1429382-50-2Relevant articles and documents
Asymmetric Transfer Hydrogenation: Dynamic Kinetic Resolution of α-Amino Ketones
Gediya, Shweta K.,Clarkson, Guy J.,Wills, Martin
, p. 11309 - 11330 (2020/10/12)
A series of α-amino ketones were reduced using asymmetric transfer hydrogenation (ATH) through a dynamic kinetic resolution (DKR). The protecting group was matched to the reducing agent, and following optimization, a series of substrates were investigated, giving products in high diastereoselectivity, over 99% ee in several cases and full conversion. The methodology was applied to the enantioselective synthesis of an MDM2-p53 inhibitor precursor.
Rational design and binding mode duality of MDM2-p53 inhibitors
De Turiso, Felix Gonzalez-Lopez,Sun, Daqing,Rew, Yosup,Bartberger, Michael D.,Beck, Hilary P.,Canon, Jude,Chen, Ada,Chow, David,Correll, Tiffany L.,Huang, Xin,Julian, Lisa D.,Kayser, Frank,Lo, Mei-Chu,Long, Alexander M.,McMinn, Dustin,Oliner, Jonathan D.,Osgood, Tao,Powers, Jay P.,Saiki, Anne Y.,Schneider, Steve,Shaffer, Paul,Xiao, Shou-Hua,Yakowec, Peter,Yan, Xuelei,Ye, Qiuping,Yu, Dongyin,Zhao, Xiaoning,Zhou, Jing,Medina, Julio C.,Olson, Steven H.
, p. 4053 - 4070 (2013/06/27)
Structural analysis of both the MDM2-p53 protein-protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone 10, an MDM2 inhibitor with a biochemical IC 50 of 1.0 μM. The cocrystal structure of 10 with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones 16 and 27 possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone 27 (IC50 = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21WAF1 mRNA induction (2.7-fold over vehicle) upon oral dosing of 27 at 300 mg/kg.
