Abstract
In order to produce potent new leads for anticancer drugs, a new series of quinazoline analogs was designed to resemble methotrexate (MTX,
1) structure features and fitted with functional groups believed to enhance inhibition of mammalian DHFR activity. Molecular modeling studies were used to assess the fit of these compounds within the active site of human DHFR. The synthesized compounds were evaluated for their ability to inhibit mammalian DHFR in vitro and for their antitumor activity in a standard in vitro tissue culture assay panel. Compounds
28,
30, and
31 were the most active DHFR inhibitors with IC
50 values of 0.5, 0.4, and 0.4
μM, respectively. The most active antitumor agents in this study were compounds
19,
31,
41, and
47 with median growth inhibitory concentrations (GI
50) of 20.1, 23.5, 26.7, and 9.1
μM, respectively. Of this series of compounds, only compound
31 combined antitumor potency with potent DHFR inhibition; the other active antitumor compounds (
19,
41, and
47) all had DHFR IC
50 values above 15
μM, suggesting that they might exert their antitumor potency through some other mode of action. Alternatively, the compounds could differ significantly in uptake or concentration within mammalian cells.