DNA Minor-Groove Binding Drugs

Since neoplastic transformation is likely related to oncogene activation or alterations in specific genes, there is much interest in the development of drugs capable of specific gene inactivation. In particular, DNA minor-groove binding drugs have been extensively studied to determine their ability to influence the regulation of gene expression. Sequence-selective groove binders have been designed · as carriers of alkylating moieties. Prototypical agents of this class are alkylating derivatives of distamycin. These compounds exhibit a markedly enhanced cytotoxicity over conventional benzoyl N­ mustards and a significant antitumor activity in preclinical evaluation . Cyclopropylpyrroloindole analogs are very potent antitumor agents which interact with minor-groove DNA favoring an alkylation reaction in a sequence-selective manner. In addition, a number of DNA-damaging cytotoxic agents or DNA topoisomerase inhibitors are known to contain minor­ groove binding elements. The identification of. drug structural factors that have a role in promoting DNA recognition during formatiOn of DNA cleavage or covalent modificatwn represents a basis for a rational design of more specific inhibitors. The antitumor efficacy in preclinical evaluation and early clinical studies of sequence-specific minor-groove alkylators is described.