title: Synthesis and evaluation of 2-anilinopyrimidines bearing 3-aminopropamides as potential epidermal growth factor receptor inhibitors.
abstract: Novel compounds 12a-i were synthesized and biologically evaluated. Several ones exhibited stronger inhibitory activity than gefitinib against EGFR L858R/T790M and antiproliferative effects on H1975 and HCC827 cells. The 3-aminopropamide in compounds like 12h could be converted to the active acrylamide in the presence of arginine. Importantly, 12h showed improved stability relative to compound 1 whose structure is same to 12h excepting an acrylamide moiety. Interestingly, 12i, a NO donating compound of 12h, showed more potent and selective inhibition than 12h on H1975 cells. Significantly, 12i produced high levels of NO in H1975 cells but not in non-tumorous 16HBE cells, and its inhibition was diminished by NO scavenger. Furthermore, 12i dose-dependently produced inhibitory effects on EGFR downstream signaling in H1975 cells.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China; Department of Chemistry, Changzhi University, Changzhi 046011, PR China.
authors.forename: Chun
authors.initials: C
authors.lastname: Han
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Ledong
authors.initials: L
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, PR China.
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.affiliation: Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China.
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: cpudahuang@163.com.
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: lcpu333@yahoo.com.cn.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: zyhtgd@163.com.
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D015394:Molecular Structure; D009569:Nitric Oxide / Q000096:biosynthesis; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: C000593385:4-(2-(4-(3-((3-((5-chloro-2-((2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)amino)-3-oxopropyl)piperazin-1-yl)ethoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide; D000970:Antineoplastic Agents; D010069:Oxadiazoles; D011743:Pyrimidines; D011799:Quinazolines; D009569:Nitric Oxide; D066246:ErbB Receptors; D000077156:Gefitinib
keywords: 3-Aminopropamides; Acrylamide; Anilinopyrimidine; Antiproliferative effects; EGFR inhibitor; Nitric oxide