2. Academic Validation
  3. Synthesis and evaluation of 2-anilinopyrimidines bearing 3-aminopropamides as potential epidermal growth factor receptor inhibitors

Synthesis and evaluation of 2-anilinopyrimidines bearing 3-aminopropamides as potential epidermal growth factor receptor inhibitors

  • Eur J Med Chem. 2014 Apr 22:77:75-83. doi: 10.1016/j.ejmech.2014.02.032.
Chun Han 1,  Ledong Wan 2,  Hongbin Ji 3,  Ke Ding 4,  Zhangjian Huang 5,  Yisheng Lai 6,  Sixun Peng 2,  Yihua Zhang 7
Affiliations

Affiliations

  • 1 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.
  • 2 State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China; Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, PR China.
  • 3 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.
  • 4 Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China.
  • 5 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.
  • 6 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.
  • 7 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.
PMID: 24607591 DOI: 10.1016/j.ejmech.2014.02.032
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.

Keywords

3-Aminopropamides; Acrylamide; Anilinopyrimidine; Antiproliferative effects; EGFR inhibitor; Nitric oxide.

Figures