Chiral resolution, absolute configuration determination, and stereo-activity relationship study of IDO1 inhibitor NLG919. Issue 24 (14th June 2018)

• Record Type: Journal Article
• Authors: Liu, Wen-Qiang; Lai, Fang-Fang; Zhang, Jie; Sheng, Li; Li, Yan; Li, Li; Chen, Xiao-Guang
• Is Part Of: Tetrahedron. Volume 74:Issue 24(2018)
• Page Start: 3045
• Page End: 3051
• Publication Date: 2018-06-14
• Subjects: Indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor -- Single crystal X-ray diffraction -- Optical resolution -- Absolute configuration -- Electronic circular dichroism; Chemistry, Organic -- Periodicals; 547.005
• DOI: 10.1016/j.tet.2018.05.005
• Languages: English
• ISSNs: 0040-4020

Abstract

Abstract: NLG919 (1 ) with two chiral carbon atoms on its chemical structure is a potent indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor. We developed an effective way to prepare all stereoisomers of1, the key step being the chiral resolution of racemic intermediate2 . The optimal resolution solvent system was identified as dichloromethane and n -pentane or petroleum ether. Using (−)-di- p -toluoyl-d -tartaric acid as resolution reagent, optical pure ( R )-2 (e.e. > 99%, yield = 70%) was obtained. The mechanism of chiral resolution was clarified through single-crystal X-ray diffraction of the diastereomeric salt. The absolute configurations of four stereoisomers of1 were established through electronic circular dichroism spectra, quantum chemical calculation and transition metal method. Their IDO1 inhibitory activity was assessed by pharmacological experiments in vitro and in mouse, demonstrating that S configuration of C5 played an important role on the inhibition of IDO1, while the stereochemistry on C2′ exerted little effect on the IDO1 inhibitory activity in mouse. Graphical abstract: