4101-32-0Relevant articles and documents
Photocaged and Mixed Photocaged Bioreversible-Protected ATP Derivatives as Tools for the Controlled Release of ATP
Jeschik, Nils,Meier, Chris,Schneider, Tobias
, p. 6776 - 6789 (2020/11/23)
Adenosine triphosphate (ATP) is known as the universal energy source for cellular processes, in addition, ATP also plays an important role in inflammation and cell signaling. Extracellular ATP binds to purinergic receptors and initiates further immune responses. To investigate these processes in-depth and to understand the complex mechanism of purinergic signaling, chemical tools are necessary. Here we present the synthesis of different photocaged ATP derivatives and the investigation of the light-induced release of ATP depending on the different synthesized photocleavable protecting groups based on the 2-nitrobenzyl moiety. Furthermore, we also present the synthesis of a mixed protected ATP-derivative as an example for a novel class of lipophilically caged nucleoside triphosphates. This new type of compounds is protected with a highly lipophilic non-toxic bio-removable acyloxybenzyl group and a photocleavable group. This combination may allow both passive cell uptake and controlled release of ATP by irradiation with non-harmful UV light.
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.
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.
Novel substituted pyrazolo [1, 5-a] pyrimidine compound and preparation method and application thereof
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Paragraph 0199-0203, (2020/08/02)
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.
Design, synthesis, and biological evaluation of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives as FLT3 inhibitors for the treatment of acute myeloid leukemia
Xu, Qiaoling,Dai, Baozhu,Li, Zhiwei,Xu, Le,Yang, Di,Gong, Ping,Hou, Yunlei,Liu, Yajing
supporting information, (2019/08/27)
FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N′-dimeth
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.
EGFR INHIBITOR, AND PREPARATION AND APPLICATION THEREOF
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Paragraph 0106; 0354; 0355, (2017/09/02)
A 4-substituted-2-(N-(5-substituted allyl amide)phenyl)amino)pyrimidine derivative as represented by formula (I), and a preparation and application thereof as an EGFR inhibitor. The compound has activity of inhibiting the L858R EGFR mutant, the T790M EGFR mutant and the exon 19 deletion activating mutant, may be used to treat diseases mediated alone or in part by EGFR mutant activity, and has a wide application in drugs preventing and treating cancers, particularly non-small cell lung cancer.
Triggering a [2]Rotaxane Molecular Shuttle by a Photochemical Bond-Cleavage Strategy
Gao, Chuan,Luan, Zhou-Lin,Zhang, Qi,Yang, Shun,Rao, Si-Jia,Qu, Da-Hui,Tian, He
supporting information, p. 1618 - 1621 (2017/04/13)
The successful triggering of ring-shuttling motion between two stations in a [2]rotaxane is demonstrated by employing a photochemical bond-cleavage strategy. A photolabile bulk barrier is covalently introduced into two identical stations of the thread to
A new and practical synthesis of tivozanib
Zhu, Chunping,Mao, Yongjun,Wang, Han,Xu, Jingli
, p. 1882 - 1887 (2016/11/06)
New and improved synthetic route of tivozanib is described on a hectogram scale. An reduction cyclization process to prepare the key intermediate 6,7-dimethoxyquinolin-4-ol from the 3-(dimethylamino)-1-(2-nitrophenyl)prop-2-en-1-one compound at H2/Ni cond
