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Lookup NU author(s): Professor Alan Calvert
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The synthesis is described of a series of C2-methyl-N10-alkylquinazoline-based antifolates in which the p-aminobenzoate ring is replaced by the heterocycles thiophene, thiazole, thiadiazole, pyridine, and pyrimidine. These were generally elaborated by the reaction of (bromomethyl)quinazoline 18 or its N3-[(pivaloyloxy)methyl]-protected derivative 36 with suitable heterocyclic amines although each heterocyclic system required its own particular synthetic approach. The compounds were tested as inhibitors of partially purified L1210 thymidylate synthase (TS). They were also examined for their inhibition of the growth of L1210 cells in culture. The thiophene system 7 and its related thiazole 8 gave analogues that were considerably more potent than the parent benzene series 2 as inhibitors of L1210 cell growth although in general these heterocycles were somewhat poorer inhibitors of the isolated TS enzyme. The enhanced cytotoxicities of the thiophene and thiazole analogues result, at least in part, from their efficient transport into the cells via the reduced folate carrier mechanism and very good substrate activity for folylpolyglutamate synthetase. The replacement of the C2-methyl group by C2-(fluoromethyl) and C2-(hydroxymethyl) substituents in the thiophene and thiazole series gave derivatives that were only slightly less potent inhibitors of the TS enzyme but which were considerably less cytotoxic.
Author(s): Marsham PR, Hughes LR, Jackman AL, Hayter AJ, Oldfield J, Wardleworth JM, Bishop JAM, O'Connor BM, Calvert AH
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Year: 1991
Volume: 34
Issue: 5
Pages: 1594-1605
Print publication date: 01/05/1991
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
URL: http://dx.doi.org/10.1021/jm00109a011
DOI: 10.1021/jm00109a011
PubMed id: 2033585
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