- QUINOLINE OR QUINAZOLINE COMPOUND AND APPLICATION THEREOF
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The present invention relates to quinoline or quinazoline compound represented by the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a prodrug molecule thereof, or a deuterated compound thereof. The compound of the presen
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Paragraph 0086; 0089
(2021/02/18)
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- Discovery of 1,6-naphthyridinone-based MET kinase inhibitor bearing quinoline moiety as promising antitumor drug candidate
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A series of 1,6-naphthyridinone-based MET kinase inhibitors bearing quinoline moiety in block A were designed and synthesized based on the structures of Cabozantinib and our reported compound IV. Extensive SAR and DMPK studies led to the identification of 20j, a potent and orally bioavailable MET kinase inhibitor with favorable kinase selectivity. More importantly, 20j exhibited statistically significant tumor growth inhibition (Tumor growth inhibition/TGI of 131%, 4/6 partial regression/PR) in the U-87 MG xeograft model, which is superior to that of Cabozantinib (TGI of 97%, 2/6 PR), and significantly better than that of compound IV (TGI of 15%, 0/6 PR) at the same dose (12.5 mg/kg). Combined with favorable in vitro potency, kinase selectivity, pharmacokinetic profile and in vivo efficacy, the promising antitumor drug candidate 20j has subsequently advanced into preclinical research.
- Chen, Tao,Fang, Wei-Rong,Huang, Wei,Li, Yun-Man,Liu, Peng-Fei,Zhuo, Lin-Sheng
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- Discovery of small molecule FLT3 inhibitors that are able to overcome drug-resistant mutations
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Herein we report the discovery of 1-(5-(tert-butyl)isoxazol-3-yl)-3- (3-fluorophenyl)urea derivatives as new FLT3 inhibitors that are able to overcome the drug resistance mutations: the secondary D835Y and F691L mutations on the basis of the internal tandem duplications (ITD) mutation of FLT3 (FLT3-ITD/D835Y and FLT3-ITD/F691L, respectively). The most potent compound corresponds to 1-(5-(tert-butyl)isoxazol-3-yl)-3-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3- fluorophenyl)urea (4d), which showed IC50s (half maximal inhibitory concentrations) of 0.072 nM, 5.86 nM and 3.48 nM against FLT3-ITD, FLT3-ITD/F691L and FLT3-ITD/D835Y, respectively. Compound 4d also showed good selectivity for FLT3 in a kinase profiling assay. Collectively, 4d could be a good lead compound and deserves further in-depth studies.
- Chen, Ming,Lai, Shusheng,Li, Bolin,Li, Linli,Nan, Jinshan,Shen, Chenjian,Wang, Tianqi,Wang, Yifei,Yang, Shengyong,Zhang, Guo,Zhang, Wenqing,Zhong, Jiemin
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supporting information
(2020/10/02)
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- Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof
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The invention provides a novel substituted pyrazolo [1, 5-a]pyrimidine compound and a preparation method and application thereof, and particularly relates to a pyrazolo [1, 5-a]pyrimidine-containing quinoline derivative shown as a general formula (I) and pharmaceutically acceptable salts thereof, and substituent groups X, Ar and A have meanings given in the specification. The invention also relates to a compound represented by the general formula (I), wherein the compound has a strong c-Met kinase inhibition effect. The invention also relates to application of the compound and the pharmaceutically acceptable salt thereof in preparation of drugs for treating and/or preventing diseases caused by abnormal high expression of c-Met kinase, especially application in preparation of drugs for treating and/or preventing cancers.
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- Compound and application thereof in preparation of drugs for treating diseases caused by high expression of Flt3/c-Met kinase
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The invention belongs to the technical field of chemical drug synthesis, and provides a compound and application thereof in preparation of drugs for treating diseases caused by high expression of Flt3/cMet kinase. The compound provided by the invention is prepared by amidation reaction of an intermediate A and an intermediate B. The compound provided by the invention has a strong effect of inhibiting Flt3/cMet kinase. The invention also discloses application of the compound and salt, solvate or prodrug thereof, or application of a pharmaceutical composition composed of one of the compound, salt, hydrate, solvate and prodrug thereof and an excipient in preparation of drugs for treating diseases caused by abnormal high expression of Flt3/cMet kinase, and application in drugs for treating and/or preventing proliferative diseases or cancers.
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- Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction
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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.
- Fang, Sen-Biao,Li, Hui-Jing,Nan, Xiang,Wu, Rui,Wu, Yan-Chao,Zhang, Jing,Zhang, Zhi-Zhou
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- QUINOLINE DERIVATIVES USEFUL AS TYROSINE KINASE INHIBITORS
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Disclosed are imidazole compounds, as well as pharmaceutical compositions and methods of use thereof. One embodiment is a compound having the structure (I) and pharmaceutically acceptable salts, prodrugs and N-oxides thereof (and solvates and hydrates thereof), wherein R1, X, Y1, Y2, Y3 and Z are as described herein. In certain embodiments, a compound disclosed herein inhibits a cellular TAM receptor, and can be used to treat disease mediated by or involving the TAM receptor family.
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- Design, synthesis and evaluation of sulfonylurea-containing 4-phenoxyquinolines as highly selective c-Met kinase inhibitors
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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.
- Nan, Xiang,Jiang, Yi-Fan,Li, Hui-Jing,Wang, Jun-Hu,Wu, Yan-Chao
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p. 2801 - 2812
(2019/05/15)
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- Design, synthesis, and biological evaluation of 4-phenoxyquinoline derivatives as potent c-Met kinase inhibitor
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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.
- Yang, Yifeng,Li, Yingxiu,Hou, Yunlei,Qin, Mingze,Gong, Ping,Liu, Ju,Zhao, Yanfang
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- Preparation methods of tyrosine kinase inhibitor XJF007 and its intermediate
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The invention discloses preparation methods of tyrosine kinase inhibitor XJF007 with a general structural formula (I) and its intermediate. The preparation method of the tyrosine kinase inhibitor XJF007 employs a collecting synthesis strategy of construct
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Paragraph 0049; 0050; 0060-0062
(2019/07/04)
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- Preparation and application of 6,7-disubstituted-4-aromatic quinoline compound
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The invention relates to a 6,7-disubstituted-4-aromatic quinoline derivative shown as a general formula I as well as pharmaceutically-acceptable salt, a hydrate, a solvate and pro-drug thereof, wherein substituents R1, X and Y have meanings given in the description. The invention further relates to a compound with a strong effect on inhibiting c-Met kinase shown as the general formula I and further relates to application of the compound and pharmaceutically-acceptable salt, a hydrate, a solvate and pro-drug thereof to preparation of a drug for treating a disease caused by the abnormally-high expression of the c-Met kinase, in particular to application to preparation of a drug for treating and/or preventing a cancer.
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- Design, synthesis and biological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing pyridazinone moiety as c-Met Inhibitors
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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.
- Liu, Xiaobo,Kou, Jianlan,Xiao, Zhen,Tian, Fajuan,Hu, Jiayi,Zheng, Pengwu,Zhu, Wufu
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- Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety
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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.
- Tang, Qidong,Duan, Yongli,Xiong, Hehua,Chen, Ting,Xiao, Zhen,Wang, Linxiao,Xiao, Yueyue,Huang, Shunmin,Xiong, Yinhua,Zhu, Wufu,Gong, Ping,Zheng, Pengwu
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p. 201 - 213
(2018/09/18)
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- Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors
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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.
- Szabadkai, István,Torka, Robert,Garamv?lgyi, Rita,Baska, Ferenc,Gyulavári, Pál,Boros, Sándor,Illyés, Eszter,Choidas, Axel,Ullrich, Axel,órfi, László
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supporting information
p. 6277 - 6292
(2018/07/05)
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- Polysubstituted quinolone compounds, and preparation method and use thereof
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The invention provides polysubstituted quinolone compounds, and a preparation method and a use thereof, and concretely provides a polysubstituted quinolone compound represented by formula I, and optical isomers, pharmaceutically acceptable salts or solvates thereof. All groups in the formula I are defined in the description. The quinolone compound has excellent c-Met inhibition activity, and can be used for treating c-Met activity or expression level corrected diseases.
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Paragraph 0165; 0166; 0167
(2017/09/19)
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- Quinolines compound containing diarylurea structure and application thereof
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The invention relates to a quinolines compound containing a diarylurea structure, which is shown as a general formula I, pharmaceutically acceptable salts thereof and application of a pharmaceutical composition taking the compound as an active component to preparation of medicines for treating and/or preventing diseases caused by abnormal expression of FLT3 kinase. Substituent groups R1, R2, Ar, X, Y, Z and n have definitions given in the description. The general formula I is as shown in the specification.
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- Quinoline derivatives (by machine translation)
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A compound represented by general formula (I) (I) has a strong Axl inhibiting activity by introducing a distinctive bicyclic structure in which a saturated carbocyclic ring is fused to a pyridone ring, and thus may be used as a therapeutic agent for Axl related diseases such as acute myeloid leukemia, melanoma, breast cancer, pancreatic cancer, cancer such as glioma, kidney disease, immune system disease, and circulatory system disease.
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- Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors
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In continuing our efforts to identify small molecules able to inhibit c-Met kinase, three series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives (23a-w, 26a-d and 30a-d) bearing (thio)semicarbazone scaffold were designed, synthesized and evaluated for their cytotoxicity. The biological data revealed that most compounds exhibited moderate-to-excellent activity against HT-29, MKN-45, A549 cancer cell lines and relative poor potency toward MDA-MB-231 cell as well as hardly any cytotoxicity in normal PBL cell. Eleven compounds were further examined for their inhibitory activity against c-Met kinase and three compounds (23h, 23n and 26a) demonstrated good inhibitory activity. This work resulted in the discovery of a potent c-Met inhibitor 23n, bearing 2-hydroxy-3-allylphenyl group at R2 moiety, as a valuable lead molecule, which possessed remarkable cytotoxicity and high selectivity against A549 and HT-29 cell lines with IC50 values of 11 nM and 27 nM. Besides, it displayed excellent c-Met kinase inhibition on a single-digital nanomolar level (IC50 = 1.54 nM). Meanwhile, the results from preliminarily in vivo study reflected that compound 23n showed promising overall PK profiles, consistent with the efficacy in both MKN-45 and HT-29 tumor xenograft mice model. These results clearly indicated that compound 23n is a potent and highly selective c-Met inhibitor and its favorable in vitro and in vivo profiles warrant further investigation.
- Zhai, Xin,Bao, Guanglong,Wang, Limei,Cheng, Mingke,Zhao, Meng,Zhao, Sijia,Zhou, Hongyang,Gong, Ping
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p. 1331 - 1345
(2016/03/01)
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- 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
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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.
- Liu, Mingmei,Hou, Yunlei,Yin, Weile,Zhou, Shunguang,Qian, Ping,Guo, Zhuang,Xu, Liying,Zhao, Yangfang
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- Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing 1,2,4-triazolone moiety as c-Met kinase inhibitors
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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.
- Liu, Ju,Nie, Minhua,Wang, Yanjing,Hu, Jinxing,Zhang, Feng,Gao, Yanlin,Liu, Yajing,Gong, Ping
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p. 431 - 446
(2016/08/04)
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- Design, Synthesis, and Biological Evaluation of 4-Phenoxyquinoline Derivatives Containing Benzo[d]thiazole-2-yl Urea as c-Met Kinase Inhibitors
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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.
- Lei, Hongrui,Hu, Gang,Wang, Yu,Han, Pei,Liu, Zijian,Zhao, Yanfang,Gong, Ping
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p. 651 - 661
(2016/08/27)
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- Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety
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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.
- Tang, Qidong,Zhai, Xin,Tu, Yayi,Wang, Ping,Wang, Linxiao,Wu, Chunjiang,Wang, Wenhui,Xie, Hongbo,Gong, Ping,Zheng, Pengwu
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p. 1794 - 1798
(2016/12/22)
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- Design and biological evaluation of novel 4-(2-fluorophenoxy)quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors
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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.
- Liao, Weike,Hu, Gang,Guo, Zhuang,Sun, Deyu,Zhang, Lixia,Bu, Yanxin,Li, Yingxiu,Liu, Yajing,Gong, Ping
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p. 4410 - 4422
(2015/08/03)
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- Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5-(aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors
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A series of novel quinoline derivatives bearing 5-(aminomethylene) pyrimidine-2,4,6-trione moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 45 (c-Met half-maximal inhibitory concentration [IC50] = 1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2, Flt-3, PDGFR-β, c-Kit, and EGFR. Structure-activity relationship studies indicated that electron-donating groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the electron density on the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety.
- Tang, Qidong,Zhang, Guogang,Du, Xinming,Zhu, Wufu,Li, Ruijuan,Lin, Huafang,Li, Pengcheng,Cheng, Maosheng,Gong, Ping,Zhao, Yanfang
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p. 1236 - 1249
(2014/03/21)
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- Design, synthesis and structure-activity relationships of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety as potential antitumor agents
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A series of novel 4-phenoxyquinoline derivatives containing pyridazinone moiety were synthesized and evaluated for their in vitro cytotoxic activity against five cancer cell lines (HT-29, H460, A549, MKN-45, and U87MG). Most of the compounds exhibited moderate-to-significant cytotoxicity and high selectivity against one or more cell lines. Compounds 15a, 20a, 15b, 15c, 20d, and 16e were further examined for their inhibitory activity against c-Met kinase. The most promising compound 15a (c-Met half-maximal inhibitory concentration [IC50] = 2.15 nM) showed remarkable cytotoxicity against HT-29, H460, and A549 cell lines with IC50 values of 0.10 μM, 0.13 μM, and 0.05 μM, respectively, and thus it was 1.5- 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.
- Zhou, Shunguang,Liao, Huimin,He, Chao,Dou, Yanan,Jiang, Mingyan,Ren, Lixiang,Zhao, Yanfang,Gong, Ping
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p. 581 - 593
(2014/07/21)
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- Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4- phenoxyquinoline derivatives as potential antitumor agents
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Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50 = 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50 values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
- Zhou, Shunguang,Ren, Jianguo,Liu, Mingmei,Ren, Lixiang,Liu, Yajing,Gong, Ping
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- Design, synthesis and pharmacological evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents
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Two series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 2,4-imidazolinedione/pyrazolone scaffold were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against HT-29, H460, A549, MKN-45, and U87MG cancer cell lines in vitro. The pharmacological data indicated that most of the tested compounds showed moderate to significant cytotoxicity and high selectivity against HT-29, H460 and A549 cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially trifluoromethyl groups at 2-position on the phenyl ring (moiety B) were more effective. In this study, a promising compound 17 (c-Met IC50= 2.20 nM, a multi-target tyrosine kinase inhibitor) showed the most potent antitumor activities with IC50values of 0.14 μM, 0.18 μM, 0.09 μM, 0.03 μM, and 1.06 μM against HT-29, H460, A549, MKN-45, and U87MG cell lines, respectively.
- Zhou, Shunguang,Ren, Jianguo,Liu, Mingmei,Ren, Lixiang,Liu, Yajing,Gong, Ping
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- Discovery and biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors
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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 biological activities against c-Met kinase and five typical cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG). Most compounds showed moderate to excellent antiproliferative activity. In this study, a promising compound 34, with a c-Met IC50 value of 1.04 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor. The SAR analyses indicated that compounds with halogen group, especially fluoro group, at 4-position on the phenyl ring (moiety B) have potent antitumor activity, and methylation on the 5-atom linker played an important role in the c-Met enzymatic activity.
- Zhou, Shunguang,Liao, Huimin,Liu, Mingmei,Feng, Guobing,Fu, Baolin,Li, Ruijuan,Cheng, Maosheng,Zhao, Yanfang,Gong, Ping
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p. 6438 - 6452
(2015/02/02)
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- Design, synthesis and biological evaluation of novel 6,7-disubstituted-4- phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties as c-Met kinase inhibitors
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A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 4-oxo-3,4-dihydrophthalazine-1-carboxamide moieties were designed, synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against H460, MKN-45, HT-29 and MDA-MB-231 cancer cell lines in vitro. Most compounds displayed good to excellent potency against four tested cancer cell lines as compared with foretinib. The SAR analyses indicated that compounds with halogen groups, especially fluoro groups at 4-position on the phenyl ring (moiety B) were more effective than those with nitro groups or methoxy groups. In this study, a promising compound 33 (c-Met IC50 = 1.63 nM) was identified, which showed the most potent antitumor activities with IC50 values of 0.055 μM, 0.071 μM, 0.13 μM, and 0.43 μM against H460, MKN-45, HT-29 and MDA-MB-231 cell lines, respectively.
- Liu, Zijian,Wang, Rui,Guo, Ruiming,Hu, Jinxing,Li, Ruijuan,Zhao, Yanfang,Gong, Ping
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p. 3642 - 3653
(2014/07/07)
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- Discovery and biological evaluation of novel dual EGFR/c-Met inhibitors
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Activating mutations in the epidermal growth factor receptor (EGFR) have been identified in a subset of non-small cell lung cancer (NSCLC), which is one of the leading cancer types worldwide. Application of EGFR tyrosine kinase inhibitors leads to acquire
- Szokol, Balint,Gyulavari, Pal,Kurko, Ibolya,Baska, Ferenc,Szantai-Kis, Csaba,Greff, Zoltan,Orfi, Zoltan,Petak, Istvan,Penzes, Kinga,Torka, Robert,Ullrich, Axel,Orfi, Laszlo,Vantus, Tibor,Keri, Gyoergy
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supporting information
p. 298 - 303
(2014/05/06)
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- Discovery and optimization of novel 4-phenoxy-6,7-disubstituted quinolines possessing semicarbazones as c-Met kinase inhibitors
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A novel series of N1-(3-fluoro-4-(6,7-disubstituted-quinolin-4- yloxy)phenyl)-N4-arylidenesemicarbazide derivatives were synthesized and evaluated for their c-Met kinase inhibition and cytotoxicity against A549, HT-29, MKN-45 and MDA-MB-231 cancer cell lines in vitro. Several potent compounds were further evaluated against three other cancer cell lines (U87MG, NCI-H460 and SMMC7721). Most of compounds tested exhibited moderate to excellent activity. The studies of SARs identified the most promising compound 28 (c-Met IC50 = 1.4 nM) as a c-Met kinase inhibitor. In this study, a promising compound 28 was identified, which displayed 2.1-, 3.3-, 48.4- and 3.6-fold increase against A549, HT-29, U87MG and NCI-H460 cell lines, respectively, compared with that of Foretinib.
- Qi, Baohui,Mi, Bin,Zhai, Xin,Xu, Ziyi,Zhang, Xiaolong,Tian, Zeru,Gong, Ping
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p. 5246 - 5260
(2013/09/02)
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- Design, synthesis, and structure-activity relationships of novel 6,7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents
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Two series of quinoline derivatives bearing the pyridine/pyrimidine scaffold were synthesized, and evaluated for their c-Met kinase inhibitory activity and antiproliferative activity against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) were evaluated in vitro. Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 18b (c-Met half-maximal inhibitory concentration [IC50] = 1.39 nM) showed a 7.3-fold increase in activity against HT-29 cell line in vitro. Structure-activity relationship studies indicated that regulation of the electron density on the pyridine/pyrimidine ring to a proper degree was a key factor in improving the antitumor activity.
- Tang, Qidong,Zhao, Yanfang,Du, Xinming,Chong, Lian'E,Gong, Ping,Guo, Chun
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- Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors
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A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.
- Li, Sai,Zhao, Yanfang,Wang, Kewen,Gao, Yali,Han, Jianming,Cui, Bingbing,Gong, Ping
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p. 2843 - 2855
(2013/06/27)
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- Synthesis and antitumor activity of novel 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-Oxo-1,4-dihydroquinoline-3-carboxamide moiety
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A series of 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-oxo-1,4-dihydroquinoline-3-carboxamide moiety were designed, synthesized, and evaluated for their in vitro antitumor activity against the H460, HT-29, MKN-45, U87MG, and SMMC-7721 cancer cell lines. Most of the tested compounds showed potent activity and high selectivity toward the HT-29 and MKN-45 cell lines. Furthermore, compounds 21b, 21c, and 21i were further examined for their c-Met kinase activity and exhibited strong efficacy with IC50 values in the single-digit nanomolar range, which was comparable with the positive control foretinib. The most promising compound 21c showed excellent cytostatic activity with IC50 values from 0.01 to 0.53 μM against all tested cell lines, thus being 1.7-2.2 times more active than foretinib. Novel 4-(2-fluorophenoxy)quinoline derivatives bearing the 4-oxo-1,4-dihydroquinoline- 3-carboxamide moiety were evaluated for their in vitro antitumor activity against several cancer cell lines. Compounds 21b, 21c, and 21i were also examined for their c-Met kinase activity in comparison to foretinib. Compound 21c showed excellent cytostatic activity with IC50 values from 0.01 to 0.53 μM against all tested cell lines and higher activity than foretinib.
- Li, Sai,Jiang, Rui,Qin, Mingze,Liu, Haicheng,Zhang, Guangyan,Gong, Ping
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p. 521 - 533
(2013/07/26)
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- Design, synthesis and antitumour activity of bisquinoline derivatives connected by 4-oxy-3-fluoroaniline moiety
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A series of novel bisquinoline derivatives connected by a 4-oxy-3-fluoroaniline moiety were synthesized and evaluated for their in vitro antitumour activities against a panel of five cancer cell lines (H460, HT-29, MKN-45, U87MG, and SMMC-7721). Most of compounds tested showed a potent activity and high selectivity towards the H460 and MKN-45 cell lines. Among the compounds tested, six (15d, 15e, 15m, 15n, 16a, and 16i) were further examined for their c-Met kinase activity; the compounds showed high efficacy with IC 50 values in the single-digit nM range. An analysis of structure-activity relationships indicated that an unsubstituted or a halogen-substituted phenyl ring on the 2-arylquinoline-4-carboxamide moiety was favourable for antitumour activity.
- Li, Sai,Huang, Qiang,Liu, Yajing,Zhang, Xiaolong,Liu, Shuang,He, Chao,Gong, Ping
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- PROCESS FOR PREPARING QUINOLINE DERIVATIVES
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A process for preparing a compound of Formula I is disclosed, comprising the steps: wherein: R1 is halo; R2 is halo; R3 is (C1-C6)alkyl or (C1-C6)alkyl optionally substituted wit
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- METHODS OF PREPARING QUINOLINE DERIVATIVES
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A Method of preparing a compound of formula i(1) or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 join together with the nitrogen atom to which they are attached form a 6 membered heterocycloalkyl X1 is H,
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Page/Page column 36-37
(2010/06/15)
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- METHODS OF PREPARING QUINOLINE DERIVATIVES
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Methods of preparing compounds of formula i(1): or a pharmaceutically acceptable salt R1 and R2 join together with the nitrogen atom to which they are attached to form a 6 membered heterocycloalkyl group; X1 is H, Br, Cl o
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Page/Page column 29; 30
(2010/06/20)
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- QUINOLINE COMPOUNDS AND METHODS OF USE
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Compounds of Formula I, and stereoisomers, geometric isomers, tautomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs thereof, are useful for inhibiting receptor tyrosine kinases and for treating hyperproliferative disorders mediated thereby. Methods of using compounds of Formula I, and stereoisomers, geometric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed. [ Formula I]
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Page/Page column 133; 134
(2008/06/13)
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- QUINOLINE DERIVATIVE AND QUINAZOLINE DERIVATIVE INHIBITING SELF?PHOSPHORYLATION OF HEPATOCYTUS PROLIFERATOR RECEPTOR, AND MEDICINAL COMPOSITION CONTAINING THE SAME
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An objective of the present invention is to provide compounds having potent antitumor activity. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: wherein X = CH or N; Z = O or S
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