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

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 muM.