放线菌素类似物的合成Ⅳ——2-氨基-4,6-二甲基吩(口恶)嗪酮-(3)-1,9-双多肽的合成

放线菌素是一类具有良好抗肿瘤作用而有较大毒性的抗菌素。作者等推测放线菌素的抗癌作用与其共有的色基结构有较为密切的关系,而环肽部分可能起一种载体作用。基于上述设想,我们曾合成了一系列有关化合物试验其抗肿瘤作用。其中发现放线菌素色基与叶酸的二肽部分结合的化合物具有明显的抗肿瘤作用。本文继续报道将放线菌素的环肽部分调换为简单的二肽、三肽或五肽的化合物;用丝氨酸代替苏氨酸,用甘氨酸和N-甲基甘氨酸代替其他氨基酸。共合成了七个化合物(2～8)。

Synthesis of actinomycin analogues. IV. Synthesis of 2-amino-4, 6-dimethylphe-noxazone-(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).