Distamycin derivatives as potential anticancer agents.
Distamycin A was used as DNA minor groove sequence-selective vector of alkylating functions and led to the synthesis of compounds endowed with relevant cytotoxic and antitumor activity. In particular, tallimustine (Pharmacia), a benzoic acid nitrogen mustard derivative of distamycin, showed excellent antitumor activity against murine transplanted solid tumors and human xenografts, and, in the early 1990s, prompted several groups to search for new cytotoxic agents derived from distamycin. Unfortunately, tallimustine showed severe myelotoxicity and its clinical development was discontinued. Nevertheless this compound has represented an important model for the design of new cytotoxic minor groove binders derived from distamycin and distamycin-like frames. Some recently reported derivatives of distamycin-like frames with high cytotoxicity and antitumor activity also show significantly improved cytotoxicity/myelotoxicity ratio, which promises drugs with clinical efficacy. Distamycin-derived cytotoxics have been extensively reviewed in the recent past. This review will focus on cytotoxics derived structurally from distamycin or distamycin-like frames disclosed between 1997 and the third quarter of 2000.
Cozzi
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Pharmacia, Global Chemistry, Discovery Research Oncology, Viale Pasteur 10, 20014 Nerviano, Milano, Italy. paolo.cozzi@eu.pnu.com