title: Nitric oxide donating anilinopyrimidines: synthesis and biological evaluation as EGFR inhibitors.
abstract: To search for potent nitric oxide (NO) donating epidermal growth factor receptor (EGFR) inhibitors, a series of phenylsulfonylfuroxan-based anilinopyrimidines 10a-h were synthesized and biologically evaluated. Compounds 10f-h exhibited potent inhibitory activity against EGFR L858R/T790M and were as potent as WZ4002 in inhibition of H1975 cells harboring EGFR L858R/T790M. Additionally, 10h produced high levels of NO in H1975 cells but not in normal human cells, and its antiproliferative activity was diminished by hemoglobin, an NO scavenger. Furthermore, 10h inhibited EGFR activation and downstream signaling in H1975 cells. These results suggest that the strong antiproliferative activity of 10h could be attributed to the synergic effects of high levels of NO production and inhibition of EGFR and downstream signaling in the cancer cells.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Chun
authors.initials: C
authors.lastname: Han
authors.forename: Zhangjian
authors.initials: Z
authors.lastname: Huang
authors.forename: Chao
authors.initials: C
authors.lastname: Zheng
authors.forename: Ledong
authors.initials: L
authors.lastname: Wan
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lai
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.forename: Ke
authors.initials: K
authors.lastname: Ding
authors.forename: Hongbin
authors.initials: H
authors.lastname: Ji
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D000077156:Gefitinib; D006801:Humans; D009569:Nitric Oxide / Q000737:chemistry*; D047428:Protein Kinase Inhibitors / 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
chemical_list: D000970:Antineoplastic Agents; D016166:Free Radical Scavengers; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D009569:Nitric Oxide; D066246:ErbB Receptors; C030986:pyrimidine; D000077156:Gefitinib
keywords: Anilinopyrimidine; Antiproliferative activity; EGFR inhibitor; Nitric oxide; WZ4002