Robert O. Dempcy

Rational design of purine nucleoside phosphorylase inhibitors: Design of 2-(2′-Haloethyl) and 2-ethenyl substituted quinazolinone alkylating agents.

Abstract The synthesis, elimination/addition mechanism, and purine nucleoside phosphorylase inhibitory properties of 2-(2′-bromoethyl) and 2-ethenyl substituted quinazolinone-based quinones are described herein. Both 2-substituted quinazolinone derivatives were designed to act as reductive alkylating agents of glutamate residues in the purine nucleoside phosphorylase active site. Mechanistic studies provided evidence of a novel alkylation process involving a quinazolinone prototropic tautomer. The tautomer is the result of a prototropic shift of the C(1′) proton of the 2-alkyl group to the N(1) position of the quinazolinone ring. Both 2-substituted quinazolinones rapidly and irreversibly inactivate purine nucleoside phosphorylase.