Quinazoline Antifolate Thymidylate Synthase Inhibitors: Heterocyclic Benzoyl Ring Modifications

Article abstract of DOI:10.1021/jm00109a011

The synthesis is described of a series of C²-methyl-N¹⁰-alkylquinazoline-based antifolates in which the p-aminobenzoate ring is replaced by the heterocycles thiophene, thiazole, thiadiazole, pyridine, and pyrimidine.These were generally elaborated by the reaction of (bromomethyl)quinazoline 18 or its N³-<(pivaloyloxy)methyl>-protected derivative 36 with suitable heterocyclic amines although each heterocyclic system required its own particular synthetic approach.The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS).Theywere also examined for their inhibition of the growth of L1210 cells in culture.The thiophene system 7 and its related thiazole 8 gave analogues that were considerably more potent than the parent benzene series 2 as inhibitors of L1210 cell growth although in general these heterocycles were somewhat poorer inhibitors of the isolated TS enzyme.The enhanced cytotoxicities of the thiophene and thiazole analogues result, at least in part, from their efficient transport into the cells via the reduced folate carrier mechanism and very good substrate activity for folypolyglutamate synthetase.The replacement of the C²-methyl group by C²-(fluoromethyl) and C²-(hydroxymethyl) substituents in the thiophene and thiazole series gave derivatives that were only slightly less potent inhibitors of the TS enzyme but which were considerably less cytotoxic.