Browse by author
Lookup NU author(s): Professor Alan Calvert, Professor Herbie Newell
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
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.
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 provided by Altmetric
