Analogues of the cytostatic cyclic tetrapeptide chlamydocin. Synthesis of N beta-(N-maleoylglycyl) and N beta-(tert-butyloxycarbonyl) derivatives of cyclo(Gly-L-Phe-D-Pro-L-Dap).
The synthesis of analogues of the cytostatic cyclic tetrapeptide chlamydocin is described. cyclo(Gly-L-Phe-D-Pro-N beta-Boc-L-Dap) (4) was prepared from N beta-(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 degrees 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-N beta-(N-maleoylglycyl)-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 (6 nM).
D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D010835:Phytohemagglutinins / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D010456:Peptides, Cyclic; D010835:Phytohemagglutinins; C006963:chlamydocin; C030467:cyclo(glycyl-phenylalanyl-prolyl-N(beta)-(N-maleoylglycyl)-alpha,beta-diaminopropanoyl); C030466:cyclo(glycyl-phenylalanyl-prolyl-N-(beta)-(tert-butoxycarbonyl)-alpha,beta-diaminopropanyoly); D004247:DNA; D013936:Thymidine