title: Design and synthesis of 4-amino-2-phenylquinazolines as novel topoisomerase I inhibitors with molecular modeling.
abstract: 4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3-arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA-topo I complex. Among the synthesized 4-amino group-substituted analogs, 4-cyclohexylamino-2-phenylquinazoline 7h exhibited potent topo I inhibitory activity and strong cytotoxicity. Interestingly, consistency was observed between the cytotoxicities and topo I activities in these quinazoline analogs, suggesting that the target of 4-amino-2-phenylquinazolines is limited to topo I. Molecular docking studies were performed with the Surflex-Dock program to afford the ideal interaction mode of the compound into the binding site of the DNA-topo I complex in order to clarify the topo I activity of 7h.
authors.affiliation: College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Thanh Nguyen
authors.initials: TN
authors.lastname: Le
authors.forename: Su Hui
authors.initials: SH
authors.lastname: Yang
authors.forename: Daulat Bikram
authors.initials: DB
authors.lastname: Khadka
authors.forename: Hue Thi My
authors.initials: HT
authors.lastname: Van
authors.forename: Suk Hee
authors.initials: SH
authors.lastname: Cho
authors.forename: Youngjoo
authors.initials: Y
authors.lastname: Kwon
authors.forename: Eung-Seok
authors.initials: ES
authors.lastname: Lee
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000201:enzymology; D059004:Topoisomerase I Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D011799:Quinazolines; D059004:Topoisomerase I Inhibitors; C568690:cyclohexyl(2-phenylquinazolin-4-yl)amine; D004264:DNA Topoisomerases, Type I