498568-17-5Relevant articles and documents
Pyrrole and pyrazole compound of preparation and use as medicaments (by machine translation)
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, (2018/03/26)
The invention relates to the field of medical technology, this invention has offered a kind of sulfonamide and nitrogen mixed uncle butane pyrrole and pyrazole compound, including optical isomers, racemic modification, and any combination of the trans isomer or a pharmaceutically acceptable salt thereof, having a structure of formula (I); the invention also provides the preparation method of the compound and its application, in particular in the preparation of anti-tumor drug application. (by machine translation)
Design, synthesis and structure–activity relationship of 4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-ones as potent p53-MDM2 inhibitors
Zhou, Wei-Huang,Xu, Xi-Guo,Li, Jin,Min, Xiao,Yao, Jian-Zhong,Dong, Guo-Qiang,Zhuang, Chun-Lin,Miao, Zhen-Yuan,Zhang, Wan-Nian
, p. 422 - 425 (2017/01/28)
In the past decade, the p53-MDM2 protein–protein interaction by small molecules has been confirmed as a successful strategy for cancer therapy. In our previous work, pyrrolo[3,4-c]pyrazol-6(1H)-ones were found to be potent p53-MDM2 inhibitors. Further optimization and structure–activity relationship studies were described in the present work. The result revealed that benzyl group on position N1 of imidazole and bromine on C4-phenyl of pyrrolidone showed higher inhibitory activities. In vitro antiproliferative assay demonstrated the potent p53-MDM2 inhibitor 5c with 4-fold selectivity for U2 OS and Saos-2 cells. These data indicated that 4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one moiety is a valuable scaffold for further development of p53-MDM2 inhibitors.
Gyrrolone and pyrromonazole compound and its use as medicine
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, (2016/11/14)
The present invention belongs to the technical field of medicine. Provided in the present invention is pyrrolidone compounds, including optical isomers, racemates, cis and trans isomers and any combination thereof or pharmaceutically acceptable salts thereof, having a structure as shown in formula (I). The compounds of the present invention can be used as a small molecule inhibitor for p53-MDM2/X protein interactions. The compounds of the present invention can be used to prepare antineoplastic or anti-inflammatory drugs.
Double-edged swords as cancer therapeutics: Novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway
Zhuang, Chunlin,Miao, Zhenyuan,Wu, Yuelin,Guo, Zizhao,Li, Jin,Yao, Jianzhong,Xing, Chengguo,Sheng, Chunquan,Zhang, Wannian
, p. 567 - 577 (2014/03/21)
Simultaneous inactivation of p53 and hyperactivation of nuclear factor-κB (NF-κB) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-κB. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-κB pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-κB pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-κB activation through inhibition of IκBα phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKKα/β. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-κB pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).
Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction
Zhuang, Chunlin,Miao, Zhenyuan,Zhu, Lingjian,Dong, Guoqiang,Guo, Zizhao,Wang, Shengzheng,Zhang, Yongqiang,Wu, Yuelin,Yao, Jianzhong,Sheng, Chunquan,Zhang, Wannian
, p. 9630 - 9642 (2013/01/16)
The p53-MDM2 interaction has been proved to be a valuable target to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (Ki = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to the discovery of a number of highly potent pyrrolidone derivatives with improved p53-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (Ki = 260.0 nM) and 60a (Ki = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two compounds also effectively inhibited the tumor growth in the A549 xenograft model. Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development of novel antitumor agents.
