Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some 3-amino- and 3-methylbenzo[f]quinazolin-1(2H)-ones.
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.
Pendergast
W
W
Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Johnson
J V
JV
Dickerson
S H
SH
Dev
I K
IK
Duch
D S
DS
Ferone
R
R
Hall
W R
WR
Humphreys
J
J
Kelly
J M
JM
Wilson
D C
DC
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
D011799:Quinazolines; D013940:Thymidylate Synthase