960299-66-5Relevant academic research and scientific papers
Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
Fang, Sen-Biao,Li, Hui-Jing,Nan, Xiang,Wu, Rui,Wu, Yan-Chao,Zhang, Jing,Zhang, Zhi-Zhou
, (2020/06/04)
In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.
Design, synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor
Yang, Yifeng,Li, Yingxiu,Hou, Yunlei,Qin, Mingze,Gong, Ping,Liu, Ju,Zhao, Yanfang
, (2019/10/28)
A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 μM, 0.18 μM, 0.38 μM, 0.81 μM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.
Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors
Szabadkai, István,Torka, Robert,Garamv?lgyi, Rita,Baska, Ferenc,Gyulavári, Pál,Boros, Sándor,Illyés, Eszter,Choidas, Axel,Ullrich, Axel,órfi, László
, p. 6277 - 6292 (2018/07/05)
The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL kinase. Through optimization and detailed SAR studies we developed low nanomolar inhibitors, and after further biological characterization we identified a potent AXL kinase inhibitor with favorable pharmacokinetic profile. The antitumor activity was determined in xenograft models, and the lead compounds reduced the tumor size by 40% with no observed toxicity as well as lung metastasis formation by 66% when compared to vehicle control.
Design, synthesis and biological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing pyridazinone moiety as c-Met Inhibitors
Liu, Xiaobo,Kou, Jianlan,Xiao, Zhen,Tian, Fajuan,Hu, Jiayi,Zheng, Pengwu,Zhu, Wufu
, (2018/07/13)
Deregulation of the receptor tyrosine kinase mesenchymal epithelial transition factor (MET) has been implicated in several human cancers and is an attractive target for small molecule drug discovery. Herein, a series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing pyridazinone derivatives were designed, synthesized and evaluated for their enzymatic inhibitory activity against c-Met kinase and cellular potency against A549, HepG2, and MCF-7 cell lines. Eight of them are equal to more active than positive control Foretinib against one or more cell lines and enzyme. The most promising compound 53 showed superior activity to Foretinib, which possessed excellent c-Met kinase inhibition on a singledigital nanomolar level (IC50 = 0.6 nM), and cancer cells of A549 (IC50 = 0.003 μM), HepG2 (IC50 = 0.49 μM) and MCF-7 cells (IC50 = 0.006 μM). The result of AO single staining indicated that compound 53 could induce remarkable apoptosis of HepG2 cell.
Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety
Tang, Qidong,Duan, Yongli,Xiong, Hehua,Chen, Ting,Xiao, Zhen,Wang, Linxiao,Xiao, Yueyue,Huang, Shunmin,Xiong, Yinhua,Zhu, Wufu,Gong, Ping,Zheng, Pengwu
, p. 201 - 213 (2018/09/18)
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety were designed, synthesized and evaluated for their biological activities. The target compounds exhibited moderate to high antiproliferative activity against three cancer cell lines (A549, HepG2 and MCF-7) and several compounds (25, 27, 33, 37, 41, 43, 49 and 53) were evaluated for the activity against c-Met kinase. The most promising compound 33 (IC50 c-Met = 2.36 nM) showed excellent activity against A549, HepG2 and MCF-7 cell lines with IC50 values of 0.23 μM, 0.42 μM and 0.21 μM, respectively, which was 1.5–2.1 times of the positive control. Furthermore, compound 33 was evaluated for the activity against Flt3, PDGFR-α PDGFR-β c-Kit, Flt4, ALK and EGFR kinase. Structure activity relationship studies indicated that mono-EWGs (such as R2 = F) at 4-position of moiety C was a key factor in improving the antitumor activity. In addition, further research on compound 33 was mainly including concentration dependence, apoptosis (acridine orange staining), apoptosis result analyzing and molecular docking.
Discovery of a novel 6,7-disubstituted-4-(2-fluorophenoxy)quinolines bearing 1,2,3-triazole-4-carboxamide moiety as potent c-Met kinase inhibitors
Liu, Mingmei,Hou, Yunlei,Yin, Weile,Zhou, Shunguang,Qian, Ping,Guo, Zhuang,Xu, Liying,Zhao, Yangfang
, p. 96 - 108 (2016/05/24)
A series of 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety were designed, synthesized and evaluated for their in vitro cytotoxic activities against four typical cancer cell lines (A549, H460, HT-29, and MKN-45). Most compounds showed moderate-to-excellent antiproliferative activity. Compounds 32, 36, 37, 45, 51, and 52 were further examined for their inhibitory activity against c-Met kinase. The promising compound 37, with a c-Met IC50 value of 2.27 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The analysis of their structure-activity relationships indicated that compounds with EWGs, especially chloro group, at 2-position on the phenyl ring (moiety B) have potent antitumor activity.
Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors
Liu, Ju,Nie, Minhua,Wang, Yanjing,Hu, Jinxing,Zhang, Feng,Gao, Yanlin,Liu, Yajing,Gong, Ping
, p. 431 - 446 (2016/08/04)
A series of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety were synthesized and evaluated for their in?vitro cytotoxic activity against four cancer cell lines (HT-29, H460, A549 and MKN-45). Most of the compounds exhibited moderate-to-significant cytotoxicity. Compounds 33, 37, 39, 44, 46, 47, 53, 55, 61, 64 and 66 were further examined for their inhibitory activity against c-Met kinase. The most promising compound 47 (with c-Met IC50value of 1.57?nM) showed remarkable cytotoxicity against HT-29, H460, A549 and MKN-45?cell lines with IC50values of 0.08?μM, 0.14?μM, 0.11?μM and 0.031?μM, respectively, and thus it was 1.1- to 2.3- fold more potent than foretinib. Their preliminary structure-activity relationships (SARs) studies indicate that electron-withdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity.
Design, Synthesis, and Biological Evaluation of 4-Phenoxyquinoline Derivatives Containing Benzo[d]thiazole-2-yl Urea as c-Met Kinase Inhibitors
Lei, Hongrui,Hu, Gang,Wang, Yu,Han, Pei,Liu, Zijian,Zhao, Yanfang,Gong, Ping
, p. 651 - 661 (2016/08/27)
A series of novel 4-phenoxyquinoline derivatives containing the benzo[d]thiazole-2-yl urea moiety were synthesized and evaluated for their cytotoxicity against the HT-29, MKN-45, and H460 cell lines. The structures of the target compounds were confirmed by 1H NMR and MS spectra. Most of them showed moderate to excellent potency against the three tested cell lines. Especially, compound 23 was identified a promising agent (c-Met IC50 = 17.6 nM), showing the most potent anticancer activities with IC50 values of 0.18, 0.06, and 0.01 μM against the HT-29, MKN-45, and H460 cell lines, respectively. The docking results of 23 with the c-Met kinase model 3LQ8 showed a specific binding mode between the ligand and the target protein.
Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety
Tang, Qidong,Zhai, Xin,Tu, Yayi,Wang, Ping,Wang, Linxiao,Wu, Chunjiang,Wang, Wenhui,Xie, Hongbo,Gong, Ping,Zheng, Pengwu
, p. 1794 - 1798 (2016/12/22)
A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50= 1.21/2.15 nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure–activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity.
Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors
Liao, Weike,Hu, Gang,Guo, Zhuang,Sun, Deyu,Zhang, Lixia,Bu, Yanxin,Li, Yingxiu,Liu, Yajing,Gong, Ping
, p. 4410 - 4422 (2015/08/03)
A series of 4-(2-fluorophenoxy)quinoline derivatives containing an imidazolone moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, H460, HT-29 and MKN-45). Most compounds showed moderate to excellent activities in enzyme and cellular assays. The most promising analog, 58 (c-Met IC50 = 1.42 nM), displayed 2.1-, 8.6-fold increase against H460, and MKN-45 cell lines, respectively, compared with foretinib. An analysis of structure-activity relationships revealed that an ortho substituted phenyl ring as well as an N-unsubstituted imidazolone linker is favorable for antitumor activity.
