13425-93-9Relevant articles and documents
A New Synthesis of Cabozantinib
Fang, Ran,Wang, Bin,Zhao, Zhiwei,Yin, Lingfeng,Wang, Han,Xu, Jingli
, p. 381 - 387 (2019)
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Design, Synthesis and Biological Evaluation of Novel α-Acyloxycarboxamide-Based Derivatives as c-Met Inhibitors
Feng, Yu-juan,Ren, Yu-Lin,Zhao, Li-Ming,Xue, Guo-Qiang,Yu, Wen-Hao,Yang, Jia-Qi,Liu, Jun-Wei
, p. 2241 - 2250 (2021/06/28)
Dysregulated HGF/c-Met signalling has been associated with many human cancers, poor clinical outcomes, and even resistance acquisition to some approved targeted therapies. As such, c-Met kinase has emerged as an attractive target for anticancer drug discovery. Herein, a series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives bearing α-acyloxycarboxamide moiety were designed, synthesized via Passerini reaction as the key step, and evaluated for their in vitro biological activities against c-Met kinase and five selected cancer cell lines. The preliminary structure-activity relationship demonstrated that α-acyloxycarboxamide as the 5-atom linker maintained the potent antitumor potency. Among these compounds, compound 25s (c-Met IC50 = 4.06 nmol/L) was identified as the most promising lead compound and displayed the most potent antiproliferative activities against A549, HT-29 and MDA-MB-231 cell lines with IC50 of 0.39, 0.20, and 0.58 μmol/L, which were 1.3-, 1.4- and 1.2-fold superior to foretinib, respectively. The further studies indicated that compound 25s can induce apoptosis of A549 cells and arrest efficiently the cell cycle distribution in G2/M phase of A549 cells. Moreover, compound 25s can also inhibit c-Met phosphorylation in A549 cells by a dose-dependent manner. Collectively, these results indicated that compound 25s could be a potential anticancer lead compound deserving for further development.
N-(5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound
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, (2021/06/09)
The invention belongs to the technical field of medicines, relates to a compound with antitumor activity and a specific chemical structure, and in particular relates to an N-((6, 7-dimethoxyquinoline-4-yl) oxy) methyl)-N-(5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound and a preparation method and an application thereof. The structural general formula of the compound is shown in the specification, wherein an R group is mono-substituted or double-substituted phenyl, fluorophenyl, chlorphenyl, bromophenyl, benzyl, benzyloxy, benzene nitro or trifluoromethyl substituted at 2-position, 3-position or 4-position. Pharmacological studies show that the compound provided by the invention has a relatively remarkable proliferation inhibition effect on HER-2 positive breast cancer cells SK-Br-3, the effect is obviously superior to that of HER-2 negative breast cancer cells MCF-7, the compound can be used for preparing antitumor drugs, and a new way is opened up for deep research and development of tumor drugs in the future. The preparation method provided by the invention is simple and feasible, relatively high in yield and easy for large-scale production.
Structure-based discovery of novel 4-(2-fluorophenoxy)quinoline derivatives as c-Met inhibitors using isocyanide-involved multicomponent reactions
Fang, Sen-Biao,Li, Hui-Jing,Li, Qin-Ying,Nan, Xiang,Wu, Yan-Chao
, (2020/03/23)
The c-Met kinase has emerged as a promising target for the development of small molecule antitumor agents because of its close relationship with the progression of many human cancers, poor clinical outcomes and even drug resistance. In this study, two novel series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives containing α-acyloxycarboxamide or α-acylaminoamide scaffolds were designed, synthesized, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (H460, HT-29, MKN-45, and MDA-MB-231). Most of the target compounds exhibited moderate to significant potency and possessed selectivity for H460 and HT-29 cancer cell lines. The preliminary structure-activity relationships indicated that α-acyloxycarboxamide or α-acylaminoamide as 5-atom linker contributed to the antitumor potency. Among these compounds, compound 10m (c-Met IC50 = 2.43 nM, a multitarget tyrosine kinase inhibitor) exhibited the most potent inhibitory activities against H460, HT-29 and MDA-MB-231 cell lines with IC50 of 0.14 ± 0.03 μM, 0.20 ± 0.02 μM and 0.42 ± 0.03 μM, which were 1.7-, 1.3- and 1.6-fold more active than foretinib, respectively. In addition, concentration-dependent assay and time-dependent assay indicated compound 10m can inhibit the proliferation of H460 cell in a time and concentration dependent manner. Moreover, docking studies revealed the common mode of interaction with the c-Met binding site, suggesting that 10m is a potential candidate for cancer therapy deserving further study.
