title: Synthesis, dihydrofolate reductase inhibition, antitumor testing, and molecular modeling study of some new 4(3H)-quinazolinone analogs.
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.
authors.affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, PO Box 2457, Riyadh 11451, Saudi Arabia.
authors.forename: Sarah T
authors.initials: ST
authors.lastname: Al-Rashood
authors.forename: Ihsan A
authors.initials: IA
authors.lastname: Aboldahab
authors.forename: Mahmoud N
authors.initials: MN
authors.lastname: Nagi
authors.forename: Laila A
authors.initials: LA
authors.lastname: Abouzeid
authors.forename: Alaa A M
authors.initials: AA
authors.lastname: Abdel-Aziz
authors.forename: Sami G
authors.initials: SG
authors.lastname: Abdel-Hamide
authors.forename: Khairia M
authors.initials: KM
authors.lastname: Youssef
authors.forename: Abdulrahman M
authors.initials: AM
authors.lastname: Al-Obaid
authors.forename: Hussein I
authors.initials: HI
authors.lastname: El-Subbagh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D002417:Cattle; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008727:Methotrexate / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry*; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005493:Folic Acid Antagonists; D052999:Quinazolinones; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate