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Quinazoline antifolates inhibiting thymidylate synthase: variation of the amino-acid

Lookup NU author(s): Professor Alan Calvert

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Abstract

Five new analogues (1c-g) of the antifolate N10-propargyl-5,8-dideazafolic acid (1a) are described in which the benzoyl-L-glutamate moiety was replaced by benzoic acid (desglutamyl-N10-propargyl-5,8-dideazafolic acid), benzoyl-L-aspartate, 4-phenylbutyrate, benzoylglycine, and benzoyl-L-alanine. The esters of the appropriate 4-aminophenyl (benzoyl) starting materials were sequentially alkylated upon nitrogen, first with a propargyl halide and then with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide. Saponification of the antifolate esters so produced gave the desired analogues. The new derivatives (1c-g) and also the known diethyl ester of 1a (1b) were tested for their inhibition of purified L1210 thymidylate synthase (TS) and for their inhibition of the growth of L1210 cells in culture. The TS inhibition of the analogues 1b-g was estimated by calculating the inverse relative potency, defined as the ratio IC50(compound)/IC50(1a). The results obtained were as follows: greater than 62, 84, 9, 333, 21, and 5, respectively. All were thus less inhibitory than 1a. None of the compounds improved upon 1a in inhibiting the growth of L1210 cells in culture.


Publication metadata

Author(s): Jones TR, Smithers MJ, Betteridge RF, Taylor MA, Jackman AL, Calvert AH, Davies LC, Harrap KR

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 1986

Volume: 29

Issue: 6

Pages: 1114-1118

Print publication date: 01/06/1986

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm00156a033

DOI: 10.1021/jm00156a033

PubMed id: 3712376


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