The Role of a Quinone Methide in the Sequence Specific Alkylation of DNA

• Published in: Journal of the American Chemical Society Vol. 116; no. 5; pp. 1690 - 1697
• Main Authors: Chatterjee, Moneesh, Rokita, Steven E
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.03.1994; Amer Chemical Soc
• Subjects: Analytical, structural and metabolic biochemistry; Biological and medical sciences; Chemistry; Chemistry, Multidisciplinary; Dna, deoxyribonucleoproteins; Fundamental and applied biological sciences. Psychology; Nucleic acids; Physical Sciences; Science & Technology; OLIGONUCLEOTIDE DERIVATIVES; CROSS-LINKING AGENTS; BIOREDUCTIVE ALKYLATION; NAPHTHOQUINONE DERIVATIVES; NUCLEOTIDE RESOLUTION; MITOMYCIN-C; TRIPLE-HELIX FORMATION; SINGLE-STRANDED-DNA; N-BROMOACETYLDISTAMYCIN; ALPHA-OLIGODEOXYNUCLEOTIDES; Alkylating agent; Nucleotide sequence; DNA; Quinone; Alkylation
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja00084a009

Oligonucleotide-naphthoquinone conjugates were prepared and examined for use as inducible, site-directed alkylating agents of DNA. Reaction was found to be sequence specific and under control of either biomimetic reduction or near-UV irradiation. Both conditions induced the formation of a transient and highly electrophilic intermediate consistent with a quinone methide. Enzymatic reduction of 5-((mesyloxy) methyl)- and 5-(bromomethyl) naphthoquinone derivatives produced cross-linking between a target and probe sequence, but the equivalent 5-(acetoxymethyl), 5-(hydroxymethyl) and 5-methyl analogues were predictably inactive. Conversely, irradiation of the 5-methylnaphthoquinone derivative produced cross-linking through a mechanism of photochemical enolization that was not available to the 6-methyl, 3-methyl, or unsubstituted analogues. Hydroxyl radical footprinting of the modified DNA demonstrated that guanine and cytosine were targets of alkylation.