Effect of n3-methyladenine and an isosteric stable analogue on DNA polymerization.

N3-methyladenine (3-mA) is a cytotoxic lesion formed by the reaction of DNA with many methylating agents, including antineoplastic drugs, environmental agents and endogenously generated compounds. The toxicity of 3-mA has been attributed to its ability to block DNA polymerization. Using Me-lex, a compound that selectively and efficiently reacts with DNA to afford 3-mA, we have observed in yeast a mutational hotspot at the 5'-terminus of an A(4) tract.

DNA damage and cytotoxicity induced by minor groove binding methyl sulfonate esters.

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.