SYNTHESIS OF ACTINOMYCIN ANALOGUES——Ⅳ. SYNTHESIS OF 2-AMINO-4, 6-DIMETHYLPHENOXAZONE-(3)-1, 9-BIS-PEPTIDES

In previous papers, we have reported the synthesis of several analogues of actinomycin, among which the bis-dipeptide (Ib) exhibited inhibitory action against sarcoma 180 in mice. On the basis of the concept that the antitumour action of the actinomycin may arise from the chromophore group and peptide moiety functions as a carrier, we have synthesized seven peptide analogues (2～8) of actinomycin.The synthetic scheme is shown in figure 1. The starting material for all the compounds prepared was 2-nitro-3-benzyloxy-4-methylbenzoyl chloride (10). Treatment of DL-serine with benzoyl chloride (10) afforded the compound (11), which was coupled with ethyl glycyl-glycinate under the action of DCCI in dioxane to give tripeptide ester (12), Hydrazinolysis of (12) gave N-(2-nitro-3-benzyloxy-4-methylbezoyl)-serinyl-glycyl-glycyl hydrazide (15) The azide generated from (15) was coupled with ethyl glycylglycinate to give the pentapeptide (16) which was reduced and oxidatively dimerized to yield (7). Similarly, the other bistetrapeptide and pentapeptide were all prepared via intermadiate (11).