title: Synthesis, biological evaluation, and physicochemical property assessment of 4-substituted 2-phenylaminoquinazolines as Mer tyrosine kinase inhibitors.
abstract: Current results identified 4-substituted 2-phenylaminoquinazoline compounds as novel Mer tyrosine kinase (Mer TK) inhibitors with a new scaffold. Twenty-one 2,4-disubstituted quinazolines (series 4-7) were designed, synthesized, and evaluated against Mer TK and a panel of human tumor cell lines aimed at exploring new Mer TK inhibitors as novel potential antitumor agents. A new lead, 4b, was discovered with a good balance between high potency (IC50 0.68μM) in the Mer TK assay and antiproliferative activity against MV4-11 (GI50 8.54μM), as well as other human tumor cell lines (GI50<20μM), and a desirable druglike property profile with low logP value (2.54) and high aqueous solubility (95.6μg/mL). Molecular modeling elucidated an expected binding mode of 4b with Mer TK and necessary interactions between them, thus supporting the hypothesis that Mer TK might be a biologic target of this kind of new active compound.
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Sheng-Biao
authors.initials: SB
authors.lastname: Wang
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Mu-Tian
authors.initials: MT
authors.lastname: Cui
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China; Pharmacy Department, Urumqi General Hospital, Lanzhou Military Region, Urumqi 830000, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Wang
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Masuo
authors.initials: M
authors.lastname: Goto
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: De-Xuan
authors.initials: DX
authors.lastname: Yang
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Linna
authors.initials: L
authors.lastname: Li
authors.affiliation: Beijing Institute of Radiation Medicine, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Shoujun
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.affiliation: Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA; Chinese Medicine Research and Development Center, China Medical University & Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC 27599, USA. Electronic address: lanxie4@gmail.com.
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D055598:Chemical Phenomena; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011505:Protein-Tyrosine Kinases
keywords: 4-Substituted 2-phenylaminoquinazolines; Antiproliferative; Mer tyrosine kinase inhibitors; Molecular modeling; Physicochemical properties