Structural features of substituted purine derivatives compatible with depletion of human O6-alkylguanine-DNA alkyltransferase.
A series of O6- and S6-substituted purine derivatives were tested for their ability to deplete the human DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) in cell-free extracts from HT29 colon tumor cells and intact HT29 cells. The order of potency was O6-(p-Y-benzyl)-guanine (Y = H, F, Cl, and CH3) > O6-benzyl-2'-deoxyguanosine > O6-(p-Y-benzyl)guanosine (Y = H, Cl, and CH3) > or = a series of 9-substituted O6-benzylguanine derivatives > or = O6-allylguanine > O6-benzylhypoxanthine > O6-methylguanine. A series of 7-substituted O6-benzylguanine derivatives, 2-amino-6-(p-Y-benzylthio)purine (Y = H, CH3), 2-amino-6-[(p-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine, and 7-benzylguanine were inactive. It is concluded that for efficient AGT depletion, an allyl or benzyl group attached through exocyclic oxygen at position 6 of a 2-aminopurine derivative is required. Activity is preserved with a variety of substituent groups attached to position 9 while substitution at position 7 leads to a complete loss of activity.
Moschel
R C
RC
Chemistry of Carcinogenesis Laboratory, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702.
McDougall
M G
MG
Dolan
M E
ME
Stine
L
L
Pegg
A E
AE
D004260:DNA Repair / Q000187:drug effects; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D011687:Purines; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase