960299-69-8Relevant 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 evaluation of sulfonylurea-containing 4-phenoxyquinolines as highly selective c-Met kinase inhibitors
Nan, Xiang,Jiang, Yi-Fan,Li, Hui-Jing,Wang, Jun-Hu,Wu, Yan-Chao
, p. 2801 - 2812 (2019/05/15)
Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of 4-phenoxyquinoline derivatives bearing sulfonylurea moiety were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against tested four cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant potency as compared with foretinib, with the most promising compound 13x (c-Met kinase IC50 = 1.98 nM) demonstrated relatively good selectivity versus 10 other tyrosine kinases and remarkable cytotoxicities against HT460, MKN-45, HT-29 and MDA-MB-231 with IC50 values of 0.055 μM, 0.064 μM, 0.16 μM and 0.49 μM, respectively. The preliminary structure activity relationships indicated that a sulfonylurea moiety as linker as well as mono-EGWs (such as R1 = 4-F) on the terminal phenyl rings contributed to the antitumor activity.
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.
Quinoline compound containing five-membered heterocycle structure as well as preparation and application thereof
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, (2018/11/22)
The invention relates to a quinoline derivative containing a five-membered heterocycle structure shown as a general formula I as well as a pharmaceutically acceptable salt, hydrate or prodrug and a preparation method thereof. Substituents X, Ar, R1, R2, R3, Y, W and Z are defined in the description. The invention further relates to a compound shown as the general formula I as well as application of a pharmaceutically acceptable salt, hydrate or prodrug thereof in a medicament for treating diseases caused by unexcepted high expression of Axl kinase, in particular to application to the preparation of medicaments for treating and/or preventing cancer. The general formula I is shown in the description.
2-aryl-substituted quinoline compound and use thereof
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, (2016/10/24)
The invention provides 2-aryl-substituted quinoline compounds and application thereof. The invention relates to quinoline derivatives represented by a general formula I as described in the specification and pharmaceutically acceptable salts, solvates and prodrugs thereof. In the general formula I, substituent Ar, R1, R2, R3, R4, X, L and n are defined in the specification. The invention further relates to the strong c-Met kinase inhibiting effect of the compounds represented by the general formula I and to application of the compounds and the pharmaceutically acceptable salts, solvates and prodrugs thereof in preparation of drugs used for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, especially in preparation of drugs used for treating and/or preventing cancers.
Quinoline compound and its preparation method and application (by machine translation)
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, (2017/02/17)
The invention relates to the general formula I shown quinoline derivatives and their pharmaceutically acceptable salt, hydrate, solvate and prodrug, wherein substituent R1 , R2 , X, Y, Z, n has the meaning given in the specification. The invention also relates to the compounds of the general formula I has strong inhibition of c - Met kinase function, and also relates to the compounds and its pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof in the preparation of the treatment because the c - Met kinase abnormal high expression of diseases caused by the use of the medicaments, in particular in preparing and treating and/or preventing cancer of the use of the medicament. (by machine translation)
Pyrimidones including six hydrogens quinoline compound and its preparation method and application
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, (2018/02/04)
The invention relates to a quinolines compound containing hexahydropyrimidone, which is represented by a formula I, as well as pharmaceutically acceptable configurational isomers, salts, hydrates, solvates and prodrugs thereof. According to the quinolines compound, substituent groups R1, R2, R3, X, Y, Z and n have definitions given in the specification. The invention further relates to the compound of the formula I and the configurational isomers which have a very strong effect of inhibiting c-Met kinase, further relates to an application of the compounds and the pharmaceutically acceptable salts, hydrates, solvates or prodrugs in preparing a medicine for treating diseases caused by hydrates high expression of the c-Met kinase, and particularly relates to an application of a medicine for preparing a medicine for treating and/or preventing cancers.
