title: Novel hybrids of (phenylsulfonyl)furoxan and anilinopyrimidine as potent and selective epidermal growth factor receptor inhibitors for intervention of non-small-cell lung cancer.
abstract: A series of hybrids (12a-k) from (phenylsulfonyl)furoxan and anilinopyrimidine were synthesized and biologically evaluated as epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Compound 12k exhibited strong and selective EGFR L858R/T790M inhibitory activity (IC50 = 0.047 μM) and displayed antiproliferative effects on EGFR mutation NSCLC cell lines HCC827 (del E746_A750) and H1975 (L858R/T790M) with IC50 values of 0.007 and 0.029 μM, respectively. Additionally, 12k released high levels of NO in H1975 cells but not in normal human cells, and its activity was diminished by pretreatment with a NO scavenger. Furthermore, 12k induced apoptosis of H1975 and HCC827 cells more strongly than WZ4002 (1), inhibited EGFR downstream signaling in H1975 cells, and suppressed the nuclear factor-κB activation in H1975 cells, while 1 had no significant effects under the same conditions. Finally, 12k substantially inhibited tumor growth in an H1975 xenograft mouse model. Overall, 12k might be a promising candidate for the treatment of NSCLC.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, People's Republic of 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: Lianwen
authors.initials: L
authors.lastname: Zhang
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: Jide
authors.initials: J
authors.lastname: Tian
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009368:Neoplasm Transplantation; D009569:Nitric Oxide / Q000378:metabolism; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D014183:Transplantation, Heterologous
chemical_list: C582928:4-((6-(2-(4-(4-((4-(3-acrylamidophenoxy)-5-chloropyrimidin-2-yl)amino)-3-methoxyphenyl)piperazin-1-yl)acetoxy)hexyl)oxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole 2-oxide; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D016328:NF-kappa B; D010069:Oxadiazoles; D011743:Pyrimidines; C010166:furoxans; D009569:Nitric Oxide; D066246:ErbB Receptors