Biomedical subjects
Publications and source records attributed to D J Faulkner.
A specimen of the ascidian Aplidium uouo from Maui contained two piperidine alkaloids, uoamines A and B, that differed only in the geometry of a 3-thiomethylacrylate ester group. The alkaloids exhibit conformational mobility in the NMR time frame, which complicated the elucidation of their structures by interpretation of spectroscopic data.
[structure--see text] Bioassay-guided fractionation of extracts of the Palauan ascidian Didemnum guttatum led to the isolation of cyclodidemniserinol trisulfate (1) as an inhibitor of HIV-1 integrase, which is an attractive target for anti-retroviral chemotherapy. The structure of cyclodidemniserinol trisulfate (1), the stereochemistry of which was only partially determined, was elucidated by interpretation of NMR and mass spectral data.
A collection of Lyngbya majuscula from Palau contained the peptides dolastatin 3 (1), homodolastatin 3 (2), and kororamide (3), together with aplysiatoxin (4), debromoaplysiatoxin (5), and oscillatoxin A (6). The structures of the new peptides homodolastatin 3 (2) and kororamide (3) were determined by interpretation of spectroscopic data and chemical degradation.
A new 4-methylene sterol, 7alpha-hydroxytheonellasterol (3), was isolated from the Philippines sponge Theonella swinhoei, along with the known compounds theonellasterol (1) and bistheonellide A. The structure of 3 was elucidated by interpretation of its spectroscopic data, which were compared with those of 1.
Marine organisms have provided a large proportion of the bioactive natural products reported over the last 20 years, but none of these compounds have reached the pharmaceutical marketplace. This review describes current progress in the development of a selection of new antiinflammatory and anticancer agents, discusses some difficulties encountered during the development process and suggests how these difficulties may be overcome in the near future through applications of recent advances in biotechnology.
Explore the source record for details and available documents.
Marine Natural Products Chemistry is essentially a child of the 1970's that developed rapidly during the 1980's and matured in the last decade. With a few notable exceptions, it is difficult to select individual papers that significantly impacted the field. However, marine natural products chemistry has often influenced other fields and that aspect is the focus of this review. It is clear that the early directions taken by marine natural products chemists drew as much from the examples provided by insect chemical ecology as from the longer history of phytochemistry. By 1975 there were already three parallel tracks in marine natural products chemistry: marine toxins, marine biomedicinals and marine chemical ecology. It is the integration of the three fields of study that has given marine natural products chemistry its unique character and vigour.
We have shown previously that the betagamma subunits of the heterotrimeric G proteins regulate the organization of the pericentriolarly localized Golgi stacks. In this report, evidence is presented that the downstream target of Gbetagamma is protein kinase D (PKD), an isoform of protein kinase C. PKD, unlike other members of this class of serine/threonine kinases, contains a pleckstrin homology (PH) domain. Our results demonstrate that Gbetagamma directly activates PKD by interacting with its PH domain. Inhibition of PKD activity through the use of pharmacological agents, synthetic peptide substrates, and, more specifically, the PH domain of PKD prevents Gbetagamma-mediated Golgi breakdown. Our findings suggest a possible mechanism by which the direct interaction of Gbetagamma with PKD regulates the dynamics of Golgi membranes and protein secretion.
HIV-1 integrase is an attractive target for anti-retroviral chemotherapy, but to date no clinically useful inhibitors have been developed. We have screened diverse marine natural products for compounds active against integrase in vitro and found a series of ascidian alkaloids, the lamellarins, that show selective inhibition. A new member of the family named lamellarin alpha 20-sulfate (1), the structure of which was determined from spectroscopic data, displayed the most favorable therapeutic index. The site of action of lamellarin alpha 20-sulfate on the integrase protein was mapped by testing activity against deletion mutants of integrase. Inhibition of isolated catalytic domain was detectable though weaker than inhibition of full length integrase; possibly lamellarin alpha 20-sulfate binds a site composed of multiple integrase domains. Lamellarin alpha 20-sulfate also inhibited integration in vitro by authentic HIV-1 replication intermediates isolated from infected cells. Lamellarin alpha 20-sulfate was tested against wild type HIV using the MAGI indicator cell assay and found to inhibit early steps of HIV replication. To clarify the inhibitor target, we tested inhibition against an HIV-based retroviral vector bearing a different viral envelope. Inhibition was observed, indicating that the HIV envelope cannot be the sole target of lamellarin alpha 20-sulfate in cell culture. In addition, these single round tests rule out action against viral assembly or budding. These findings provide a new class of compounds for potential development of clinically useful integrase inhibitors.
A specimen of Plakortis lita from Palau yielded the new carboxylic acids, homo-plakotenin (2a), the sodium salt of homo-plakotenin (2b), the sodium salt of nor-plakotenin (3), the sodium salt of plakotenin (1b), and the known compound plakotenin (1a). The structures of the new acids were elucidated by interpretation of spectral data and by comparison with the known compound. Compounds 1a, 1b, and 2a were found to significantly reduce proliferation of rheumatoid synovial fibroblasts.
Marine invertebrates are sources of a diverse array of bioactive metabolites with great potential for development as drugs and research tools. In many cases, microorganisms are known or suspected to be the biosynthetic source of marine invertebrate natural products. The application of molecular microbiology to the study of these relationships will contribute to basic biological knowledge and facilitate biotechnological development of these valuable resources. The bryostatin-producing bryozoan B. neritina and its specific symbiont "Candidatus Endobugula sertula" constitute one promising model system. Another fertile subject for investigation is the listhistid sponges that contain numerous bioactive metabolites, some of which originate from bacterial symbionts.
Members of the kinesin superfamily of motor proteins are essential for mitotic and meiotic spindle organization, chromosome segregation, organelle and vesicle transport, and many other processes that require microtubule-based transport. A compound, adociasulfate-2, was isolated from a marine sponge, Haliclona (also known as Adocia) species, that inhibited kinesin activity by targeting its motor domain and mimicking the activity of the microtubule. Thus, the kinesin-microtubule interaction site could be a useful target for small molecule modulators, and adociasulfate-2 should serve as an archetype for specific inhibitors of kinesin functions.
A specimen of Dysidea sp. from Palau contained three new dolabellane diterpenes 1-3 and an unstable 14-membered macrolide, arenolide (4), which showed modest cytotoxicity. From a chemotaxonomic viewpoint, these metabolites are so unusual that we discuss their possible origin.
Three new cyclic peroxides 5-7 and a new carboxylic acid ester 8 were isolated as minor metabolites from the hexane extract of a Plakinastrella species from the Philippines. The structures of compounds 5-8 were elucidated by interpretation of spectral data and by chemical interconversion, and the absolute stereochemistry of peroxide 6 was determined by application of Mosher's method to a derivative. Although the major compounds in the sponge showed activity against Candida albicans prior to decomposition, the minor metabolites 5-8 are essentially inactive.
We have previously shown that ilimaquinone (IQ), a marine sponge metabolite, causes complete vesiculation of the Golgi stacks. By reconstituting the IQ-mediated vesiculation of the Golgi apparatus in permeabilized cells, we now demonstrate that this process does not require ARF and coatomers, which are necessary for the formation of Golgi-derived COPI vesicles. We find that IQ-mediated Golgi vesiculation is inhibited by G alpha(s)-GDP and G alpha(i3)-GDP. Interestingly, adding betagamma subunits in the absence of IQ is sufficient to vesiculate Golgi stacks. Our findings reveal that IQ-mediated Golgi vesiculation occurs through activation of heterotrimeric G proteins and that it is the free betagamma, and not the activated alpha subunit, that triggers Golgi vesiculation.
The Palauan sponge Luffariella sp. contained manoalide (6) and secomanoalide (7) as the major metabolites. The minor metabolites, luffasterols A-C (3-5) are 9,11-secosterols that contain a 3 beta-acetoxy-5 alpha,6 alpha-epoxy-9-oxo-9,11-secocholest-7-en-11-al ring system joined to three different side chains. The structures of the luffasterols were elucidated by interpretation of spectroscopic data.