Didemnin B

The majority of promising drug candidates emerging from marine natural products research to date are potential cancer treatments. Six anti-cancer compounds that are either marine natural products or synthetic analogs of marine natural products have made it to clinical trials. The first of these compounds to enter clinical trials was didemnin B (43), one of a family of cyclic depsipetides isolated from the Caribbean tunicate Trididemnum solidum Didemnin B was advanced to Phase II clinical trials for treatment of small cell lung cancer, myeloma, prostate cancer, and melanoma. Unfortunately, no favorable responses were found so the compound has been withdrawn. Crude extracts of another Caribbean tunicate, Ecteinascidia turbinata, showed extremely... 

Larvae of the tunicate Trididemnum solidum are most likely protected by didemnins like 44-46, cyclic depsipeptides that were initially identified from adults of this species [92]. The larvae are highly unpalatable to the wrasse Thalassoma bifasciatum, which rejected the larvae while readily consuming krill eyes that served as larval mimics. Coating one krill eye with the lipid soluble compounds from a single T. solidum larva rendered it as unpalatable as the larvae themselves. Reduced feeding was also observed when didemnin B (45) and nor-didemnin B (46) were administered to reef fishes in the field (Scheme 12) [92]. 

Considerable effort has gone into investigating compounds from tunicates over the past two decades. For unknown reasons these chemicals are often potent antiviral agents, whereas clinicians have few drugs active against viruses. Didemnin B was the first of these candidate compounds to be examined and initially it showed promise against a broad spectrum of viruses. After lengthy clinical trials, however, it was finally abandoned as too toxic for safe human use. 

Reef fishes Thalassoma Caribbean ascidian Macrolides didemnin B and Lindquist eta/.. 

Johnson KL, Vaillant F, Lawen A. 1996. Protein tyrosine kinase inhibitors prevent didemnin B-induced apoptosis in HL-60 cells. FEBS Lett 383 1-5. 

Didemnin B (347) is a cyclic depsipeptide isolated from the Caribbean tunicate Trididemnum solidum and is currently in phase II clinical trials as an anticancer agent. Didemnin B also shows antiviral and immunosuppressive activity. The structure of didemnin B was revised to 347 containing... 

The Caribbean tunicate Trididemnum solidum and its larvae contain a complex mixture of didemnin/ nordidemnin metabolites that act as feeding deterrents in field-based assays at below natural concentrations. The most potent metabolite is nordidemnin B 147.28 Crude extract mixtures enriched in didemnin B 148 induce vomiting in the spotted pinfish L. rhomboides, causing these fish to avoid feeding.173 The larvae of other didemnid ascidians are also protected by the presence of deterrent chemicals.28 174... 

Diazonamide A 46 (Scheme 6.4) is toxic to human colon HCT-116 cancer cells at 15 ng/mL. Other structures include cyclic peptides such as didemnin B 47 which has been discontinued in Phase II clinical trials, aplidin 48 which is currently in Phase II clinical studies for multiple myeloma and vitilevuamide 50 which effects tubulin polymerisation at micromolar concentrations. One of the... 

Bugula neritina) and related organisms produce substances with antibacterial, antitumor (e.g. bryostatins, didemnin B, dolastatin, girodazol, halichondrin B), anti-inflammatory (e.g. pseudopterosin E, manoalide derivatives), antifungal, antiviral, or immuno-suppressive (e.g. microcolin A and B) activity [399,400]. These compounds and/or their synthetic derivatives may be important novel bioactive pharmaceutical substances. It is also very Hkely that some new natural marine substances or their derivatives can be used as antifouling compounds, insecticides, or fungicides. 

It has been amply demonstrated that ascidians are prolific producers of novel bioactive secondary metabolites [64-66]. A significant number of ascidian-derived compounds have entered into preclinical trials as antitumor agents [67]. Examples include didemnin B (went through phase... 

Fig. 7. Clinical candidates from plants and marine environment Huperzine A, didemnin B, bryostatin 1, and ecteinascidin 743.

The sea covers almost three-quarters of the earth s surface and contains a broader genetic variation among species relative to the terrestrial environment (155,158).Althoughanum-ber of important molecules have been derived from marine sources, including arabinosyl nucleotides, didemnin B, and bryostatin 1, there has been an inadequate focus on this potentially chemically productive biosphere. Sea snails, often called "nature s combinatorial chemistry factories," produce a bewildering array of novel conotoxins active at mamma-... 

Although historically most useful antibiotics have come from spore forming microorganisms, marine organisms have yielded the candidate antitumor peptide didemnin B [77327-50-0] (2) and cytostatic peptides such as the patellamides (3). Many of the marine peptides have little or no antimicrobial activity. Antibacterial peptides called magainins are found in frog skin (4) and antibacterial proteins called defensins are found in mammalian white blood cells (5). The commercially important insecticidal proteins from Bacillus thuringensis (6) are not discussed herein nor are the numerous peptide siderophores (7,8), which, except for the albomycins (9), are usually not antimicrobial. 

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