363-77-9Relevant articles and documents
Design, synthesis, and evaluation of novel CXCR4 antagonists based on an aminoquinoline template
Hao, Yongjin,He, Sudan,Li, Zhanhui,Lin, Yu,Luo, Lusong,Ma, Haikuo,Wu, Shuwei,Xia, Kaijiang,Xu, Chen,Yang, Qing,Zhang, Xiaohu,Zheng, Jiyue,Zhu, Fang
, (2020/04/23)
The chemokine receptor CXCR4 has been explored as a drug target due to its involvement in pathological conditions such as HIV infection and cancer metastasis. Here we report the structure–activity relationship study of novel CXCR4 antagonists based on an aminoquinoline template. This template is devoid of the chiral center in the classical tetrahydroquinoline (THQ) ring moiety and therefore can be easily synthesized. A number of potent CXCR4 antagonists were identified, exemplified by compound 3, which demonstrated excellent binding affinity with CXCR4 receptor (IC50 = 57 nM) and inhibited CXCL12 induced cytosolic calcium increase (IC50 = 0.24 nM). Furthermore, compound 3 potently inhibited CXLC12/CXCR4 mediated cell migration in a transwell invasion assay. The simplified synthetic approach combined with good physicochemical properties (e.g. MW 362, clogP 2.1, PSA 48, pKa 7.0 for compound 3) demonstrate the potential of this aminoquinoline template as a novel scaffold to develop CXCR4 antagonists.
Structural optimization of aminopyrimidine-based CXCR4 antagonists
Du, Qian,Fu, Chunyan,Ge, Wenxiang,He, Sudan,Li, Zhanhui,Luo, Lusong,Ma, Haikuo,Sun, Xiaotian,Tian, Sheng,Wang, Xu,Wang, Yujie,Zhang, Xiaohu,Zhang, Yi,Zheng, Jiyue,Zhu, Fang
, (2019/12/24)
Structural optimization of aminopyrimidine-based CXCR4 antagonists is reported. The optimization is guided by molecular docking studies based on available CXCR4-small molecule crystal complex. The optimization identifies a number of compounds with improved receptor binding affinity and functional activity exemplified by compound 23 (inhibition of APC-conjugate clone 12G5 for CXCR4 binding in a cell based assay: IC50 = 8.8 nM; inhibition of CXCL12 induced cytosolic calcium increase: IC50 = 0.02 nM). In addition, compound 23 potently inhibits CXCR4/CXLC12 mediated chemotaxis in a matrigel invasion assay. Furthermore, compound 23 exhibits good physicochemical properties (MW 367, clogP 2.1, PSA 48, pKa 7.2) and in vitro safety profiles (marginal/moderate inhibition of CYP isozymes and hERG). These results represent significant improvement over the initial hit from scaffold hybridization and suggest that compound 23 can be used as a starting point to support lead optimization.
Direct fluorination of 1,3-dicarbonyl compounds
Chambers, Richard D.,Greenhall, Martin P.,Hutchinson, John
, p. 1 - 8 (2007/10/02)
In acid media, 1,3-diketones and 1,3-keloesters can be fluorinated in high yield and often with high conversion mainly to the corresponding 2-fluoro- compounds. Diesters such as diethyl malonate do not react with fluorine under the same reaction conditions. The mechanism of these reactions has been investigated and while the identity of the electrophilic fluorinating species is uncertain, we believe that the essential features of the reaction pathway are understood. Copyright
