DNA Damage and Cytotoxicity Induced by Minor Groove Binding Methyl Sulfonate Esters

Sridhar Varadarajan, Dharini Shah, Prasad Dande, Samuel Settles, Fa Xian Chen, Gilberto Fronza, Barry Gold

Research output: Contribution to journalArticlepeer-review


Minor groove specific DNA equilibrium binding peptides (lex) based on N-methylpyrrole-carboxamide and/or N-methylimidazolecarboxamide subunits have been modified with an O-methyl sulfonate ester functionality to target DNA methylation in the minor groove at Ade/Thy- and/or Gua/ Cyt-rich sequences. HPLC and sequencing gel analyses show that the Me-lex compounds all selectively react with DNA to afford N3-alkyladenine as a major adduct. The formation of the N3-alkyladenine lesions is sequence-dependent based on the equilibrium binding preferences of the different lex peptides. In addition to the reaction at adenine, the molecules designed to target Gua/Cyt sequences also generate lesions at guanine; however, the methylation is not sequence dependent and takes places in the major groove at the N7-position. To determine if and how the level of the different DNA adducts and the sequence selectivity for their formation affects cytotoxicity, the Me-lex analogues were tested in wild type Escherichia coli and in mutant strains defective in base excision repair (tag and/or alkA or apn). The results demonstrate the importance of 3-methyladenine, and in some cases 3-methylguanine, lesions in cellular toxicity, and the dominant protective role of the DNA glycosylases. There is no evidence that the sequence specificity is related to toxicity.

Original languageEnglish
Pages (from-to)14318-14327
Number of pages10
Issue number48
Publication statusPublished - Dec 9 2003

ASJC Scopus subject areas

  • Biochemistry


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