Toggle Main Menu Toggle Search

Open Access padlockePrints

Quinazoline antifolates inhibiting thymidylate synthase: variation of the N-10 substituent

Lookup NU author(s): Professor Alan Calvert, Professor Herbie Newell

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

The synthesis of 12 new 5,8-dideazafolates with isopropyl, cyclopropylmethyl, 2-fluoroethyl, carbamoylmethyl, phenacyl, 3-fluorobenzyl, 5-uracilylmethyl, carboxymethyl, 2-carboxyethyl, 3-cyanopropyl, 3-hydroxypropyl, and cyanomethyl substituents at N10 is described. In general, the synthetic route involved monoalkylation of diethyl N-(4-amino-benzoyl)-L-glutamate, coupling of the resulting secondary amine with 2-amino-6-(bromomethyl)-4-hydroxyquinazoline hydrobromide in N,N-dimethylacetamide with calcium carbonate as the base, and deprotection using mild alkali. The cyanomethyl derivatives was found to be unexpectedly base labile and was therefore prepared by mild acid deprotection of a di-tert-butyl ester. The compounds were tested as inhibitors of purified L1210 thymidylate synthase (TS). Four members of the series were more potent that the N10-hydrogen compound, but none was superior to the previously described N10-propargyl-5,8-dideazafolic acid. Selected compounds were examined as inhibitors of purified L1210 dihydrofolate reductase (DHFR). As desired, N10 substitution in general reduced DHFR inhibitory activity; these results are discussed. As a measure of cytotoxicity, the compounds were examined for their inhibition of the growth of L1210 cells in culture. None of the new substituents conferred enhanced potency relative to N10-propargyl-5,8-dideazafolic acid (ID50 = 5 microM), which, as the best TS inhibitor and a relatively poor DHFR inhibitor, continues to lead this series.


Publication metadata

Author(s): Jones TR, Calvert AH, Jackman AL, Eakin MA, Smithers MJ, Betteridge RF, Newell DR, Hayter AJ, Stocker A

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 1985

Volume: 28

Issue: 10

Pages: 1468-1476

Print publication date: 01/10/1985

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm00148a016

DOI: 10.1021/jm00148a016

PubMed id: 4045922


Altmetrics

Altmetrics provided by Altmetric


Share