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.
- 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: [email protected].
- 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: [email protected].
- 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: [email protected].
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.