title: Recognition and cleavage at the DNA major groove.
abstract: DNA recognition agents based on the indole-based aziridinyl eneimine and the cyclopent[b]indole methide species were designed and evaluated. The recognition process involved either selective alkylation or intercalating interactions in the major groove. DNA cleavage resulted from phosphate backbone alkylation (hydrolytic cleavage) and N(7) -alkylation (piperidine cleavage). The formation and fate of the eneimine was studied using enriched 13C NMR spectra and X-ray crystallography. The aziridinyl eneimine specifically alkylates the N(7) position of DNA resulting in direction of the aziridinyl alkylating center to either the 3'- or 5'-phosphate of the alkylated base. The eneimine species forms dimers and trimers that appear to recognize DNA at up to three base pairs. The cyclopent[b]indole quinone methide recognizes 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 summary, new classes of DNA recognition agents are described and the utility of 13C-enrichment and 13C NMR to study DNA alkylation reactions is illustrated.
authors.affiliation: Department of Chemistry and Biochemistry, Arizona State University, Tempe, AZ 85287-1604, USA. eskibo@asu.edu
authors.forename: E B
authors.initials: EB
authors.lastname: Skibo
authors.forename: C
authors.initials: C
authors.lastname: Xing
authors.forename: T
authors.initials: T
authors.lastname: Groy
mesh_terms: D000477:Alkylating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000478:Alkylation; D004247:DNA / Q000378:metabolism* / Q000648:ultrastructure; D004591:Electrophoresis, Polyacrylamide Gel; D006868:Hydrolysis / Q000187:drug effects; D045563:Indolequinones; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D011809:Quinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000477:Alkylating Agents; D045563:Indolequinones; D007211:Indoles; D011809:Quinones; C068040:quinone methide; D004247:DNA