Studies of Extended Quinone Methides. Synthesis and Physical Studies of Purine-like Monofunctional and Bifunctional Imidazoquinazoline Reductive Alkylating Agents

Article abstract of DOI:10.1021/jo00276a022

Described herein are the synthesis, quinone methide reactivity, and electrochemistry of purine-like imidazo<4,5-g>quinazoline reductive alkylating agents possessing a leaving group at the 6α-position.Also described is the synthesis of a dual-alkylating analogue possessing a leaving group at both the 2α- and 6α-positions.The reductive alkylating agent design involves leaving group placement on the 4,9-dione (quinone) derivative of the title ring system so as to permit formation of an alkylating quinone methide species upon reduction to the hydroquinone and elimination of the leaving group.The purine-like structure of these reductive alkylating agents may permit selective inactivation of purine-utilizing enzymes in low reduction potential tumor cells.Comparisons of our finding with those obtained for an analogous reductive alkylation system revealed the following: (i) lowering the quinone reduction potential greatly enhances the rate of leaving group elimination (e.g., a 2300-fold increase in the rate of chloride elimination accompanies a 200-mV potential decrease), and (ii) lower potentials favor electrophile trapping (ketonization) over nucleophile trapping of the quinone methide intermediate.The results of our studies indicate electrochemical studies are valuable in predicting the reactivity pattern of a reductive alkylating agent.