Recognition and cleavage at the DNA major groove

DNA recognition agents based on the indole-based aziridinyl eneimine and th e cyclopent[b]indole methide species were designed and evaluated. The recog nition process involved either selective alkylation or intercalating intera ctions in the major groove. DNA cleavage resulted from phosphate backbone a lkylation (hydrolytic cleavage) and N(7) -alkylation (piperidine cleavage). The formation and fate of the eneimine was studied using enriched C-13 NMR spectra and X-ray crystallography. The aziridinyl eneimine specifically al kylates the N(7) position of DNA resulting in direction of the aziridinyl a lkylating center to either the 3 '- or 5 ' -phosphate of the alkylated base . The eneimine species forms dimers and trimers that appear to recognize DN A at up to three base pairs. The cyclopent[b]indole quinone methide recogni zes the 3 ' -GT-5 ' sequence and alkylates the guanine N(7) and the thymine 6-carbonyl oxygen causing the hydrolytic removal of these bases. In summar y, new classes of DNA recognition agents are described and the utility of C -13-enrichment and C-13 NMR to study DNA alkylation. reactions is illustrat ed. (C) 2001 Elsevier Science Ltd. All rights reserved.