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Current Pharmaceutical Analysis

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ISSN (Print): 1573-4129
ISSN (Online): 1875-676X

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Research Article

Synthesis, Structure Confirmation of Deuterium-substituted Kynurenine and the Conformation Analysis of Kynurenine in Daptomycin

Author(s): Hanzhi Zhang*, Feng Qin, Ning Sun, Mengmeng Zheng, Wenyan Luo, Ya Qiu, Hao Liu and Xiangmin Zhang*

Volume 19, Issue 4, 2023

Published on: 16 February, 2023

Page: [282 - 288] Pages: 7

DOI: 10.2174/1568026622666220526102946

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Abstract

Background: After the hydrolysis of daptomycin in deuterated hydrochloric acid, the deuterium-substituted kynurenine was found, but the structure of deuterium-substituted kynurenine has not been reported.

Introduction: The deuterium-substituted kynurenines were simply synthesized and confirmed to be tri- and tetra-substituted products by high resolution mass spectrum and NMR. In further, the deuterium-substituted kynurenines were used to determine the conformation of kynurenine to be L-type in daptomycin through conformation analysis combined with derivation and high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLCQ/ TOF-MS).

Methods: In the present study, a simple synthesis method was developed for deuteriumsubstituted kynurenine, and its structure was confirmed by high resolution mass spectrometry and NMR. L-kynurenine was mixed with the deuterated hydrochloric acid and heated at 110 °C for 7 h. The hydrogen/deuterium exchange products of L-kynurenine were obtained through the hydrogen/deuterium exchange method. After the derivation of deuterium-substituted L-kynurenine by Marfey’s reagent, the conformation of kynurenine in daptomycin was deduced by HPLC-Q/TOF-MS.

Results: The deuterium-substituted kynurenines were confirmed to be tri- and tetra-substituted products by high resolution mass spectrum. Further, Hydrogen NMR spectrum indicated that the deuterium-substitution positions were β-position on amino acid and 3’ and 5’ positions on the benzene ring. Thus, the tri-deuterium-substituted product was L-[β, 3’, 5’-2H3] kynurenine-d3, while the tetra-deuterium-substituted product was L-[β, β, 3’, 5’-2H4] kynurenine-d4. Furthermore, the deuterium-substituted kynurenines were used to determine the conformation of kynurenine to be L-type in daptomycin through conformation analysis combined with derivation and HPLC-Q/TOF-MS.

Conclusion: The synthesis, structures, and application of tri- or tetra- deuterium-substituted kynurenine were reported in this study.

Keywords: L-[β, 3’, 5’- 2 H3] kynurenine-d3, L-[β, β, 5’- 2 H4] Kynurenine-d4, H/D exchange, NMR, HPLC-Q/TOF-MS, Daptomycin

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