SYNTHESIS OF NOVEL QUINAZOLINE-BASED ANTIFOLATES WITH MODIFIED GLUTAMATE SIDE-CHAINS AS POTENTIAL INHIBITORS OF THYMIDYLATE SYNTHASE AND ANTITUMOR AGENTS

Several novel antifolates, derivatives of -desamino-2-methyl-N-10-prop argyl-5,8-dideazafolic acid, were synthesised as inhibitors of thymidy late synthase (TS) and antitumour agents. This was accomplished by fir st 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 6-quinazolinyl)-methyl]-N-prop-2-yny lamino]benzoic acid (9) or 4-[N-[(3, -oxo-6-quinazolinyl)methyl]-N-pro p-2-ynylamino]-2- fluorobenzoic acid (24), and finally removal of the protecting groups. The resulting quinazoline-based antifolates with mo dified glutamate side chains, and in particular, the tetrazole derivat ives 26 and 29 displayed potent TS and L1210 cell growth inhibitory ac tivities (e.g., for 26: TS IC50 = 2.4 nM, L1210 IC50 = 1.3 mu M). (C) 1997 Elsevier Science Ltd.