BENZOQUINAZOLINE INHIBITORS OF THYMIDYLATE SYNTHASE - ENZYME-INHIBITORY ACTIVITY AND CYTOTOXICITY OF SOME 3-AMINOBENZO[F]QUINAZOLIN-1(2H)-ONES AND 3-METHYLBENZO[F]QUINAZOLIN-1(2H)-ONES

Authors
PENDERGAST W JOHNSON JV DICKERSON SH DEV IK DUCH DS FERONE R HALL WR HUMPHREYS J KELLY JM WILSON DC
Citation
W. Pendergast et al., BENZOQUINAZOLINE INHIBITORS OF THYMIDYLATE SYNTHASE - ENZYME-INHIBITORY ACTIVITY AND CYTOTOXICITY OF SOME 3-AMINOBENZO[F]QUINAZOLIN-1(2H)-ONES AND 3-METHYLBENZO[F]QUINAZOLIN-1(2H)-ONES, Journal of medicinal chemistry, 36(16), 1993, pp. 2279-2291
Citations number
36
Categorie Soggetti
Chemistry Medicinal
Journal title
Journal of medicinal chemistry → ACNP
ISSN journal
00222623
Volume
36
Issue
16
Year of publication
1993
Pages
2279 - 2291
Database
ISI
SICI code
0022-2623(1993)36:16<2279:BIOTS->2.0.ZU;2-B
Abstract
The synthesis and thymidylate synthase (TS) inhibitory activity of a s eries of simple benzo-[f]-quinazolin-1(2H)-ones are described. Fully a romatic 3-amino compounds with compact lipophilic substituents in the 9-position were found to have I50 values as low as 20 nM on the isolat ed 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 t he compounds also showed moderate growth inhibitory activity against a human colon adenocarcinoma cell line (SW480), with IC50 values as low as 2 muM.