Search

As part of an investigation to generate optimized drug leads from marine natural pharmacophores for the treatment of neoplastic and infectious diseases, a series of novel isoaaptamine analogs were prepared by coupling acyl halides to the C9 position of isoaaptamine (2) isolated from the Aaptos sponge. This library of new semisynthetic products was evaluated for biological activity against HIV-1, Mtb, AIDS-OI, tropical parasitic diseases, and cancer. Compound 4 showed potent activity against HIV-1 (EC(50) 0.47microg/mL), compound 19 proved to possess remarkable activity against Mycobacterium intracellulare with an IC(50) and MIC value of 0.15 and 0.31microg/mL, while compounds 4 and 17 possessed anti-leishmanial activity with IC(50) values of 0.1 and 0.4microg/mL, respectively. Compounds 16 and 17 showed antimalarial activity with EC(50) values of 230 and 240ng/mL, respectively, and compound 14 exhibited an EC(50) of 0.05microM against the Leukemia cell line K-562.

Two new cyclic heptapeptides, stylisin 1(1) and stylisin 2 (2), were isolated and characterized from the Jamaican sponge Stylissa caribica, in addition to the cyclic heptapeptide phakellistatin 13 (3) and the known bromopyrrole alkaloids sceptrin (4), stevensine (5), and oroidin (6). The new structures were assigned on the basis of 1D and 2D NMR spectroscopic data, as well as chemical methods for the elucidation of the absolute configuration of amino acids. The peptides and alkaloids have been evaluated for their antimicrobial, antimalarial, anticancer, anti-HIV-1, anti-Mtb, and antiinflammatory activities.

[Structure: see text] The synthesis and biological evaluation of a series of analogues of manzamine A, representing partial structures of the pentacyclic ABCDE diamine core, is described. All new compounds were screened against Plasmodium falciparum and demonstrated attenuated antimalarial activity relative to that of manzamine A.

Several aaptamine derivatives were selected as potential zebra mussel (Dreissena polymorpha) antifoulants because of the noteworthy absence of fouling observed on Aaptos sponges. Sponges of the genus Aaptos collected in Manado, Indonesia consistently produce aaptamine-type alkaloids. To date, aaptamine and its derivatives have not been carefully evaluated for their antifoulant properties. Structure-activity relationship studies were conducted using several aaptamine derivatives in a zebra mussel antifouling assay. From these data, three analogs have shown significant antifouling activity against zebra mussel attachment. Aaptamine, isoaaptamine, and the demethylated aaptamine compounds used in the zebra mussel assay produced EC(50) values of 24.2, 11.6, and 18.6 microM, respectively. In addition, neither aaptamine nor isoaaptamine produced a phytotoxic response (as high as 300 microM) toward a nontarget organism, Lemna pausicostata, in a 7-day exposure. The use of these aaptamine derivatives from Aaptos sp. as potential environmentally benign antifouling alternatives to metal-based paints and preservatives is significant, not only as a possible control of fouling organisms, but also to highlight the ecological importance of these and similar biochemical defenses.

Four new manzamine-type alkaloids, 12,28-oxamanzamine E (2), 12,34-oxa-6-hydroxymanzamine E (3), 8-hydroxymanzamine B (5), and 12,28-oxaircinal A (11), were isolated from three collections of an Indonesian sponge of the genus Acanthostrongylophora together with 13 known manzamine alkaloids, ircinal A, ircinol A, xestomanzamine A, manzamines A, E, F, J, and Y, manadomanzamines A and B, neo-kauluamine, 8-hydroxymanzamine A, and manzamine A N-oxide. The structures of the new compounds were elucidated by means of 1D and 2D NMR spectroscopic methods. Three of these compounds (2, 3, and 11) possess a unique manzamine-type aminal ring system generated through an ether linkage between carbons 12-28 or between carbons 12-34. In the case of manzamine B and related metabolites, carbons 11 and 12 of the typical manzamine structure have an epoxide group and add to our growing understanding of manzamine structure-activity relationships (SAR) and metabolism. The bioactivity and SAR for a number of previously reported manzamine-related metabolites against malaria, leishmania, tuberculosis, and HIV-1 are also presented. Manzamine Y (9) showed significant inhibitory activity of GSK3, an enzyme implicated in Alzheimer's disease pathology. The toxicity of manzamine A and neo-kauluamine was evaluated against both medaka fry and eggs.

Manzamine A represents an important lead structure for the development of novel antimalarial chemotherapies. The synthesis and biological evaluation of a group of simplified analogues of manzamine A, which were designed to examine the roles of the A and D rings and of both the relative stereochemistry and the orientation of the beta-carboline heterocycle on the antimalarial activity of manzamine A, are described. [structure: see text]

Lissoclimides are cytotoxic compounds produced by shell-less molluscs through chemical secretions to deter predators. Chlorinated lissoclimides were identified as the active component of a marine extract from Pleurobranchus forskalii found during a high-throughput screening campaign to characterize new protein synthesis inhibitors. It was demonstrated that these compounds inhibit protein synthesis in vitro, in extracts prepared from mammalian and plant cells, as well as in vivo against mammalian cells. Our results suggest that they block translation elongation by inhibiting translocation, leading to an accumulation of ribosomes on mRNA. These data provide a rationale for the cytotoxic nature of this class of small molecule natural products.

Microbial transformation studies of the marine diterpene cyanthiwigin B (1), isolated from the Jamaican sponge Myrmekioderma styx, were accomplished. Two actinomycete cultures, Streptomyces NRRL 5690 and Streptomyces spheroides, significantly metabolized cyanthiwigin B to new metabolites. Streptomyces NRRL 5690 transformed cyanthiwigin B to three new compounds, cyanthiwigins AE (2), AF (3), and AG (4), and the known cyanthiwigin R (5). S. spheroides transformed cyanthiwigin B to cyanthiwigins S (6), E (7), and AE (2). All microbial-metabolized derivatives (2-7) of cyanthiwigin B exhibited the ability to increase the antimicrobial activity of curcuphenol, the major antimicrobial sesquiterpene isolated from M. styx.

The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biological activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacological activities.

SPK-843 is a water-soluble antibiotic under co-development by Aparts and Kaken for the potential treatment of systemic fungal infections. By November 2004, SPK-843 was in phase II trials for systemic mycosis.

The marine natural product kahalalide A, a cyclic depsipeptide, was prepared by total synthesis on solid-phase. A backbone cyclization strategy was followed, using the Kenner sulfonamide safety-catch linker. By NMR comparison of synthetic and naturally isolated material, the stereochemistry of the methylbutyrate side chain was established as (S). Several analogues were synthesized and tested for antimycobacterial activity. The results indicate that the alcohol functional group in the serine and threonine residues is important, while the methylbutyrate side chain can be replaced by an achiral hexanoate with an increase in activity.

During 2001--2002, research on the pharmacology of marine chemicals continued to be global in nature involving investigators from Argentina, Australia, Brazil, Canada, China, Denmark, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Pakistan, the Philippines, Russia, Singapore, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Thailand, United Kingdom, and the United States. This current article, a sequel to the authors' 1998, 1999 and 2000 marine pharmacology reviews, classifies 106 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria, on the basis of peer-reviewed preclinical pharmacology. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 56 marine chemicals. An additional 19 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as to possess anti-inflammatory and antidiabetic effects. Finally, 31 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2001--2002 pharmacological research with marine chemicals continued to contribute potentially novel chemical leads for the ongoing global search for therapeutic agents for the treatment of multiple disease categories.

Three tricyclic guanidine alkaloids, including 1,8a;8b,3a-didehydro-8beta-hydroxyptilocaulin (1), 1,8a;8b,3a-didehydro-8alpha-hydroxyptilocaulin (2) and mirabilin B (3), were identified from the marine sponge Monanchora unguifera. 1,8a;8b,3a-Didehydro-8alpha-hydroxyptilocaulin (2) is a new stereoisomer of 1, the structure of which was elucidated by spectroscopic analysis, comparison of its spectral data with those of 1, and confirmed by X-ray analysis. Compounds 1 and 2 co-crystallized in an unusual perfect order and packed around an approximate inversion center. A mixture of 1 and 2 is active against the malaria parasite Plasmodium falciparum with an IC50 value of 3.8 microg/mL while mirabilin B (3) exhibited antifungal activity against Cryptococcus neoformans with an IC50 value of 7.0 microg/mL and antiprotozoal activity against Leishmania donovani with an IC50 value of 17 microg/mL.

Several dibromotyramine derivatives including moloka'iamine were selected as potential zebra mussel (Dreissena polymorpha) antifoulants due to the noteworthy absence of fouling observed on sponges of the order Verongida. Sponges of the order Verongida consistently produce these types of bromotyrosine-derived secondary metabolites. Previously reported antifouling data for the barnacle Balanus amphitrite(EC50 = 12.2 microM) support the results reported here that the compound moloka'iamine may be a potential zebra mussel antifoulant compound (EC50 = 10.4 microM). The absence of phytotoxic activity of the compound moloka'iamine toward Lemna pausicostata and, most importantly, the compound's significant selectivity against macrofouling organisms such as zebra mussels suggest the potential utility of this compound as a naturally derived antifoulant lead.

Kahalalide F is a depsipeptide under development by PharmaMar as a potential treatment for solid tumors. It is currently undergoing phase II clinical trials.

Antibiotics remain essential tools in the control of infectious diseases. With the emergence of new diseases, resistant forms of diseases such as tuberculosis and malaria, as well as the emergence of multidrug-resistant bacteria, it has become essential to develop novel antibiotics. Development of the existing antibiotics involved three strategies, including discovery of new target sites, modification of existing antibiotic structures, and the identification of new resources for novel antibiotics. Marine microorganisms have clearly become an essential new resource in the discovery of new antibiotic leads.

Three new manzamine-type alkaloids, 12,34-oxamanzamine E (3), 8-hydroxymanzamine J (4), and 6-hydroxymanzamine E (8), as well as 12 previously characterized manzamine alkaloids have been isolated from a common Indonesian sponge of the genus Acanthostrongylophora. The structures of the new compounds have been established on the basis of 1D and 2D NMR spectroscopic analysis and comparison of the data to literature values of related compounds. The biological activities and structure-activity relationship of the manzamines against malaria, Mycobacterium tuberculosis, Leishmania, HIV-1, and AIDS opportunistic infections are discussed. A plausible pathway for the formation of the 12,34-oxaether bridge in compound 3 is also provided.

12,28-Oxamanzamine A (1), 12,28-oxa-8-hydroxymanzamine A (2), and 31-keto-12,34-oxa-32,33-dihydroircinal A (3) were isolated from two collections of an Indo-Pacific sponge, and their structures were assigned on the basis of 1D and 2D NMR spectroscopic data. These compounds possess a novel manzamine-type ring system generated through a new ether bridge formed between carbons 12 and 28 or between carbons 12 and 34 of the typical manzamine structure and add to our growing understanding of manzamine SAR and metabolism. Based on molecular modeling studies, the formation of these oxidation products is highly sterically favored. The potent antiinflammatory, antifungal, and anti-HIV-1 activity for a number of previously reported manzamines is also presented in addition to the pharmacokinetic studies of manzamine A (5). Oral and intravenous pharmacokinetic studies of manzamine A in rats indicated the compound to have low metabolic clearance, a reasonably long pharmacokinetic half-life, and good absolute oral bioavailability of 20.6%, which supports the value of these compounds as potential leads for further preclinical assessment and possible development.

During 2000 research on the pharmacology of marine chemicals involved investigators from Australia, Brazil, Canada, Egypt, France, Germany, India, Indonesia, Israel, Italy, Japan, the Netherlands, New Zealand, Phillipines, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, United Kingdom, and the United States. This current review, a sequel to the authors' 1998 and 1999 reviews, classifies 68 peer-reviewed articles on the basis of the reported preclinical pharmacologic properties of marine chemicals derived from a diverse group of marine animals, algae, fungi, and bacteria. Antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis, or antiviral activity was reported for 35 marine chemicals. An additional 20 marine compounds were shown to have significant effects on the cardiovascular and nervous system, and to possess anti-inflammatory or immunosuppressant properties. Finally, 23 marine compounds were reported to act on a variety of molecular targets and thus could potentially contribute to several pharmacologic classes. Thus, as in 1998 and 1999, during 2000 pharmacologic research with marine chemicals continued to contribute potentially novel chemical leads to the ongoing global search for therapeutic agents in the treatment of multiple disease categories.

[structure: see text] Three novel diterpenes, called cyanthiwigins AB (1), AC (2), and AD (3), were isolated from the Jamaican sponge Myrmekioderma styx. Their structures were elucidated by means of 1D and 2D NMR spectroscopic methods. Cyanthiwigin AC (2) and AD (3) represent novel diterpene-type skeletons.

Two novel alkaloids, named manadomanzamines A (1) and B (2), were isolated from an Indonesian sponge Acanthostrongylophora sp. (Haplosclerida: Petrosiidae). Their structures were elucidated and shown to be a novel organic skeleton related to the manzamine type alkaloids. Their absolute configuration and conformation were determined by CD, NOESY, and molecular modeling analysis. The microbial community analysis for the sponge that produces these unprecedented alkaloids has also been completed. Manadomanzamines A (1) and B (2) exhibited strong activity against Mycobacterium tuberculosis (Mtb) with MIC values of 1.9 and 1.5 mug/mL, respectively. Manadomanzamines A and B also exhibit activities against human immunodeficiency virus (HIV-1) and AIDS opportunistic fungal infections.

Current anti-HIV drugs have extreme side effects and resistance to these drugs develops rapidly. The marine environment holds an unprecedented number of unusual chemical structural classes with activity against HIV. We review the literature on anti-HIV activity of marine natural products and discuss the efficacy of different structural classes.

The oceans are a unique resource that provide a diverse array of natural products, primarily from invertebrates such as sponges, tunicates, bryozoans, and molluscs, and from marine bacteria and cyanobacteria. As infectious diseases evolve and develop resistance to existing pharmaceuticals, the marine environment provides novel leads against fungal, parasitic, bacterial, and viral diseases. Many marine natural products have successfully advanced to the late stages of clinical trials, including dolastatin 10, ecteinascidin-743, kahalalide F, and aplidine, and a growing number of candidates have been selected as promising leads for extended preclinical assessment. Although many marine-product clinical trials are for cancer chemotherapy, drug resistance, emerging infectious diseases, and the threat of bioterrorism have all contributed to the interest in assessing natural ocean products in the treatment of infectious organisms. In this review, we focus on the pharmacologically tested marine leads that have shown in-vivo efficacy or potent in-vitro activity against infectious and parasitic diseases.

Eleven manzamine type alkaloids, two beta-carbolines, and five nucleosides have been isolated from an Indonesian sponge. Among these are the previously characterized 12,34-oxamanzamine A, 12,34-oxamanzamine E, manzamine A (1), 8-hydroxymanzamine A, 6-deoxymanzamine X, manzamine E (2), manzamine X, manzamine F (4), norharman, thymine, 2',3'-didehydro-2',3'-dideoxyuridine, uracil, thymidine, and 2'-deoxyuridine. The structures for the five new compounds have been assigned as 32,33-dihydro-31-hydroxymanzamine A (3), 32,33-dihydro-6-hydroxymanzamine A-35-one (5), des-N-methylxestomanzamine A (6), 32,33-dihydro-6,31-dihydroxymanzamine A (7), and 1,2,3,4-tetrahydronorharman-1-one (8), on the basis of NMR and X-ray data. The bioactivity and SAR of the manzamines against malaria, TB, and leishmania are also presented. The structural revision of two previously reported pyrazoles as uracil and thymine is also discussed.

Pure natural products isolated from marine sponges, algae, and cyanobacteria were examined for antioxidant activity using a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) solution-based chemical assay and a 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) cellular-based assay. The DCFH system detects only antioxidants that penetrate cellular membranes. Potent antioxidants were identified and the results from each system compared. The algal metabolites cymopol (1), avrainvilleol (3), and fragilamide (4), and the invertebrate constituent puupehenone (5) showed strong antioxidant activity in both systems. Several compounds were active in the DPPH assay but significantly less active in the DCFH system. The green algal metabolite 7-hydroxycymopol (2) was isolated from Cymopolia barbataand its structure determined. Compound 2 was significantly less active in the DCFH system than cymopol (1). The sponge metabolites (1S)-(+)-curcuphenol (6), aaptamine (7), isoaaptamine (8), and curcudiol (9) and the cyanobacterial pigment scytonemin (10) showed strong antioxidant activity in the DPPH assay, but were relatively inactive in the DCFH system. Thus, cellular uptake dramatically affects the potential significance of antioxidants discovered using only the DPPH assay. The apparent "proantioxidants" hormothamnione A diacetate (11) and Laurencia monomer diacetate (12) require metabolic activation for antioxidant activity. Significant advantages are achieved using both a solution- and cellular-based assay to discover new antioxidants.

In the interest of identifying new leads that could serve as prototype agrochemical agents, 18 structurally diverse marine-derived compounds were examined for insecticidal, herbicidal, and fungicidal activities. Several new classes of compounds have been shown to be insecticidal, herbicidal, and fungicidal, which suggests that marine natural products represent an intriguing source for the discovery of new agrochemical agents.

In the last several decades the plants, animals and microbes from the marine environment have revealed a portion of what is clearly a tremendous resource for structurally diverse and bioactive secondary metabolites. Many of these extraordinarily sophisticated and bioactive natural products can be isolated in significant quantities without great difficulty. As a result these readily available bioactive natural products provide valuable starting materials for the rational generation of libraries of compounds prepared through semisynthesis and biocatalysis. A review of our work using marine natural products to generate rationally designed compound libraries and their biological activity against infectious diseases, cancer and neurological targets is presented. The marine natural products utilized to date as starting materials consist of compounds from a variety of structural classes and include: aureol, puupehenone, sarcophine, palinurin, and the manzamine alkaloids. The possibility to generate diverse bioactive products beginning with a marine natural product scaffold is a direct result of improvements made in the technologies to harvest samples from the ocean, purify and characterize complex natural products quickly and complete chemical reactions and biotransformations in parallel. As a result the vast resources of the ocean can now be utilized routinely to design and produce countless products to be evaluated as part of drug discovery and development programs.

Two new compounds, pulveraven A (1) and pulveraven B (2), as well as vulpinic acid (3) and its previously unreported polymorph were isolated from the fruiting body of Pulveroboletus ravenelii. The structures were determined using a combination of NMR, MS, IR, optical rotation, molecular modeling, and X-ray analysis. The isolates were evaluated for antimicrobial activity as well as their potential to inhibit cyclooxygenase (COX) activity and carcinogen-induced preneoplastic lesion formation with mouse mammary organ culture (MMOC).

In addition to the previously reported (+)-araguspongine A, (+)-araguspongine C, (+)-araguspongine D, (-)-araguspongine E, and (+)-xestospongin B, two new N-oxide araguspongines, (+)-araguspongine K and (+)-araguspongine L, are described here. Their structures were established on the basis of spectral analyses including (1)H-(15)N HMBC. The promising in vitro antimalarial and antituberculosis activities of araguspongine C are reported.

Polar plants and animals survive in subzero waters (-2 degrees C) and many of these marine organisms produce antifreeze proteins (AFPs) to better adapt themselves to these conditions. AFPs prevent the growth of ice crystals which disrupt cellular membranes and destroy cells by inhibiting crystallization of water within the organism. The hydrophilic extract of an Antarctic sponge Homaxinella balfourensis exhibited a non-colligative freezing point depression effect on the crystal morphology of water. The extract was purified by repeated reverse phase high-pressure liquid chromatography, then assayed and shown to contain several AFPs. The major peptide was isolated, analyzed using matrix-assisted laser desorption ionization mass spectrometry and the partial structure of the peptide identified through amino acid sequencing. AFPs have potential applications in agriculture, medicine and the food industry.

Microbial and chemical transformation studies of the marine sesquiterpene phenols (S)-(+)-curcuphenol (1) and (S)-(+)-curcudiol (2), isolated from the Jamaican sponge Didiscus oxeata, were accomplished. Preparative-scale fermentation of 1 with Kluyveromyces marxianus var. lactis (ATCC 2628) has resulted in the isolation of six new metabolites: (S)-(+)-15-hydroxycurcuphenol (3), (S)-(+)-12-hydroxycurcuphenol (4), (S)-(+)-12,15-dihydroxycurcuphenol (5), (S)-(+)-15-hydroxycurcuphenol-12-al (6), (S)-(+)-12-carboxy-10,11-dihydrocurcuphenol (7), and (S)-(+)-12-hydroxy-10,11-dihydrocurcuphenol (8). Fourteen-days incubation of 1 with Aspergillus alliaceus (NRRL 315) afforded the new compounds (S)-(+)-10beta-hydroxycurcudiol (9), (S)-(+)-curcudiol-10-one (10), and (S)-(+)-4-[1-(2-hydroxy-4-methyl)phenyl)]pentanoic acid (11). Rhizopus arrhizus (ATCC 11145) and Rhodotorula glutinus (ATCC 15125) afforded (S)-curcuphenol-1alpha-D-glucopyranoside (12) and (S)-curcudiol-1alpha-D-glucopyranoside (13) when incubated for 6 and 8 days with 1 and 2, respectively. The absolute configuration of C(10) and C(11) of metabolites 7-9 was established by optical rotation computations. Reaction of 1 with NaNO(2) and HCl afforded (S)-(+)-4-nitrocurcuphenol (14) and (S)-(+)-2-nitrocurcuphenol (15) in a 2:1 ratio. Acylation of 1 and 2 with isonicotinoyl chloride afforded the expected esters (S)-(+)-curcuphenol-1-O-isonicotinate (16) and (S)-(+)-curcudiol-1-O-isonicotinate (17), respectively. Curcuphenol (1) shows potent antimicrobial activity against Candida albicans, Cryptococcus neoformans, methicillin-resistant Staphylococcus aureus, and S. aureus with MIC and MFC/MBC ranges of 7.5-25 and 12.5-50 microg/mL, respectively. Compounds 1 and 3 also display in vitro antimalarial activity against Palsmodium falciparium (D6 clone) with MIC values of 3600 and 3800 ng/mL, respectively (selectivity index >1.3). Both compounds were also active against P. falciparium (W2 clone) with MIC values of 1800 (S.I. >2.6) and 2900 (S.I. >1.6) ng/mL, respectively. Compound 14 shows anti-hepatitis B virus activity with an EC(50) of 61 microg/mL.

In addition to several known sterols, a new C(29) marine sterol with a normal ergosterol nucleus but a modified side chain, named 26-nor-25-isopropyl-ergosta-5,7,22E-trien-3beta-ol, was isolated from the Jamaican sponge Agelas sceptrum. The structures were assigned by spectroscopic methods including high-resolution 2D NMR techniques., (Copyright 2002 Elsevier Science Inc.)

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

The title compound, 16-epi-latrunculin B (3), has been isolated from the sponge Negombata magnifica collected from the Red Sea near Hurghada, Egypt. This new natural product was determined to be an epimer of latrunculin B (1), which was found in the same sponge collection. The structure of 3 was initially deduced from proton and carbon NMR chemical shift trends and proton-proton nuclear Overhauser effect experiments. The cytotoxicity (murine tumor and normal cell lines) and antiviral (HSV-1) properties of 3 and 1 were determined. A computational study applicable to this class of stereochemical problems was then investigated. Specifically, the complete set of vicinal and allylic coupling constants was calculated for each of the four diastereomers whose configurations differed at C(8) and C(16). These computed J's were then compared with the experimental J values (28 in number) determined for 1 and 3. This analysis resulted in the same assignment of relative configuration for compound 3 reached using the more classical methods. The validity of the method is established by the fact that the 28 computed coupling constants for (known) 1 and (newly determined) 3 varied from the experimental J values with an average of just 0.57 and 0.53 Hz, respectively. This strategy represents a general, powerful, and readily adoptable tool for determining the relative configuration of complex molecules.

In addition to the sesquiterpene-phenol aureols (1), 6'-chloroaureol (2), and aureol acetate (3), eight indole alkaloids including the new N-3'-ethylaplysinopsin (9) have been isolated from the Jamaican sponge Smenospongia aurea. Makaluvamine O (10), a new member of the pyrroloiminoquinone class, was also isolated. The structures were characterized by spectroscopic methods, and two new derivatives of aureol were prepared to optimize the biological activity. Aureol N,N-dimethyl thiocarbamate (1a) and 6-bromoaplysinopsin (7) exhibit significant antimalarial and antimycobacterial activity in vitro. Compound 6 showed activity against the Plasmodium enzyme plasmepsin II. The 6-bromo-2'-de-N-methylaplysinopsin (6), 6-bromoaplysinopsin (7), and N-3'-ethylaplysinopsin (9) displaced high-affinity [(3)H]antagonist ligands from cloned human serotonin 5-HT(2) receptor subtypes, whereas the other compounds tested did not. Remarkably, the 6-bromo-2'-de-N-methylaplysinopsin (6) showed a > 40-fold selectivity for the 5-HT(2C) subtype over the 5-HT(2A) subtype.

The bioassay- and spectroscopic-guided fractionation of the antimalarial extract from a Jamaican sponge, Plakortis sp., resulted in the isolation of three metabolites. The previously reported bromoaromatic filiformin (1) was obtained from our sample of Plakortis sp., and the potential origins of this compound are discussed. The peroxide-containing metabolite, plakortide F (2), is a more typical Plakortis metabolite and was shown to exhibit significant activity against Plasmodium falciparum in vitro. The isolation, structure, and bioactivity of a new lactone, plakortone G (3), are also reported.

A new norsesterterpene acid, named muqubilone (1), along with the known sigmosceptrellin-B and muqubilin were isolated from the Red Sea sponge Diacarnus erythraeanus. The structure determination of 1 was based primarily on 1D and 2D NMR analyses. Sigmosceptrellin-B exhibits significant in vitro antimalarial activity against Plasmodium falciparum (D6 and W2 clones) with IC(50) values of 1200 and 3400 ng/mL, respectively. Muqubilin and 1 show in vitro antiviral activity against herpes simplex type 1 (HSV-1) with ED(50) values of 7.5 and 30 microg/mL, respectively. Muqubilin and sigmosceptrellin-B display potent in vitro activity against Toxoplasma gondii at a concentration of 0.1 microM without significant toxicity.

The isolation of the new enantiomers of 8-hydroxymanzamine A (1), manzamine F (2), along with the unprecedented manzamine dimer, neo-kauluamine from an undescribed genus of Indo-Pacific sponge (family Petrosiidae, order Haplosclerida) is reported. The relative stereochemistry of neo-kauluamine was established through detailed analysis of NOE-correlations combined with molecular modeling. The significance of the manzamines as in vivo antimalarial agents with superior activity to the clinically used drugs artemisinin and chloroquine is discussed along with the activity in vitro against the AIDS-opportunistic infectious diseases tuberculosis and toxoplasmosis. Reexamination of the sponges identified as Prianos, and Pachypellina, in earlier publications has confirmed that these are members of the same genus as the sponge described here, but differ at the species level.

Microbial transformation studies of the antimelanoma agent betulinic acid (1) were conducted. Screening experiments showed a number of microorganisms capable of biotransforming 1. Three of these cultures, Bacillus megaterium ATCC 14581, Cunninghamella elegans ATCC 9244, and Mucor mucedo UI-4605, were selected for preparative scale transformation. Bioconversion of 1 with resting-cell suspensions of phenobarbital-induced B. megaterium ATCC 14581 resulted in the production of the known betulonic acid (2) and two new metabolites: 3beta,7beta-dihydroxy-lup-20(29)-en-28-oic acid (3) and 3beta,6alpha, 7beta-trihydroxy-lup-20(29)-en-28-oic acid (4). Biotransformation of 1 with growing cultures of C. elegans ATCC 9244 produced one new metabolite characterized as 1beta,3beta, 7beta-trihydroxy-lup-20(29)-en-28-oic acid (5). Incubation of 1 with growing cultures of M. mucedo UI-4605 afforded metabolite 3. Structure elucidation of all metabolites was based on NMR and HRMS analyses. In addition, the antimelanoma activity of metabolites 2-5 was evaluated against two human melanoma cell lines, Mel-1 (lymph node) and Mel-2 (pleural fluid).

Microbial transformation of the antimelanoma agent betulinic acid was studied. The main objective of this study was to utilize microorganisms as in vitro models to predict and prepare potential mammalian metabolites of this compound. Preparative-scale biotransformation with resting-cell suspensions of Bacillus megaterium ATCC 13368 resulted in the production of four metabolites, which were identified as 3-oxo-lup-20(29)-en-28-oic acid, 3-oxo-11alpha-hydroxy-lup-20(29)-en-28-oic acid, 1beta-hydroxy-3-oxo-lup-20(29)-en-28-oic acid, and 3beta,7beta, 15alpha-trihydroxy-lup-20(29)-en-28-oic acid based on nuclear magnetic resonance and high-resolution mass spectral analyses. In addition, the antimelanoma activities of these metabolites were evaluated with two human melanoma cell lines, Mel-1 (lymph node) and Mel-2 (pleural fluid).

Four new caryophyllene derivatives-14-hydroxy-4, 5-dihydro-beta-caryophyllene (1), 14-acetoxy-4, 5-dihydro-beta-caryophyllene (2), 4, 5-dihydro-beta-caryophyllene-14-al (3), and caryophylla-8(14)-en-5-one (4)-are reported from the essential oil of Betula litwinowii. Compounds 1-4 were characterized by MS and 1D and 2D NMR analyses and chemical transformations. The antibacterial and antifungal activity of 1 is also reported.

Manzamine A, a beta-carboline alkaloid present in several marine sponge species, inhibits the growth of the rodent malaria parasite Plasmodium berghei in vivo. More than 90% of the asexual erythrocytic stages of P. berghei were inhibited after a single intraperitoneal injection of manzamine A into infected mice. A remarkable aspect of manzamine A treatment is its ability to prolong the survival of highly parasitemic mice, with 40% recovery 60 days after a single injection. Oral administration of an oil suspension of manzamine A also produced significant reductions in parasitemia. The plasma manzamine A concentration peaked 4 h after injection and remained high even at 48 h. Morphological changes of P. berghei were observed 1 h after treatment of infected mice. (-)-8-Hydroxymanzamine A also displayed antimalarial activity, whereas manzamine F, a ketone analog of manzamine A, did not. Our results suggest that manzamine A and (-)-8-hydroxymanzamine A are promising new antimalarial agents.

A new series of lipids called mololipids have been identified from an Hawaiian sponge of the order Verongida. The structures of these lipids was deduced from spectroscopic data of the lipid mixture combined with GC-MS analysis. The core of this novel series of lipids is a bromotyramine homoserine-derived moiety known as moloka'iamine (1) which is found in many Verongid sponge metabolites. Moloka'iamine forms bisamides with a diverse series of fatty acids and the mololipids mixture (2) was active against HIV-1 with an EC(50) of 52.2 microM without cytotoxicity in human lymphocytes (IC(50) > 100 microM).

Resveratrol (trans-3,4',5-trihydroxystilbene) is produced by grapes (Vitis spp.) in response to microbial attack by the fungal grapevine pathogen Botrytis cinerea. Several reports indicate that pathogenic B.cinerea strains are capable of biotransforming resveratrol into an assortment of unidentified oxidized metabolites as a means of reducing the antifungal effects of resveratrol and facilitating Botrytis invasion into host-plant tissues. Studies utilizing growing incubations of Botrytis cinerea ATCC 11542 with resveratrol resulted in the production of three new (restrytisols A-C) (1-3) and three known (resveratrol trans-dehydrodimer, leachinol F, and pallidol) oxidized resveratrol dimers. All of the metabolites were evaluated for their anti-HIV-1, cytotoxic, and cyclooxygenase (COX) I and COX II inhibitory activities.

The new sesterterpenoid 6-epi-3-anhydroophiobolin B (1) and six known ophiobolins were isolated from the extracts of the fungus Cochliobolus heterostrophus race O. The structure of 6-epi-3-anhydroophiobolin B was deduced from analysis of spectral data and the structural characterization of dehydration and dimerization products. Ophiobolin A (2) showed potent activity in cytotoxicity assays and marginal activity in antimalarial assays.

The marine natural product puupehenone (1), isolated in good yields from sponges of the genus Hyrtios, has been shown to undergo stereospecific 1,6-conjugate addition to its quinone-methide system. Several nucleophilic agents such as hydrogen cyanide, Grignard reagents, and nitroalkanes were studied, producing structurally diverse compounds. This lead optimization study was initiated due to the bioactivity of puupehenone and its natural analogues, which includes numerous previous reports of potential anticancer and antiinfective activity.

Sarcophytol A (1) and B (2) (see Chart 1) are cembrane-type diterpenes known to inhibit tumor promotion. Indicative of this inhibitory response, we currently report sarcophytol A (1) mediates dose-dependent diminution of 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced transformation of JB6 cells. Moreover, a structurally related furanocembrane diterpene, sarcophine (3), isolated in good yield from the Red Sea soft coral Sarcophyton glaucum, was also found to serve as an effective inhibitor of JB6 cell transformation. This compound was subjected to preparative-scale fermentation with Absidia glauca ATCC 22752, Rhizopus arrhizus ATCC 11145, and Rhizopus stolonifer ATCC 24795, resulting in the production of 10 new metabolites (5-14) along with the known compound 7beta,8alpha-dihydroxydeepoxysarcophine (4). Structures were elucidated primarily on the basis of 2D-NMR spectroscopy, with X-ray crystallography being used to establish the relative stereochemistry of metabolite 5. When evaluated for potential to inhibit TPA-induced JB6 cell transformation, several of the metabolites mediated inhibitory responses greater than sarcophytol A (1) or sarcophine (3), most notably 7alpha-hydroxy-Delta(8(19))-deepoxysarcophine (6), which was comparable to 13-cis-retinoic acid. These studies provide a basis for further development of novel furanocembranoids as anticancer agents.