Isolation and identification of two pairs of cytotoxic diterpene tautomers and their tautomerization mechanisms

Li-Ping Dai,Hong Wu,Xiao-Fei Li,Qing-Mei Feng,Zhi-Min Wang,Ling-Xia Zhang,Qiu-Yan Liu,Er-Ping Xu

doi:10.1038/s41598-020-58260-8

Abstract

Discovering anticancer drugs that do not have adverse side effects has been a developing research field worldwide in recent decades. In this work, four previously undescribed cytotoxic diterpenoids were isolated from the aerial parts of Isodon excisoides. Interestingly, these four diterpenoids were two pairs of tautomers that were first reported in plants. Their structures were further elucidated using various spectroscopic methods. The tautomerization phenomenon and mechanism for these two pairs of tautomers were emphatically described. The theoretical simulation results indicated that the diterpene tautomerization is greatly related to certain factors, including the existence of a transition state, the change of bond length and the level of conversion energy; the tautomerization for the two pairs of tautomers is mainly caused by proton transfer. For bioassays, the cytotoxicities of the tautomers against five human cancer cell lines were also investigated. The results indicated that each of the four diterpenoids showed significant cytotoxicity in at least three cell lines and could serve as potential anticancer agents for further investigation.

Highlights

Discovering anticancer drugs that do not have adverse side effects has been a developing research field worldwide in recent decades
The structures of 1a, 1b, 2a and 2b were elucidated by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry in conjunction with published data of their analogues, as well as their fragmentation patterns
The interconversion experiments between 1a and 1b and between 2a and 2b in methanol solutions confirmed that they exists as two pairs of tautomers

Summary

Introduction

Discovering anticancer drugs that do not have adverse side effects has been a developing research field worldwide in recent decades. Four previously undescribed cytotoxic diterpenoids were isolated from the aerial parts of Isodon excisoides These four diterpenoids were two pairs of tautomers that were first reported in plants. The results indicated that each of the four diterpenoids showed significant cytotoxicity in at least three cell lines and could serve as potential anticancer agents for further investigation. Approximately 1000 diterpenoids from the Isodon genus have been shown to exhibit significant cytotoxicity[2,3,4,5,6,7,8], and many diterpenoids with anticancer activities, such as oridonin, erycalyxin A and rabdophyllin G, have been developed into new drugs[9,10]. Their cytotoxicities against five human cancer cell lines were investigated

Methods

Results

Conclusion