Highly efficient DNA interstrand crosslinking induced by an antitumor antibiotic, carzinophilin

The alkylation of d(TAGCTA)2 by an antitumor antibiotic, carzinophilin, and its 4-methyl derivative was investigated. It was found that both carzinophilin (1a) and 4-O-methylcarzinophilin (1b) react with d(TAGCTA)2 to provide the corresponding monoadducts and the interstrand crosslinked adducts. Heating the crosslinked adduct of Ib provided a stable base adduct which consists of a 1:1:1 ratio of adenine, guanine and 4-O-methylcarzinophilin. The structure of the base adduct was consistent with double crosslinks between guanine and the epoxide moiety and between adenine and the aziridine moiety. HPLC analysis indicates that the first alkylation occurs at the aziridine moiety with adenine N7 and the second crosslinking proceeds highly efficiently between the epoxide moiety and guanine N7. (C) 1998 Elsevier Science Ltd. All rights reserved.