Rational design of reductive alkylating agents directed toward purine nucleoside phosphorylase and inosine 5'-monophosphate dehydrogenase.

摘要

The synthesis of novel reductive alkylating agents based on the quinazoline and imidazo (4,5-g) quinazoline ring systems was carried out in conjunction with the design of irreversible inhibitors directed toward human erythrocyte purine nucleoside phosphorylase (PNPase) and inosine 5;Also described herein is the elucidation of a novel acid-catalyzed mechanism for dehydrohalogenation. Elucidation of this mechanism was useful in the design of a novel nucleophile trapping moiety for use in PNPase active site alkylation.;The regioselective synthesis of 6-(chloromethyl)-3-ribofuranosylimidazo- (4,5-g) quinazoline-4,8,9(3H,7H)-trione (80) was carried out in conjunction with the design of a reductive alkylating agent directed toward IMP dehydrogenase. The preparation of 80 was carried out by regioselective ribosylation of 4-nitro-imidazo (4,5-g) -quinazolin-8(3H,7H)-one (77) followed by nitro group reduction, Fremy oxidation, and deacetylation. Regiocontrol of ribosylation has steric origins: the 4-nitro group of 77 directs silylation to the N(1)-position, which results in ribosylation exclusively at the N(3)-position under Vorbruggen reaction conditions.