γ-Linked Dipeptide Analogues of 2-Desamino-2-Methyl-N¹⁰-Propargyl-5,8-Dideazafolate as Antitumour Agents

Abstract

Quinazoline analogues of folic acid have been developed successfully as thymidylate synthase (TS) inhibitors which possess clinical activity. CB3717 (N¹⁰-propargyl-5,8-dideazafolic acid), the first of these agents to receive clinical study, was withdrawn because of nephrotoxicity¹. The more water-soluble (and consequently nonnephrotoxic) analogue (ICI D1694) is currently in Phase II clinical study worldwide. ICI D1694 is more potent as an in vitro and in vivo antitumour agent than CB3717 because of its cellular pharmacology^2,3. ICI D1694 is actively transported into cells via the reduced-folate/MTX cell membrane carrier (RFC) where it is immediately polyglutamated by the enzyme, folylpolyglutamate synthetase (FPGS). CE3717 either uses this carrier poorly or not at all and therefore enters cells slowly. This, together with poorer substrate activity for FPGS, results in relatively slow formation of polyglutamates. Polyglutamation of quinazoline TS inhibitors has three important consequences: it allows accumulation of drug inside the cell, substantially reduces drug efflux and, because polyglutamates are more potent TS inhibitors than the parent drug, results in improved TS inhibition.