147266-92-0Relevant articles and documents
Design, synthesis, and biological evaluation of novel Bcr-AblT315I inhibitors incorporating amino acids as flexible linker
Li, Yanchen,Li, Zilong,Liu, Nanxin,Pan, Xiaoyan,Shan, YuanYuan,Wang, Kai,Zhang, Jie,Zhang, Qingqing
, (2021/09/22)
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.
Epoxy amino acids produced from allylglycines intramolecularly cyclised to yield four stereoisomers of 4-hydroxyproline derivatives
Krishnamurthy, Suvratha,Arai, Toru,Nakanishi, Kanae,Nishino, Norikazu
, p. 2482 - 2490 (2014/01/06)
Derivatives of 2-amino-4-pentenoic acid (allylglycine) were efficiently resolved using Subtilisin or acylase. The side-chain unsaturated bond of the enantiomerically pure amino acid with tert-butoxycarbonyl (Boc) protection was smoothly epoxidized with m-chloroperbenzoic acid. When the Boc protection of the amino group was removed, the amino group intramolecularly attacked the side-chain epoxide, generating compounds with five-membered rings: the 4-hydroxyproline derivatives. Two diastereomeric products were formed through the cyclisation reaction, for example, (2S,4S)-4-hydroxyproline benzyl ester (cis-8) and (2S,4R)-4-hydroxyproline benzyl ester (trans-8) were formed from (2S)-amino acid with a side-chain epoxide. Compound (2S,4S)-4-hydroxyproline benzyl ester (cis-8) was transformed to a lactone (cis-hydroxyproline lactone, 10) with the removal of benzyl alcohol. The cis-conformation was essential for the intramolecular ester exchange reaction; in fact, no lactone formation was observed for the trans isomer (trans-8). The separation of cis-hydroxyproline lactone and the trans-isomeric hydroxyproline benzyl ester was facile and clear, in contrast to the difficult separation of cis- and trans-hydroxyproline derivatives. Thus, two diastereomers of hydroxyproline derivatives for l-hydroxyproline and also for d-hydroxyproline were obtained, i.e., four diastereomers of hydroxyproline derivatives.
Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists
Stocking, Emily M.,Aluisio, Leah,Atack, John R.,Bonaventure, Pascal,Carruthers, Nicholas I.,Dugovic, Christine,Everson, Anita,Fraser, Ian,Jiang, Xiaohui,Leung, Perry,Lord, Brian,Ly, Kiev S.,Morton, Kirsten L.,Nepomuceno, Diane,Shah, Chandravadan R.,Shelton, Jonathan,Soyode-Johnson, Akinola,Letavic, Michael A.
scheme or table, p. 2755 - 2760 (2010/09/09)
Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H3 receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H3 receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was extensively profiled and shows promise as a potential clinical candidate.
