) 451–453.

[141] S. Singh, B.N. Kate, U.C. Banerjee, Bioactive compounds from cyanobacteria andmicroalgae: an overview, Crit. Rev. Biotechnol. 25 (2005) 73–95.

[142] Y.W. Chin, M.J. Balunas, H.B. Chai, A.D. Kinghorn, Drug discovery from naturalsources, AAPS J. 8 (2006) E239–E253.

[143] W. Fenical, P.R. Jensen, Developing a new resource for drug discovery: marineactinomycete bacteria, Nat. Chem. Biol. 2 (2006) 666–673.

[144] S.K. Kim, E. Mendis, Bioactive compounds frommarine processing byproducts —a review [Review], Food Res. Int. 39 (2006) 383–393.

[145] P. Proksch, R. Edrada, W.H. Lin, Implications of marine biotechnology on drugdiscovery, in: P. Proksch, W.E.G. Muller (Eds.), Frontiers in Marine Biotechnology,Horizon Bioscience, 2006, pp. 1–19.

[146] J.M. Brunel, C. Salmi, C. Loncle, N. Vidal, Y. Letourneux, Squalamine: a polyvalentdrug of the future? Curr. Cancer Drug Targets 5 (2005) 267–272.

[147] M. Donia, M.T. Hamann, Marine natural products and their potential applicationsas anti-infective agents, Lancet Infect. Dis. 3 (2003) 338–348.

[148] T.O. Larsen, J. Smedsgaard, K.F. Nielsen, M.E. Hansen, J.C. Frisvad, Phenotypictaxonomy and metabolite profiling in microbial drug discovery, Nat. Prod. Rep.22 (2005) 672–695.

[149] P. Bhadury, B.T. Mohammad, P.C. Wright, The current status of natural productsfrom marine fungi and their potential as anti-infective agents, J. Ind. Microbiol.Biotechnol. 33 (2006) 325–337.

[150] S. Jude, S. Roger, E. Martel, P. Besson, S. Richard, P. Bougnoux, P. Champeroux, J.Y.Le Guennec, Dietary long-chain omega-3 fatty acids of marine origin: acomparison of their protective effects on coronary heart disease and breastcancers, Prog. Biophys. Mol. Biol. 90 (2006) 299–325.

[151] M.L. Bourguet-Kondracki, J.M. Kornprobst, Marine pharmacology: potentialitiesin the treatment of infectious diseases, osteoporosis and Alzheimer's disease,Adv. Biochem. Eng. Biotechnol. 97 (2005) 105–131.

[152] M.V. De Souza, Marine natural products against tuberculosis, Sci. World J. 6(2006) 847–861.

[153] M.J.A. Martinez, L.M.B. Del Olmo, P.B. Benito, Antiviral activities of polysacchar-ides from natural sources, Bioact. Nat. Prod. (2005) 393–418.

[154] D. Laurent, F. Pietra, Antiplasmodial marine natural products in the perspectiveof current chemotherapy and prevention of malaria: a review, Mar. Biotechnol.(NY) 8 (2006) 433–447.

[155] M.L. Dubuisson, J.F. Rees, J. Marchand-Brynaert, Coelenterazine (marinebioluminescent substrate): a source of inspiration for the discovery of novelantioxidants, Drug Dev. Ind. Pharm. 31 (2005) 827–849.

[156] L. Gomez-Paloma, M.C. Monti, S. Terracciano, A. Casapullo, R. Riccio, Chemistryand biology of anti-inflammatory marine natural products. Phospholipase A(2)inhibitors, Curr. Org. Chem. 9 (2005) 1419–1427.

[157] T.J. Heckrodt, J. Mulzer, Marine natural products from Pseudopterogorgiaelisabethae: structures, biosynthesis, pharmacology, and total synthesis, Top.Curr. Chem. 244 (2005) 1–41.

[158] S. Terracciano, M. Aquino, M. Rodriquez, M.C. Monti, A. Casapullo, R. Riccio, L.Gomez-Paloma, Chemistry and biology of anti-inflammatory marine naturalproducts: molecules interfering with cyclooxygenase, NF-kappaB and otherunidentified targets, Curr. Med. Chem. 13 (2006) 1947–1969.

[159] M.J. Alcaraz, M. Paya, Marine sponge metabolites for the control of inflammatorydiseases, Curr. Opin. Investig. Drugs 7 (2006) 974–979.

[160] K.M. Fisch, A. Abdel-Lateff, G.M. Konig, Antioxidant metabolites from marinederived fungi, in: M. Fingerman, R. Nagabhushanam (Eds.), Biomaterials fromAquatic and Terrestrial Organisms, Science Publishers, New Orleans, 2006,pp. 361–376.

[161] D. Alonso, A. Castro, A.Martinez, Marine compounds for the therapeutic treatmentof neurological disorders, Expert Opinion Therap. Pat. 15 (2005) 1377–1386.

[162] D. Sharp, Novel pain relief via marine snails, Lancet 366 (2005) 439–440.[163] M.K. Sun, D.L. Alkon, Bryostatin-1: pharmacology and therapeutic potential as a

CNS drug, CNS Drug Rev. 12 (2006) 1–8.[164] E.J. Bowman, B.J. Bowman, V-ATPases as drug targets, J. Bioenerg. Biomembr. 37

(2005) 431–435.[165] N. Dias, H. Vezin, A. Lansiaux, C. Bailly, Topoisomerase inhibitors of marine origin

and their potential use as anticancer agents, Top. Curr. Chem. 253 (2005)89–108.

[166] C. Imada, Enzyme inhibitors and other bioactive compounds from marineactinomycetes, Antonie Van Leeuwenhoek 87 (2005) 59–63.


[167] D. Alonso, A. Martinez, Marine compounds as a new source for glycogen synthasekinase 3 inhibitors, in: A. Martinez, A. Castro, M. Medine (Eds.), GlycogenSynthase Kinase 3 (GSK-3) and Its Inhibitors: Drug Discovery and Development,John Wiley and Sons, Inc, 2006, pp. 307–331.

[168] J.A. Williams, M. Day, J.E. Heavner, Ziconotide: an update and review, ExpertOpin. Pharmacother. 9 (2008) 1575–1583.

[169] U. Bickmeyer, M. Assmann, M. Kock, C. Schutt, A secondary metabolite, 4,5-dibromopyrrole-2-carboxylic acid, from marine sponges of the genus Agelasalters cellular calcium signals, Environ. Toxicol. Pharmacol. 19 (2005) 423–427.

[170] S.G. Cao, C. Foster, M. Brisson, J.S. Lazo, D.G.I. Kingston, Halenaquinone andxestoquinone derivatives, inhibitors of Cdc25B phosphatase from a Xestospongiasp, Bioorg. Med. Chem. 13 (2005) 999–1003.

[171] E. Hedner, M. Sjogren, P.A. Frandberg, T. Johansson, U. Goransson, M. Dahlstrom,P. Jonsson, F. Nyberg, L. Bohlin, Brominated cyclodipeptides from the marinesponge Geodia barretti as selective 5-HT ligands, J. Nat. Prod. 69 (2006)1421–1424.

[172] U. Bickmeyer, Bromoageliferin and dibromoageliferin, secondary metabolitesfrom the marine sponge Agelas conifera, inhibit voltage-operated, but not store-operated calcium entry in PC12 cells, Toxicon 45 (2005) 627–632.

[173] F. Robert, H.Q. Gao, M. Donia, W.C. Merrick, M.T. Hamann, J. Pelletier,Chlorolissoclimides: new inhibitors of eukaryotic protein synthesis, RNA 12(2006) 717–725.

[174] S. Mahale, C. Aubry, W.A. James, P.R. Jenkins, J.D. Marechal, M.J. Sutcliffe, B.Chaudhuri, CA224, a non-planar analogue of fascaplysin, inhibits Cdk4 but notCdk2 and arrests cells at G0/G1 inhibiting pRB phosphorylation, Bioorg. Med.Chem. Lett. 16 (2006) 4272–4278.

[175] M.E. Bordeleau, A. Mori, M. Oberer, L. Lindqvist, L.S. Chard, T. Higa, G.J. Belsham,G. Wagner, J. Tanaka, J. Pelletier, Functional characterization of IRESes by aninhibitor of the RNA helicase eIF4A, Nat. Chem. Biol. 2 (2006) 213–220.

[176] F. Marion, D.E. Williams, B.O. Patrick, I. Hollander, R. Mallon, S.C. Kim, D.M. Roll, L.Feldberg, S.R. Van, R.J. Andersen, Liphagal, a selective inhibitor of PI3 kinasealpha isolated from the sponge Aka coralliphaga: structure elucidation andbiomimetic synthesis, Org. Lett. 8 (2006) 321–324.

[177] S. Manzanaro, J. Salva, J.A. de la Fuente, Phenolic marine natural products asaldose reductase inhibitors, J. Nat. Prod. 69 (2006) 1485–1487.

[178] H. Yamaki, N. Sitachitta, T. Sano, K. Kaya, Two new chymotrypsin inhibitorsisolated from the Cyanobacterium Microcystis aeruginosa NIES-88, J. Nat. Prod.68 (2005) 14–18.

[179] M.E. Bordeleau, J. Matthews, J.M. Wojnar, L. Lindqvist, O. Novac, E. Jankowsky, N.Sonenberg, P. Northcote, P. Teesdale-Spittle, J. Pelletier, Stimulation of mamma-lian translation initiation factor eIF4A activity by a small molecule inhibitor ofeukaryotic translation, Proc. Natl. Acad. Sci. U. S. A. 102 (2005) 10460–10465.

[180] H.A. Jung, S.K. Hyun, H.R. Kim, J.S. Choi, Angiotensin-converting enzyme Iinhibitory activity of phlorotannins from Ecklonia stolonifera, Fisheries Sci. 72(2006) 1292–1299.

[181] G. Zhu, F. Yang, R. Balachandran, P. Hook, R.B. Vallee, D.P. Curran, B.W. Day,Synthesis and biological evaluation of purealin and analogues as cytoplasmicdynein heavy chain inhibitors, J. Med. Chem. 49 (2006) 2063–2076.

[182] S.J. Nam, H. Ko, M. Shin, J. Ham, J. Chin, Y. Kim, H. Kim, K. Shin, H. Choi, H. Kang,Farnesoid X-activated receptor antagonists from a marine sponge Spongia sp,Bioorg. Med. Chem. Lett. 16 (2006) 5398–5402.

[183] M.N. Chernova, D.H. Vandorpe, J.S. Clark, J.I. Williams, M.A. Zasloff, L. Jiang, S.L.Alper, Apparent receptor-mediated activation of Ca2+-dependent conductiveCl-transport by shark-derived polyaminosterols, Am. J. Physiol. 289 (2005)R1644–R1658.

[184] E. Jaimovich, C. Mattei, J.L. Liberona, C. Cardenas, M. Estrada, J. Barbier, C.Debitus, D. Laurent, J. Molgo, Xestospongin B, a competitive inhibitor of IP3-mediated Ca2+ signalling in cultured rat myotubes, isolated myonuclei, andneuroblastoma (NG108-15) cells, FEBS Lett. 579 (2005) 2051–2057.

[185] T.A. Ta, W. Feng, T.F. Molinski, I.N. Pessah, Hydroxylated xestospongins blockinositol-1,4,5-trisphosphate-induced Ca2+ release and sensitize Ca2+-inducedCa2+ release mediated by ryanodine receptors, Mol. Pharmacol. 69 (2006)532–538.

[186] S. Cao, C. Foster, J.S. Lazo, D.G. Kingston, Four diterpenoid inhibitors of Cdc25Bphosphatase from amarine anemone, Bioorg. Med. Chem.13 (2005) 5830–5834.

[187] T. Kubota, Y. Sakuma, K. Shimbo, M. Tsuda, M. Nakano, Y. Uozumi, J. Kobayashi,Amphezonol A, a novel polyhydroxyl metabolite from marine dinoflagellateAmphidinium sp, Tetrahedron Lett. 47 (2006) 4369–4371.

[188] S.F. Seibert, E. Eguereva, A. Krick, S. Kehraus, E. Voloshina, G. Raabe, J.Fleischhauer, E. Leistner, M. Wiese, H. Prinz, K. Alexandrov, P. Janning, H.Waldmann, G.M. Konig, Polyketides from the marine-derived fungus Ascochytasalicorniae and their potential to inhibit protein phosphatases, Org. Biomol.Chem. 4 (2006) 2233–2240.

[189] P.J. Sung, Y.P. Chen, T.L. Hwang, W.P. Hu, L.S. Fang, Y.C. Wu, J.J. Li, J.H. Sheu,Briaexcavatins C–F, four new briarane-related diterpenoids from the Formosanoctocoral Briareum excavatum (Briareidae), Tetrahedron 62 (2006) 5686–5691.

[190] Y.P. Chen, S.L. Wu, J.H. Su, M.R. Lin, W.P. Hu, T.L. Hwang, J.H. Sheu, T.Y. Fan, L.S.Fang, P.J. Sung, Briaexcavatins G and H, two new briaranes from the octocoralBriareum excavatum, Bull. Chem. Soc. Jpn. 79 (2006) 1900–1905.

[191] D. Muller, A. Krick, S. Kehraus, C. Mehner, M. Hart, F.C. Kupper, K. Saxena, H. Prinz,H. Schwalbe, P. Janning, H.Waldmann, G.M. Konig, Brunsvicamides A–C: sponge-related cyanobacterial peptides with Mycobacterium tuberculosis proteintyrosine phosphatase inhibitory activity, J. Med. Chem. 49 (2006) 4871–4878.

[192] S.C. Mao, Y.W. Guo, X. Shen, Two novel aromatic valerenane-type sesquiterpenesfrom the Chinese green alga Caulerpa taxifolia, Bioorg. Med. Chem. Lett. 16(2006) 2947–2950.

[193] S. Aoki, Y. Watanabe, M. Sanagawa, A. Setiawan, N. Kotoku, M. Kobayashi,Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marinesponge Corticium simplex, J. Am. Chem. Soc. 128 (2006) 3148–3149.

[194] E. von Elert, L. Oberer, P. Merkel, T. Huhn, J.F. Blom, Cyanopeptolin 954, achlorine-containing chymotrypsin inhibitor of Microcystis aeruginosa NIVA Cya43, J. Nat. Prod. 68 (2005) 1324–1327.

[195] S. Cao, C. Foster, J.S. Lazo, D.G. Kingston, Sesterterpenoids and an alkaloid from aThorectandra sp. as inhibitors of the phosphatase Cdc25B, Bioorg. Med. Chem. 13(2005) 5094–5098.

[196] Z.Y. Shao, J. Li, C.J. Sim, J.Y. Li, Z.Y. Li, F.J. Nan, Y.W. Guo, O-methyl nakafuran-8lactone, a new sesquiterpenoid from a hainan marine sponge Dysidea sp. J. AsianNat. Prod. Res 8 (2006) 223–227.

[197] O.M. Sabry, S. Andrews, K.L. McPhail, D.E. Goeger, A. Yokochi, K.T. LePage, T.F.Murray, W.H. Gerwick, Neurotoxic meroditerpenoids from the tropical marinebrown alga Stypopodium flabelliforme, J. Nat. Prod. 68 (2005) 1022–1030.

[198] H. Jayasuriya, K.B. Herath, J.G. Ondeyka, Z. Guan, R.P. Borris, S. Tiwari, W. de Jong, F.Chavez, J. Moss, D.W. Stevenson, H.T. Beck, M. Slattery, N. Zamora, M. Schulman, A.Ali, N. Sharma, K. MacNaul, N. Hayes, J.G. Menke, S.B. Singh, Diterpenoid, steroid,and triterpenoid agonists of liver X receptors fromdiversified terrestrial plants andmarine sources, J. Nat. Prod. 68 (2005) 1247–1252.

[199] S. Tsukamoto, T. Yoshida, H. Hosono, T. Ohta, H. Yokosawa, Hexylitaconic acid: anew inhibitor of p53–HDM2 interaction isolated from a marine-derived fungus,Arthrinium sp, Bioorg. Med. Chem. Lett. 16 (2006) 69–71.

[200] S. Tsukamoto, H. Hirota, M. Imachi, M. Fujimuro, H. Onuki, T. Ohta, H. Yokosawa,Himeic acidA: a newubiquitin-activatingenzyme inhibitor isolated fromamarine-derived fungus, Aspergillus sp, Bioorg. Med. Chem. Lett. 15 (2005) 191–194.

[201] X.H. Yan, X.Z. Zhu, J.L. Yu, D.Z. Jin, Y.W. Guo, E. Mollo, G. Cimino, 3-Oxo-axisonitrile-3, a new sesquiterpene isocyanide from the Chinese marine spongeAcanthella sp, J. Asian Nat. Prod. Res. 8 (2006) 579–584.

[202] A. Plaza, C.A. Bewley, Largamides A–H, unusual cyclic peptides from the marinecyanobacterium Oscillatoria sp, J. Org. Chem. 71 (2006) 6898–6907.

[203] T. Yamada, M. Doi, A. Miura, W. Harada, M. Hiramura, K. Minoura, R. Tanaka, A.Numata, Absolute stereostructures of cell-adhesion inhibitors, peribysins A, E, Fand G, produced by a sea hare-derived Periconia sp, J. Antibiot. (Tokyo) 58(2005) 185–191.

[204] T. Yamada, K. Minoura, R. Tanaka, A. Numata, Cell-adhesion inhibitors producedby a sea hare-derived Periconia sp. II. Absolute stereostructures of peribysins Hand I, J. Antibiot. (Tokyo) 59 (2006) 345–350.

[205] A.R. Carroll, A. Ngo, R.J. Quinn, J. Redburn, J.N. Hooper, Petrosamine B, an inhibitorof theHelicobacter pylori enzyme aspartyl semialdehyde dehydrogenase from theAustralian sponge Oceanapia sp, J. Nat. Prod. 68 (2005) 804–806.

[206] E.V. Levina, A.I. Kalinovsky, P.V. Andriyashenko, P.S. Dmitrenok, D.L. Aminin, V.A.Stonik, Phrygiasterol, a cytotoxic cyclopropane-containing polyhydroxysteroid,and related compounds from the pacific starfish Hippasteria phrygiana, J. Nat.Prod. 68 (2005) 1541–1544.

[207] E.H. Andrianasolo, D. France, S. Cornell-Kennon, W.H. Gerwick, DNA methyltransferase inhibiting halogenated monoterpenes from the Madagascar redmarine alga Portieria hornemannii, J. Nat. Prod. 69 (2006) 576–579.

[208] J. Mori, M. Iwashima, H. Wakasugi, H. Saito, T. Matsunaga, M. Ogasawara, S.Takahashi, H. Suzuki, T. Hayashi, Newplastoquinones isolated from thebrownalga,Sargassum micracanthum, Chem. Pharm. Bull. (Tokyo) 53 (2005) 1159–1163.

[209] Y. Xie, L. Liu, X. Huang, Y. Guo, L. Lou, Scalaradial inhibition of epidermal growthfactor receptor-mediated Akt phosphorylation is independent of secretoryphospholipase A2, J. Pharmacol. Exp. Ther. 314 (2005) 1210–1217.

[210] S. Tsukamoto, K. Koimaru, T. Ohta, Secomycalolide A: a new proteasome inhibitorisolated from a marine sponge of the genus Mycale, Marine Drugs 3 (2005)29–35.

[211] W. Wang, Y. Okada, H. Shi, Y. Wang, T. Okuyama, Structures and aldose reductaseinhibitory effects of bromophenols from the red alga Symphyocladia latiuscula,J. Nat. Prod. 68 (2005) 620–622.

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