8-SUBSTITUTED O-6-BENZYLGUANINE, SUBSTITUTED 6(4)-(BENZYLOXY)PYRIMIDINE, AND RELATED DERIVATIVES AS INACTIVATORS OF HUMAN O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE

Several 8-substituted O-6-benzylguanines, 2- and/or 8-substituted 6-(b enzyloxy)purines, substituted 6(4)-(benzyloxy)pyrimidines, and a 6-(be nzyloxy)-s-triazine were tested for their ability to inactivate the hu man DNA repair protein, O-6-alkylguanine-DNA alkyltransferase (AGT, al kyltransferase). Two types of compounds were identified as being signi ficantly more-effective than O-6-benzylguanine (the prototype low mole cular weight inactivator) at inactivating AGT in human HT29 colon tumo r cell extracts. These were 8-substituted O-6-benzylguanines bearing e lectron-withdrawing groups at the 8-position (e.g. 8-aza-O-6-benzylgua nine and O-6-benzyl-8-bromoguanine) and 5-substituted 2,4-diamino-6-(b enzyloxy)pyrimidines bearing electron-withdrawing groups at the 5-posi tion (e.g; 2,4-diamino-6-(benzyloxy)-5-nitroso- and 2,4-diamino-(benzy loxy)-5-nitropyrimidine). The latter derivatives were also more effect ive than O-6-benzylguanine at inactivating AGT in intact HT29 colon tu mor cells. Provided these types of purines and pyrimidines do not exhi bit undesirable toxicity, they may be superior to O-6-benzylguanine as chemotherapeutic adjuvants for enhancing the effectiveness of antitum or drugs for which the mechanism of action involves modification of th e O-6-position of DNA guanine residues.