Synthesis of some 8-Aza-7-deazaguanines as potential inactivators of Atase

Abstract

Certain cancer chemotherapeutic agents act by alkylating the O6-position of guanine residues in DNA. This lesion can ultimately cause the death of the targeted cancer cells. However, the efficacy of the cytotoxic effect of these alkylating agents may be greatly reduced by the action of the ubiquitous repair protein, ATase (06 - alkylguanine-DNA alkyltransferase). ATase transfers the damaging alkyl group from the alkylated guanine to one of its cysteine residues in an autoinactivating reaction. Pretreatment with a pseudosubstrate of ATase prior to the administration of the alkylating agent would knock out the ATase and can improve the cytotoxic effect of the chemotherapy.