Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs.

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Al-Rashood ST, Aboldahab IA, Nagi MN, Abouzeid LA, Abdel-Aziz AA, Abdel-Hamide SG, Youssef KM, Al-Obaid AM, El-Subbagh HI

Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs.

Bioorg Med Chem. 2006 Dec 15;14(24):8608-21. Epub 2006 Sep 12.

PubMed ID

16971132 [ View in PubMed

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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 0.4microM, 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 9.1microM, 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 15microM, 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Methotrexate	Dihydrofolate reductase	Protein	Humans	Yes	Inhibitor	Details