DNA Minor Groove Alkylators

Groove Alkylators

Recent work on a number of different classes of anticancer agents that alkylate DNA in the minor groove is reviewed. Attachment of nitrogen mustards to a variety of carrier molecules (intercalators, polypyrroles, polyimidazoles, bis(benzimidazoles), anilinoquinolinium salts and polybenzamides) can alter their normal patterns of both regio- and sequence-selectivity, from reaction primarily at most guanine N7 sites in the major groove to selected adenine N3 sites at the 3'-end of poly(A/T) sequences in the minor groove. In contrast, similar targeting of pyrrolizidine alkylators by a variety of carriers has little effect on their patterns of alkylation (at the 2-amino group of guanine). Finally, the pyrrolobenzodiazepine and cyclopropaindolone classes of natural products are intrinsic minor groove alkylating agents. Due to their large DNA binding site size, minor groove alkylators are highly sequence-selective, with potential as selective inhibitors of gene expression. However, their direct clinical use is limited by myelotoxicity, and a major new application for the more potent compounds is as effectors for prodrugs.