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Quinazoline antifolate thymidylate synthase inhibitors - 2'- fluoro-N-¹⁰-propargyl-5,8-dideazafolic acid and derivatives with modifications in the C-2 position

Lookup NU author(s): Professor Alan Calvert

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Abstract

The synthesis of 2'-fluoro-10-propargyl-5,8-dideazafolic acid and its 2-desamino, 2-desamino-2-hydroxymethyl, and 2-desamino-2-methoxy analogues is described. In general the synthetic route involved the coupling of diethyl N-[2-fluoro-4-(prop-2-ynylamino)benzoyl]-L-glutamate with the appropriate 6-(bromomethyl)quinazoline followed by deprotection with mild alkali. These four compounds together with the 2-desamino-2-methyl analogue were tested for their activity against L1210 thymidylate synthase (TS). They were also examined for their inhibition of the growth of the L1210 cell line and of two mutant L1210 cell lines, the L1210:R7A that overproduces dihydrofolate reductase (DHFR) and the L1210:1565 that has impaired uptake of reduced folates. Compared with their non-fluorinated parent compounds, the 2'-fluoro analogues were all approximately 2-fold more potent as TS inhibitors. Similarly, they also showed improved inhibition of L1210 cell growth (1.5-5-fold), and this activity was prevented by co-incubation with thymidine. All had retained or improved activity against both the L1210:R7A and L1210:1565 cell lines.

Publication metadata

Author(s): Jackman AL, Marsham PR, Thornton TJ, Bishop JAM, O'Connor BM, Hughes LR, Calvert AH, JonesTR

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 1990

Volume: 33

Issue: 11

Pages: 3067-3071

Print publication date: 01/11/1990

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http:///dx.doi.org/10.1021/jm00173a025

DOI: 10.1021/jm00173a025

PubMed id: 2231607

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