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Lookup NU author(s): Professor Alan Calvert
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Four new analogues of the antifolate N10-propargyl-5,8-dideazafolic acid were prepared that were substituted in the benzoyl ring. The 2'-chloro and 2'-methyl analogues were prepared from the appropriately substituted p-nitrobenzoic acids. The route to the 3'-chloro and 3',5'-dichloro analogues was by chlorination of diethyl N10-propargyl-5,8-dideazafolate and diethyl N-[4-(prop-2-ynylamino)benzoyl]-L-glutamate, respectively, using sulfuryl chloride. The compounds were tested for their inhibition of purified L1210 thymidylate synthase (TS), for their inhibition of purified L1210 dihydrofolate reductase (DHFR), and for their inhibition of the growth of L1210 cells in culture. The 2'-chloro substituent reduced the TS inhibition by twofold and the 2'-methyl substituent reduced it by 20-fold; the 3'-chloro and 3',5'-dichloro derivatives were very poor inhibitors. The substituents only slightly affected the DHFR inhibition. None of the compounds improved upon N10-propargyl-5,8-dideazafolic acid in inhibiting the growth of L1210 cells in culture.
Author(s): Jones TR, Smithers MJ, Taylor MA, Jackman AL, Calvert AH, Harland SJ, Harrap KR
Publication type: Article
Publication status: Published
Journal: Journal of Medicinal Chemistry
Year: 1986
Volume: 29
Issue: 4
Pages: 468-472
Print publication date: 01/04/1986
ISSN (print): 0022-2623
ISSN (electronic): 1520-4804
URL: http://dx.doi.org/10.1021/jm00154a007
DOI: 10.1021/jm00154a007
PubMed id: 3754284
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