Synthesis, Structure Confirmation of Deuterium-substituted Kynurenine and the Conformation Analysis of Kynurenine in Daptomycin-Reference-Cited by-同舟云学术

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

Published:2022-05-26 Issue: Volume:18 Page:
ISSN:1573-4129
Container-title:Current Pharmaceutical Analysis
language:en
Short-container-title:CPA

Author:

Qin Feng¹^ORCID,Zhang Hanzhi²^ORCID,Sun Ning³^ORCID,Zheng Mengmeng⁴^ORCID,Luo Wenyan⁵^ORCID,Qiu Ya⁶^ORCID,Liu Hao⁶^ORCID,Zhang Xiangmin⁷^ORCID

Affiliation:

1. Department of Chemistry, Fudan University, Shanghai 200438, China | Department of Antibiotics and Microorganisms, Shanghai Institute for Food and Drug Control, Shanghai 201203, China

2. Department of Antibiotics and Microorganisms, Shanghai Institute for Food and Drug Control, Shanghai 201203, China | Department of Antibiotics and Microorganisms, Shanghai Institute for Food and Drug Control, Shanghai 201203, China

3. Shanghai Institute of Advanced Immunochemical Studies, Shanghai Tech University, 201203 Shanghai, China

4. State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China

5. China State Institute of Pharmaceutical Industry, Shanghai 201203, China

6. Department of Antibiotics and Microorganisms, Shanghai Institute for Food and Drug Control, Shanghai 201203, China

7. Department of Chemistry, Fudan University, Shanghai 200438, China

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 o 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/TOFMS. 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’- 2 H3] kynurenine-d3, while the tetra-deuterium-substituted product was L-[β, β, 3’, 5’- 2 H4] 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.

Publisher

Bentham Science Publishers Ltd.

Subject

Pharmaceutical Science,Molecular Medicine,Biochemistry,Biophysics