title: Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some 3-amino- and 3-methylbenzo[f]quinazolin-1(2H)-ones.
abstract: The synthesis and thymidylate synthase (TS) inhibitory activity of a series of simple benzo[f]-quinazolin-1(2H)-ones are described. Fully aromatic 3-amino compounds with compact lipophilic substituents in the 9-position were found to have I50 values as low as 20 nM on the isolated enzyme, and represent the first examples of potent, folate-based TS inhibitors that completely lack any structural feature corresponding to the (p-aminobenzoyl)glutamate moiety of the cofactor. A number of the compounds also showed moderate growth inhibitory activity against a human colon adenocarcinoma cell line (SW480), with IC50 values as low as 2 microM.
authors.affiliation: Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
authors.forename: W
authors.initials: W
authors.lastname: Pendergast
authors.forename: J V
authors.initials: JV
authors.lastname: Johnson
authors.forename: S H
authors.initials: SH
authors.lastname: Dickerson
authors.forename: I K
authors.initials: IK
authors.lastname: Dev
authors.forename: D S
authors.initials: DS
authors.lastname: Duch
authors.forename: R
authors.initials: R
authors.lastname: Ferone
authors.forename: W R
authors.initials: WR
authors.lastname: Hall
authors.forename: J
authors.initials: J
authors.lastname: Humphreys
authors.forename: J M
authors.initials: JM
authors.lastname: Kelly
authors.forename: D C
authors.initials: DC
authors.lastname: Wilson
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology; D004926:Escherichia coli / Q000201:enzymology; D006801:Humans; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured
chemical_list: D011799:Quinazolines; D013940:Thymidylate Synthase