Title

Assignment of the absolute configuration of hepatoprotective highly oxygenated triterpenoids using X-ray, ECD, NMR J-based configurational analysis and HSQC overlay experiments

Authors

Xiaojuan Wang, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China; Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, United States.
Jiabao Liu, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
Pankaj Pandey, Department of BioMolecular Sciences, Division of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, MS 38677-1848, United States.
Jiabao Chen, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
Frank R. Fronczek, Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, United States.
Stuart Parnham, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States.
Xinzhu Qi, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
Robert J. Doerksen, Department of BioMolecular Sciences, Division of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, MS 38677-1848, United States.
Daneel Ferreira, Department of BioMolecular Sciences, Division of Pharmacognosy, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, MS 38677-1848, United States.
Hua Sun, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China.
Shuai Li, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, People's Republic of China. Electronic address: lishuai@imm.ac.cn.
Mark T. Hamann, Department of Drug Discovery and Biomedical Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, United States. Electronic address: hamannm@musc.edu.

Document Type

Article

Publication Date

12-1-2017

Abstract

BACKGROUND: The plants of the genus Kadsura are widely distributed in China, South Korea, and Japan. Their roots and stems are traditionally used to treat blood diseases and pain. The main bioactive constituents of Kadsura longipedunculata comprise highly oxygenated triterpenoids. Schiartane-type nortriterpenoids showed anti-HIV, anti-HBV, and cytotoxic bioactivities. For such compounds, the absolute configuration influences the bioactivities, and hence its unambiguous determination is essential. In this work, the absolute configurations of three highly oxygenated schiartane-type nortriterpenoids were unequivocally assigned using X-ray, ECD, and J-based configuration analysis and HSQC overlay data. METHODS: The ethanol extract of Kadsura longipedunculata Finet et Gagnep was purified by column chromatography using silica, Sephadex LH-20, and ODS as substrates. To help assign the absolute configuration of schiartane-type nortriterpenoids, X-ray diffraction analysis, ECD experiment compared to ab initio computed data, DP4+ analysis, HSQC overlay, NOESY, and J-based configuration analysis were carried out. Hetero- and homo-nuclear coupling constants were extracted from HETLOC experiments. RESULTS: Three new highly oxygenated triterpenoids, micrandilactone I (1), micrandilactone J (2), and 22,23-di-epi-micrandilactone J (3) were isolated. Their 2D structures were solved using NMR and HRESIMS data and their absolute configurations were elucidated using X-ray diffraction analysis, ECD experimental results compared to ab initio computed spectra, HSQC overlay, DP4+, NOESY, and J-based configuration analysis. Micrandilactone I (1) and 22,23-di-epi-micrandilactone J (3) showed moderate hepatoprotective activity against APAP-induced toxicity in HepG2 cells with cell survival rates of 53.0 and 50.2%, respectively, at 10μM (bicyclol, 49.0%), while micrandilactone J (2) was inactive. GENERAL SIGNIFICANCE: This is the first comprehensive stereochemical assignment of a non-crystalline schiartane-type nortriterpenoid like 3. This general protocol may contribute towards solving the problems hampering the assignment of the absolute configurations of other members of this class of nortriterpenoids.

Publication Source (Journal or Book title)

Biochimica et biophysica acta. General subjects

First Page

3089

Last Page

3095

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