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) ≥ a series of 9-substituted O⁶-benzylguanine derivatives ≥ O⁶-allylguanine > (y-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-nitrobenzyI)thio]-9-β-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 substitution at position 7 leads to a complete.