Benzoquinazoline inhibitors of thymidylate synthase: enzyme inhibitory activity and cytotoxicity of some 3-amino- and 3-methylbenzo[f]quinazolin-1(2H)-ones

• Published in: Journal of medicinal chemistry 1993-08, Vol.36 (16), p.2279-2291
• Main Authors: Pendergast, William, Johnson, Jay V, Dickerson, Scott H, Dev, Inderjit K, Duch, David S, Ferone, Robert, Hall, William R, Humphreys, Joan, Kelly, Joseph M, Wilson, David C
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - pathology; Cell Division - drug effects; Chemistry; Colonic Neoplasms - pathology; Escherichia coli - enzymology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Humans; Organic chemistry; Preparations and properties; Quinazolines - chemical synthesis; Quinazolines - pharmacology; Structure-Activity Relationship; Thymidylate Synthase - antagonists & inhibitors; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00068a004

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.