Synthesis of Nonclassical Quinazolinone Antifolates as Thymidylate Synthase Inhibitors and Their Antitumor Activity In Vitro

摘要

Nonclassical quinazolinone analogs I,II,and III,in which the glutamic acid moiety of the classical antifolates is substituted by phenylglycine,phenylalanine or aminobenzoic acid and their methyl esters,were synthesized and evaluated as lipophilic inhibitors of thymidylate synthase(TS).The target compounds were generally potent inhibitors of L casei and human TS with IC_50 values within the narrow range of 0.2-10 mu M.and 0.003-0.03 mu M,respectively.Further,most of the target compounds showed cytotoxicity against tumor cell lines of murine and human origin with IC_50 values of as low as 0.050 mu M.Substitution of another hydroxyl or carboxylic acid/ester group at the phenyl ring further increased the potency of TS inhibition and cell growth inhibition.Most effective were compounds If and Ic in which extra carboxylic acid/ester was present at the phenyl ring with nanomolar IC_50 values of 0.0044 and 0.0093 mu M against human TS and submicromolar cytotoxic growth inhibition against all four tumor cell lines.