8-Substituted O6-benzylguanine, substituted 6(4)-(benzyloxy)pyrimidine, and related derivatives as inactivators of human O6-alkylguanine-DNA alkyltransferase.
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 O6-position of DNA guanine residues.
Chae
M Y
MY
Chemistry of Carcinogenesis Laboratory, Maryland 21702.
Swenn
K
K
Kanugula
S
S
Dolan
M E
ME
Pegg
A E
AE
Moschel
R C
RC
D002478:Cells, Cultured; D004260:DNA Repair; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D006801:Humans; D066298:In Vitro Techniques; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D011743:Pyrimidines; D006147:Guanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase