新規エンジイン化合物の活性発現制御と分子設計

烯二炔类抗肿瘤抗生素具有新颖的分子结构、有效的作用方式和较强的DNA切割活性。我们阐明了埃司帕米星A_1、卡利卡米星伽马_1和动力霉素A等烯二炔类抗生素导致DNA链断裂的一些特征。(1)双链断裂方式：特别有趣的是，新卡西宁和C-1027导致两条链中特定位置的两个碱基对断裂。这种新的双链切割方式不同于esperamicin A_1和calicheamicin Gamma_1，后者在两条链上的切割位置之间有三个碱基的分离。(2)序列特异性切割方式：esperamicin A_1和calicheamin Gamma_1在5‘-aggA/TCCT序列上特异性切割。(3)构象选择性链断裂：dynemicin A的切割位点位于凸起、错配或缺口位置附近的核苷酸残基。这一结果证实了动力霉素类抗生素对DNA的裂解具有构象依赖性，这些信息为烯二炔类抗肿瘤抗生素的生物学作用和新的烯二炔类化合物的分子设计提供了有价值的信息。

Enediyne antitumor antibiotics show novel molecular structures, afascinating action mode, and potent DNA cleaving activity. We clarified some characteristics of DNA strand scission by enediyne antibiotics such as esperamicin A_1, calicheamicin gamma_1 and dynemicin A.(1) Double-stranded cleavage fashion : Of special interest is the fact that neocarzinostatin and C-1027 causes strand breaks two base pairs at specific sites in the two strands. This novel double-stranded cleavage fashion is different from that of esperamicin A_1 and calicheamicin gamma_1, which are found to have a three-bpseparation between cleavage sites on the two strands.(2) Sequence-specific cleavage mode : Esperamicin A_1 and calicheamicin gamma_1 cleaved specifically at 5'-AGGA/TCCT sequences.(3) Conformation-selective strand break : The cleavage sites by dynemicin A are observed at nucleotide residues near the bulge, mismatch, or nick sites. The result demonstrates conformation-dependence of DNA cleavage by dynemicin antibiotics.These informations provide valuable implications for biological action of enediyne antitumor antibiotics and for molecular disign of new enediyne compounds.