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Quinazoline antifolate thymidylate synthase inhibitors: bridge modifications and conformationally restricted analogs in the C2-methyl series

Lookup NU author(s): Professor Alan Calvert

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Abstract

Several C2-methylquinazoline-based antifolates have been prepared in which the C9,N10 bridge has been replaced by the reversed N9,C10 unit. This series was extensively studied by incorporating further substituents at N9 and C10 as well as by modifications to the p-aminobenzoate ring. The C2-methylquinazoline analogues 29, 30, and 31 containing the methyleneoxa, methylenethia, and thia bridge units were also synthesized. In general these isosteric replacements of the bridge unit in the parent C2-methyl-N10-propargylquinazoline antifolate 2 were much less potent as inhibitors of isolated thymidylate synthase (TS) but several were at least as potent as inhibitors of L1210 cell growth in culture. The fusion of the p-aminobenzoate ring into the bicyclic systems 75 and 76 also reduced activity against TS but again gave highly cytotoxic compounds. The cytotoxicities were largely prevented by thymidine, confirming that TS is the major locus.

Publication metadata

Author(s): Marsham PR, Jackman AL, Hayter AJ, Daw MR, Snowden JL, O'Connor BM, Bishop JAM, Calvert AH, Hughes LR

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 1991

Volume: 34

Issue: 7

Pages: 2209-2218

Print publication date: 01/07/1991

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm00111a042

DOI: 10.1021/jm00111a042

PubMed id: 2066994

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