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

Chun Han; Ledong Wan; Hongbin Ji; Ke Ding; Zhangjian Huang; Yisheng Lai; Sixun Peng; Yihua Zhang

doi:10.1016/j.ejmech.2014.02.032

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. Epub 2014 Feb 14.

Authors

Chun Han¹, Ledong Wan², Hongbin Ji³, Ke Ding⁴, Zhangjian Huang⁵, Yisheng Lai⁶, Sixun Peng², Yihua Zhang⁷

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.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line
Cell Proliferation / drug effects
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
ErbB Receptors / antagonists & inhibitors*
ErbB Receptors / metabolism
Gefitinib
Humans
Molecular Structure
Nitric Oxide / biosynthesis
Oxadiazoles / chemical synthesis
Oxadiazoles / chemistry*
Oxadiazoles / pharmacology*
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology*
Quinazolines / pharmacology
Signal Transduction / drug effects
Structure-Activity Relationship

Substances

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
Antineoplastic Agents
Oxadiazoles
Pyrimidines
Quinazolines
Nitric Oxide
ErbB Receptors
Gefitinib