Didemnin

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 Unfortunately, no favorable responses were found so the compound has been withdrawn.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... 

F.18 In 1978, scientists extracted a compound with antitumor and antiviral properties from marine animals in the Caribbean Sea. A sample of the compound didemnin-A of mass 1.78 mg was analyzed and found to have the following composition ... 

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]. 

Scheme 12 Didemnins from the tunicate Trididemnum solidum...

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/.. 

Rinehart, K.L., Jr. Kishore, V. Bible, K.C. Sakai, R. Sullins, D. Li, K.-M. (1988) Didemnins and tunichlorin novel natural products from the marine tunicate Trididemnum solidum. J. Nat. Prod., 57,1-21. 

Cyclosporin (Section 16.1.3) is an undecapeptide that acts as a potent immunosuppressant. Seven of its eleven residues are N-methylated. Its synthesis in solution was carried out by a series of segment condensations)32,33 The didemnins (Section 16.1.4) are isolated from marine organisms known as tunicates. Their therapeutic potential lies in applications as antitumor, antiviral, and immunosuppressant agents. The didemnin family of natural products contains peptidomimetic residues including A,0-dimethyltyrosine-proline and leucine—2-(hydroxyisovaleryl)propionic acid and (4-hydroxy)-2,5-dimethyl-3-oxo-... 

The synthesis of didemnin A (60) consists of four main elements (1) construction of the Hyvpa-isostatine unit 52 (Scheme 9), (2) synthesis of the tetrapeptide unit, Z-Leu-Pro-(Me)Tyr(Me)-0-Boc-Thr-OH (57, Scheme 10), (3) synthesis of the macrocycle, and (4) addition of the A-methyl-D-leucine unit to form didemnin A (60, Scheme 11). 

The final step, incorporation of ALmethyl-D-leutine, can be carried out as follows. D-Leucine was protected as its benzyloxycarbonyl derivative, and methylation was carried out by the phase-transfer method described above for tyrosine. BOP-promoted coupling between Z,Me-D-Leu-OH and the macrocycle, followed by deprotection, gives didemnin A (60). 

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