Of didemnin

F.14 In 1978, scientists extracted a compound with antitumor and antiviral properties from marine animals in the Caribbean Sea. A 2.52-mg sample of the compound, didemnin-C, was analyzed and found to have the following composition 1.55 mg C, 0.204 mg H, 0.209 mg N, and 0.557 mg O. The molar mass of didemnin-C was found to be 1014 g-mol-1. What is its molecular formula ... 

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). 

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... 

Magnesium or lithium enolates of thiol carboxylic esters can be acylated with suitable reagents (c/ Volume 2, Part 1). Highly functionalized new derivatives are obtained. The example shown in equation (35)33,102 J5 closely related to the C-acylation of malonyl-CoA with acetyl-CoA, which plays an important role in the biosynthesis of polypeptides and fatty acids. (S)-4-Hydroxy-5-methyl-3-oxo-hexanoyl-L-leucine esters (41), 2-demethyl analogs of the Hip-Leu moiety of didemnin antibiotics, can be prepared via the 3-keto thiol carboxylic esters (40 equation 36). ° ... 

A quite different method converted the amino moiety of isoleucine to an hydroxyl group (see 6.204). Conversion to the azide, reduction to the amine and condensation of the ester with lithio methyl (2-trimethylsilyloxycarboxy) acetate gave 6.205. Sodium borohydride reduction gave 6.206, along with 9% of 5.207. Hydrolysis and re-protection of 6.206 gave N-Boc isostatine, 6.208. In this work, it was noted that amino acid 6.208 is a component of didemnin cyclodipeptide. 

The conformation of the cyclic part of didemnin B, as determined by X-ray analysis, is that of a twisted eight, similar to that of certain cyclic peptides of Lissoclinum (see above and Hossain et al, 1988 Kessler et al, 1990 Wipf, 1995 Ramanjulu and Joullie, 1996). 

Hochster, H., Oratz, R., Ettinger, D.S., and Borden, E. (1999) A phase 11 study of didemnin B (NSC 325319) in advanced malignant melanoma an Eastern Cooperative Oncology Group study (PB687). Invest. New Drugs, 16, 259-263. 

Jiang, T.L., Liu, R.H., and Salmon, S.E. (1983) Antitumor activity of didemnin B in the human tumor stem cell assay Cancer Chemother. Pharmacol., 11, l-i. 

Jouin, P., Poncet, J., Dufour, M.-N., Aumelas, A., and Pantaloni, A. (1991) Antineoplastic activity of didemnin congeners nordidemnin and modified chain analogues. J. Med. Chem., 34,486-491. 

Malfetano, J.H., Blessing, JA., and Jacobs, A.]. (1993) A phase II trial of didemnin B (NSC 335319) in patients with previously treated epithelial ovarian cancer. Am.]. Clin. Oncd., 16, 47—49. 

Mittelman, A Chim, H,G Pucdo, C., Coombe, N., Lansen, T and Ahmed, T, (1999) Phase II clinical trial of didemnin B in patients with recurrent or refractory anaplastic astrocytoma or glioblastoma multiforme (NSC 325319), Invest. Neiv Drugs, 17,179-182. 

Motzer, R., Scher, H., Bajorin, D., Sternberg, C., and Bosl, G.(. (1990) Phase II trial of didemnin B in patients with advanced renal ceU carcinoma. Invest. New Drugs, 8, 391-392. 

Shen, G.K., Zukoski, C.F., and Montgomery, D.W. (1992) A specific binding site in Nb2 node lymphoma cells mediates the effects of didemnin B, an immunosuppressive cyclic peptide. 7nt. J. Immunopharm., 14, 63-73. 

Shin, D.M., Holoye, P.Y., Murphy, W.K., Forman, A., Papasozomenos, S.C., Hong, W.K., and Raber, M.N. (1991) Phase 1/11 clinical trial of didemnin B in non-small-cell lung cancer neuro-muscular toxicity is dose-limiting. Cancer Chemother. Pharmacol., 29,145-149. 

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