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Design of thymidylate synthase inhibitors using protein crystal structures: the synthesis and biological evaluation of a novel class of 5-substituted quinazolinones.

Abstract：

:The design, synthesis, and biological evaluation of a new class of inhibitors of thymidylate synthase (TS) is described. The molecular design was carried out by a repetitive crystallographic analysis of protein-ligand structures. At the onset of this project, we focused on the folate cofactor binding site of a high-resolution ternary crystal complex of Escherichia coli TS, 5'-fluorodeoxyuridylate (5-FdUMP) and a classical glutamate-containing folic acid analog. A preliminary ternary crystal structure of a novel compound was successfully solved. Upon analysis of this initial complex, further structural elaborations were made, and a series of active 5-(arylthio)quinazolinones was developed. The synthetic strategy was based on the displacement of a halogen at the 5-position of a quinazolinone by various aryl thioanions. The compounds were tested for inhibition of purified E. coli and/or human TS, and were assayed for cytotoxicity against three tumor cell lines in vitro. Significant thymidine protection effects were observed with several of the inhibitors, indicating that TS was the intracellular locus of activity.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Webber SE,Bleckman TM,Attard J,Deal JG,Kathardekar V,Welsh KM,Webber S,Janson CA,Matthews DA,Smith WW

doi

10.1021/jm00058a010

subject

Has Abstract,Author List Incomplete

pub_date

1993-03-19 00:00:00

pages

733-46

issue

6

eissn

0022-2623

issn

1520-4804

journal_volume

36

pub_type

杂志文章

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