新規エンジイン化合物の活性発現制御と分子設計

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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.