NOVEL DNA-DIRECTED ALKYLATING-AGENTS CONSISTING OF NAPHTHALIMIDE, NITROGEN-MUSTARD AND LEXITROPSIN MOIETIES - SYNTHESIS, DNA-SEQUENCE SPECIFICITY AND BIOLOGICAL EVALUATION

Novel DNA-directed alkylating agents comprising naphthalimide, nitroge n mustard and lexitropsin moieties: have been designed, synthesized an d characterized. Their properties have been evaluate with respect to D NA binding ability, sequence preference, influence of flanking sequenc es an alkylation efficiency and cytotoxic potency against KB human nas opharangeal tumour cells. The results indicate that, in contrast to di stamycin and bis-benzimidazole-bearing nitrogen mustard moieties where DNA alkylation is directed to adenine N3 sites in the minor groove, t he naphthalimide nitrogen mustards alkylate DNA-at accessible guanine N7 sites within the major groove. Structural factors that may affect c ytotoxic efficacy are discussed.