Hypoxia-selective O~6-alkylguanine-DNA alkyltransferase inhibitors: Design, synthesis, and evaluation of 6-(benzyloxy)-2-(aryldiazenyl)- 9H -purines as prodrugs of O~6-benzylguanine

摘要

O6-Alkylguanine-DNA alkyltransferase (AGT) is a DNA repair protein which removes alkyl groups from the O-6 position of guanine, thereby providing strong resistance to anticancer agents which alkylate this position. The clinical usefulness of these anticancer agents would be substantially augmented if AGT could be selectively inhibited in tumor tissue, without a corresponding depletion in normal tissue. We report the synthesis of a new AGT inhibitor (5c) which selectively depletes AGT in hypoxic tumor cells.