title: Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents.
abstract: Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase.
authors.affiliation: Beijing Institute of Pharmacology & Toxicology, 27 Tai-Ping Road, Beijing 100850, China.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Wang
authors.forename: Xing-Tao
authors.initials: XT
authors.lastname: Tian
authors.forename: Emika
authors.initials: E
authors.lastname: Ohkoshi
authors.forename: Bingjie
authors.initials: B
authors.lastname: Qin
authors.forename: Yi-Nan
authors.initials: YN
authors.lastname: Liu
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Wu
authors.forename: Mann-Jen
authors.initials: MJ
authors.lastname: Hour
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Hung
authors.forename: Keduo
authors.initials: K
authors.lastname: Qian
authors.forename: Rong
authors.initials: R
authors.lastname: Huang
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: William P
authors.initials: WP
authors.lastname: Janzen
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D000090063:Proto-Oncogene Mas; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D004987:Ethers; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas