- Design, synthesis, and biological evaluation of novel Bcr-AblT315I inhibitors incorporating amino acids as flexible linker
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Despite the success of imatinib in CML therapy through Bcr-Abl inhibition, acquired drug resistance occurs over time in patients. In particular, the resistance caused by T315I mutation remains a challenge in clinic. Herein, we embarked on a structural optimization campaign aiming at discovery of novel Bcr-Abl inhibitors toward T315I mutant based on previously reported dibenzoylpiperazin derivatives. We proposed that incorporation of flexible linker could achieve potent inhibition of Bcr-AblT315I by avoiding steric clash with bulky sidechain of Ile315. A library of 28 compounds with amino acids as linker has been developed and evaluated. Among them, compound AA2 displayed the most potent activity against Bcr-AblWT and Bcr-AblT315I, as well as toward Bcr-Abl driven K562 and K562R cells. Further investigations indicated that AA2 could induce apoptosis of K562 cells and down regulate phosphorylation of Bcr-Abl. In summary, the compounds with amino acid as novel flexible linker exhibited certain antitumor activities, providing valuable hints for the discovery of novel Bcr-Abl inhibitors to overcome T315I mutant resistance, and AA2 could be considered as a candidate for further optimization.
- Li, Yanchen,Li, Zilong,Liu, Nanxin,Pan, Xiaoyan,Shan, YuanYuan,Wang, Kai,Zhang, Jie,Zhang, Qingqing
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- Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity
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The phosphoinositide 3-kinase (PI3K) inhibitors potently inhibit the signaling pathway of PI3K/AKT/mTOR, which provides a promising new approach for the molecularly targeted cancer therapy. In this work, a novel series of 7-azaindole scaffold derivatives was discovered by the fragment-based growing strategy. The structure-activity relationship profiles identified that the 7-azaindole scaffold derivatives exhibit potent activity against PI3K at molecular and cellular levels as well as cell proliferation in a panel of human tumor cells.
- Yang, Chengbin,Zhang, Xi,Wang, Yi,Yang, Yongtai,Liu, Xiaofeng,Deng, Mingli,Jia, Yu,Ling, Yun,Meng, Ling-Hua,Zhou, Yaming
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supporting information
p. 875 - 880
(2017/08/16)
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- PI3K inhibitor, preparation method and application thereof in pharmacy
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The invention belongs to the technical field of pharmaceuticals and particularly relates to a PI3K inhibitor, a preparation method and application thereof in the pharmacy. The PI3K inhibitor is a compound of the structure shown by the general formula I or medically acceptable salt of the inhibitor. After the PI3K inhibitor is tested with a PI3K biochemical activity test method, the compound has excellent inhibitory activity to PI3K alpha and PI3K gamma, wherein the IC50 values of a plurality of compounds to the PI3K alpha and PI3K gamma reach nanomole grades (smaller than 100 nM). The result shows that the compounds can provide the inhibitor with better effectiveness and selectivity for curing PI3K-acted proliferative disease, and further a targeted drug for curing No. I type diabetes mellitus, lung disease, breast cancer, prostatic cancer, solid tumor, lymphoma, cardiovascular disease, rheumatoid arthritis, leukemia and the like can be hopefully developed. (Please see the general formula I in the description.).
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Paragraph 0230; 0231; 0232
(2016/12/26)
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- Discovery of novel Bcr-Abl inhibitors with diacylated piperazine as the flexible linker
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Forty-two compounds (series 8, 9 and 10) incorporated with diacylated piperazine have been synthesized and evaluated as novel Bcr-Abl inhibitors based on 'six-atom linker'. Five of them, 8d, 8h, 8l, 10m and 10p, displayed potent Bcr-Abl inhibitory activity comparable with Imatinib. Moreover, compounds 8e, 10q, 10s, and 10u were potent Bcr-Abl inhibitors with IC50 values at the sub-micromolecular level. Most compounds exhibited moderate to high antiproliferative activity against K562 cells. In particular, compound 9e was the most promising Bcr-Abl inhibitor. Docking studies revealed that the binding modes of these compounds were similar with Imatinib. These compounds could be considered as promising lead compounds for further optimization.
- Pan, Xiaoyan,Dong, Jinyun,Shi, Yaling,Shao, Ruili,Wei, Fen,Wang, Jinfeng,Zhang, Jie
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p. 7050 - 7066
(2015/06/25)
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- A practical source of chlorodifluoromethyl radicals. Convergent routes to gem -difluoroalkenes and -dienes and (2,2-Difluoroethyl)-indoles, -azaindoles, and -naphthols
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The preparation of O-octadecyl-S-chlorodifluoromethyl xanthate from chlorodifluoroacetic acid and its use as a convenient source of chlordifluoromethyl radicals is described. This reagent may be used to access gem-difluoroalkenes and -dienes, as well as (2,2-difluoroethyl)indolines, -indoles, and -naphthols.
- Salomon, Pierre,Zard, Samir Z.
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supporting information
p. 2926 - 2929
(2014/06/23)
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- Analysis of structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea analogues as TRPV1 antagonists
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The structure-activity relationships for the 'A-region' of N-(4-t-butylbenzyl)-N′-[4-(methylsulfonylamino)benzyl]thiourea analogues have been investigated as TRPV1 receptor antagonists. The 2-halogen analogues showed enhanced antagonism compared to the prototype antagonist.
- Lee, Jeewoo,Kang, Sang-Uk,Kil, Min-Jung,Shin, Myoungyoup,Lim, Ju-Ok,Choi, Hyun-Kyung,Jin, Mi-Kyoung,Kim, Su Yeon,Kim, Sung-Eun,Lee, Yong-Sil,Min, Kyung-Hoon,Kim, Young-Ho,Ha, Hee-Jin,Tran, Richard,Welter, Jacqueline D.,Wang, Yun,Szabo, Tamas,Pearce, Larry V.,Lundberg, Daniel J.,Toth, Attila,Pavlyukovets, Vladimir A.,Morgan, Matthew A.,Blumberg, Peter M.
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p. 4136 - 4142
(2007/10/03)
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