Synthesis and biological evaluation of azole-diphenylpyrimidine derivatives (AzDPPYs) as potent T790M mutant form of epidermal growth factor receptor inhibitors |
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| Affiliation: | 1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Respiratory Department, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;1. Department of Chemistry, University of Illinois at Chicago, 845 W. Taylor Street, Chicago, IL 60607, United States;2. Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States;3. Loyola University Medical Center, Maywood, IL 60153, United States;1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Clinical Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;1. School of Pharmacy, Fudan University, Shanghai 201203, China;2. Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt;2. Institute of New Drug Development, China Medical University, Taichung, 40402, Taiwan;3. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Menoufia, Egypt;4. Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, 40447, Taiwan;1. College of Pharmacy, Dalian Medical University, Dalian 116044, PR China;2. Respiratory Department, The First Affiliated Hospital of Dalian Medical University, Dalian 116011, PR China;3. Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC V5Z 4E8, Canada;1. College of Life Science, Nanjing Normal University, No. 1 Wenyuan Road, Nanjing 210046, PR China;2. Jiangsu Chia Tai Fenghai Pharmaceutical Co. Ltd., No. 9 Weidi Road, Nanjing 210046, PR China;3. College of Science, Nanjing Forestry University, No. 159 Longpan Road, Nanjing 210037, PR China |
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| Abstract: | A series of novel azole-diphenylpyrimidine derivatives (AzDPPYs) were synthesized and biologically evaluated as potent EGFRT790M inhibitors. Among these analogues, the most active inhibitor 6e not only displayed high activity against EGFRT790M/L858R kinase (IC50 = 3.3 nM), but also was able to repress the replication of H1975 cells harboring EGFRT790M mutation at a concentration of 0.118 μmol/L. In contrast to the lead compound rociletinib, 6e slightly reduces the key EGFRT790M-minduced drug resistance. Significantly, inhibitor 6e demonstrates high selectivity (SI = 299.3) for T790M-containing EGFR mutants over wild type EGFR, hinting that it will cause less side effects. |
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| Keywords: | NSCLC EGFR T790M Inhibitors Synthesis Azole-diphenylpyrimidine |
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