8-Substituted O⁶-Benzylguanine, Substituted 6(4)-(Benzyloxy)pyrimidine, and Related Derivatives as Inactivators of Human O⁶-Alkylguanine-DNA Alkyltransfer ase

Several 8-substituted O⁶-benzylguanines, 2- and/or 8-substituted 6-(benzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6-(benzyloxy)-s-triazine were tested for their ability to inactivate the human DNA repair protein, O⁶-alkylguanine-DNA alkyltransferase (AGT, alkyltransferase). Two types of compounds were identified as being significantly more effective than O⁶-benzylguanine (the prototype low molecular weight inactivator) at inactivating AGT in human HT29 colon tumor cell extracts. These were 8-substituted O⁶-benzylguanines bearing electron-withdrawing groups at the 8-position (e.g. 8-aza-O⁶-benzylguanine and O⁶-benzyl-8- bromoguanine) and 5-substituted 2,4-diamino-6-(benzyloxy)pyrimidines bearing electron- withdrawing groups at the 5-position (e.g. 2,4-diamino-6-(benzyloxy)-5-nitroso- and 2,4-diamino- 6-(benzyloxy)-5-nitropyrimidine). The latter derivatives were also more effective than O⁶- benzylguanine at inactivating AGT in intact HT29 colon tumor cells. Provided these types of purines and pyrimidines do not exhibit undesirable toxicity, they may be superior to O⁶-benzylguanine as chemotherapeutic adjuvants for enhancing the effectiveness of antitumor drugs for which the mechanism of action involves modification of the Opposition of DNA guanine residues.