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

• Published in: Tetrahedron Vol. 53; no. 39; pp. 13383 - 13396
• Main Authors: Bavetsias, Vassilios, Bisset, Graham M.F., Kimbell, Rosemary, Boyle, F.Thomas, Jackman, Ann L.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 29.09.1997; Elsevier
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; LINKED DIPEPTIDE; PEPTIDES; INVITRO; CB3717; L1210; DIPEPTIDE ANALOGS; DERIVATIVES; 2-DESAMINO-2-METHYL-N-10-PROPARGYL-5,8-DIDEAZAFOLIC ACID ICI-198583
• ISSN: 0040-4020; 1464-5416
• DOI: 10.1016/S0040-4020(97)00851-X

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-γ-ψ[CSNH]Glu(OEt)-OEt ( 8), Glu-OBu t-γ-ψ[CH 2NH]Glu(OBu t)-OBu t ( 16), Glu-OMe-γ-ψ[CN 4]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 IC 50 = 2.4 nM, L1210 IC 50 = 1.3 μM). The synthesis of novel quinazoline antifolates with modified glutamate side chains ( e. g. 26) is described.