Analogues of the Cytostatic Cyclic Tetrapeptide Chlamydocin. Synthesis of Nβ-(N-Maleoylglycyl) and Nβ-(tert-Butyloxycarbonyl) Derivatives of cyclo (Gly-L-Phe-D-Pro-L-Dap)

Daniel H. Rich, Ronald D. Jasensky, Gerald C. Mueller, Kristin E. Anderson

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Abstract

The synthesis of analogues of the cytostatic cyclic tetrapeptide chlamydocin is described. cyclo(Gly-L-Phe-DPro-Nβ-Boc-L-Dap) (4) was prepared from Nβ-(tert-butyloxycarbonyl)-L-diaminopropionic acid methyl ester (Dap) and Cbz-Gly-L-Phe-D-Pro using DCC/HOBt as the coupling reagent. The methyl ester was saponified to the acid, which was converted to the 2,4,5-trichlorophenyl (Tcp) ester by reaction with trichlorophenol and DCC. The N-(benzyloxycarbonyl) group was removed by hydrogenolysis and the amine active ester cyclized at 95 °C in pyridine. The Boc-protected cyclic tetrapeptide 4 was isolated in 14% yield. Cyclic tetrapeptide 4 was converted to cyclo- [Gly-L-Phe-D-Pro-M-CN-maleoylglycyll-L-Dap] (5) to test for a possible sulfhydryl group at the chlamydocin receptor. Removal of the tert-butyloxycarbonyl group, followed by reaction with N-maleoylglycine and DCC/HOBt in methylene chloride, gave cyclic tetrapeptide 5 in 68% yield. The maleoyl cyclic tetrapeptide 5 did not inhibit [3H]thymidine incorporation into calf thymus lymphocytes at concentrations 1000-fold higher than the IC50 for chlamydocin (6nM).

Original languageEnglish (US)
Pages (from-to)567-572
Number of pages6
JournalJournal of medicinal chemistry
Volume24
Issue number5
DOIs
StatePublished - May 1981

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