Synthesis of novel quinazoline-based antifolates with modified glutamate side chains as potential inhibitors of thymidylate synthase and antitumour agents

Several novel antifolates, derivatives of 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolic acid, were synthesised as inhibitors of thymidylate synthase (TS) and antitumour agents. This was accomplished by first developing routes to the key intermediates Glu-OMe-gamma-psi-[CSNH]Glu(OEt)-OEt (8), Glu-OBut-gamma-psi[CH2NH]Glu(oBu(t))-OBut (16), Glu-OMe-gamma-psi[CN4]Gly-OMe (23) and its 2,5-disubstituted regioisomer (22), followed by DEPC coupling to 4-[N-[(3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)-methyl]-N-prop-2-ynylamino]benzoic acid (9) or 4-[N-[(3, 4-dihydro-2,7-dimethyl-4-oxo-6-quinazolinyl)methyl]-N-prop-2-ynylamino]-2- fluorobenzoic acid (24), and finally removal of the protecting groups. The resulting quinazoline-based antifolates with modified glutamate side chains, and in particular, the tetrazole derivatives 26 and 29 displayed potent TS and L1210 cell growth inhibitory activities (e.g., for 26: TS IC50 = 2.4 nM, L1210 IC50 = 1.3 mu M). (C) 1997 Elsevier Science Ltd.