Elucidation of structure of antitumor antibiotic kapurimycin A3 and reactivity toward DNA

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Antitumor antibiotic kapurimycin A3, having a structure closely related to pluramycin family, alkylates DNA by the attack of the epoxide subunit on the guanine N7 to result in a formation of kapurimycin-DNA adduct. In order to know the factors responsible for such highly efficient and selective guanine alkylation, we have synthesized a series of truncated kapurimycin analogs as well as their epoxy alcohol and diol derivatives. DNA-cleaving activity examined by plasmid relaxation assay indicated that the ABC ring analog efficiently alkylates DNA,while the corresponding AB ring analog showed only a very weak DNA-cleaving activity. DNA cleavage experiments using ^<32>P-5'-end-labeled DNA fragment indicated that the sequence selectivity including 5'-side selectivity for 5'-GG-sequence was indistinguishable for kapurimycin A_3 and its ABC ring analog. We concluded that the ABC ring analog has a minimal structural unit for kapurimaycin A_3 to achieve effective and sequence specific guanine alkylation.