Elsevier

Phytochemistry

Volume 177, September 2020, 112450
Phytochemistry

Monoterpene indole alkaloids with diverse skeletons from the stems of Rauvolfia vomitoria and their acetylcholinesterase inhibitory activities

https://doi.org/10.1016/j.phytochem.2020.112450Get rights and content

Highlights

  • Nine undescribed MIAs were isolated from the stems of Rauvolfia vomitoria.

  • Rauvomitorine A represents an unusual C-9-methoxymethylene-sarpagine type alkaloid.

  • Twenty MIAs with diverse skeletons were evaluated for their anti-AChE activities.

  • Suaveoline framework type alkaloids exhibited potential AChE inhibitory activity.

Abstract

Nine undescribed monoterpene indole alkaloids, rauvomitorine A−I, including an unprecedented C-9-methoxymethylene-sarpagine framework alkaloid, two rare suaveoline framework type alkaloids, and six yohimbine framework type alkaloids, as well as eleven known alkaloids, were isolated from the stems of Rauvolfia vomitoria Afzel. (Apocynaceae). The structures of the unreported alkaloids were elucidated by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis with Cu Kα radiation. Rauvomitorine A with an unreported framework type represents the first example of C-9-methoxymethylene-sarpagine alkaloids and its plausible biosynthetic pathway was proposed. All the isolated alkaloids were evaluated their acetylcholinesterase inhibitory (AChE) activities and cytotoxicity against five cancer cell lines and some of them exhibited potential anti-AChE activities with IC50 values ranging from 49.76 to 186.62 μM. Importantly, this is the first report of the AChE inhibitory activities on suaveoline framework type alkaloids, suggesting this type of alkaloids may be valuable sources for the discovery of AChE inhibitory agents. A preliminary structure-activity relationship for AChE inhibitory activities of the isolated alkaloids is also discussed, providing some clues to designing lead compounds for AChE inhibitors.

Graphical abstract

Nine undescribed alkaloids, including an unprecedented C-9-methoxymethylene-sarpagine type, two rare suaveoline type, and six yohimbine type alkaloids were isolated from the stems of Rauvolfia vomitoria Afzel. The AChE inhibitory activities of the isolated compounds were evaluated.

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Introduction

Monoterpene indole alkaloids (MIAs), a critical group of N-heterocyclic specialized metabolites consisting of monoterpene and indole moieties, are one of the most extensive and fascinating classes of structurally complex and medicinally valuable natural products (Yu et al., 2018; Yee et al., 2019). To date, more than 3000 MIAs were discovered from Apocynaceae, Loganiaceae, and Rubiaceae families (Thamm et al., 2016), and some of them demonstrated various promising biological activities including cytotoxic (Liu et al., 2012), immunosuppressive (Zeng et al., 2017a, 2017b), anti-inflammatory (Zhang et al., 2015), antibacterial (Cheng et al., 2016), and acetylcholinesterase (AChE) inhibition activities (Zhan et al., 2010; Fadaeinasab et al., 2015). MIAs such as reserpine (antihypertensive agent) and yohimbine (aphrodisiac agent) are widely used in clinics and included in Model List of Essential Drugs of World Health Organization (WHO) (Thamm et al., 2016). Thus, MIAs are found to be an efficient source for the development of new drug discovery.

Rauvolfia vomitoria Afzel. (Apocynaceae) is native to tropical Africa and widely cultured in the south of China as an economic shrub to extract MIA reserpine (antihypertensive agent) (Li et al., 1995). The plants are also used as a traditional folk medicine in China to treat high fever, gastrointestinal diseases, epilepsy, pain, and hypertension (Li et al., 1995; Zeng et al., 2017a, 2017b). Previous phytochemistry investigations of R. vomitoria have focused on the chloroform fraction and resulted in the isolation of 22 MIAs, representing eight different skeletal types (Zeng et al., 2017a, 2017b; Li et al., 2007; Cheng et al., 2008; Ai et al., 1997; Sim et al., 2014). However, there are no reports of any MIAs from the n-butanol fraction of this plant.

In search of structurally interesting and bioactive natural products from n-butanol fraction of this plant, the stems of R. vomitoria were collected and studied, leading to the isolation of twenty MIAs including nine undescribed MIAs (19) and eleven known MIAs (1020) (Fig. 1). The nine unreported MIAs, rauvomitorine A−I (19), pertain to an unprecedented framework (1), suaveoline framework (23), and yohimbine framework (49) alkaloids. Rauvomitorine A (1) represents the first example of C-9-methoxymethylene-sarpagine framework type alkaloids. Suaveoline type alkaloids, possessing three nitrogen atoms, are sparse in natural products; therefore, the two unreported MIAs, rauvomitorine B and C (23), in the current study, enrich the composition of suaveoline type alkaloids. Yohimbine type alkaloids are essential to new drug discovery, among them reserpine (antihypertensive agent) and yohimbine (aphrodisiac agent) are the typical representatives. In this study, we reported 13 yohimbine analogs from R. vomitoria expanding the structural diversity of yohimbine framework type alkaloids. This is also the first time to report the potential AChE inhibitory activities of suaveoline framework type alkaloids. Herein, the isolation, structure determination, as well as cytotoxicity against five cancer cell lines and AChE inhibitory activities and of MIAs 120 are described.

Section snippets

Structural elucidation

Rauvomitorine A (1) was isolated as a colorless oil ([α]D25 +66). Its molecular formula, C21H26N2O4, was determined based on its HRESIMS ion peak at m/z 371.19692 [M + H]+ (calcd for C21H27N2O4, 371.19708) and the 13C NMR data. The 1H NMR data of 1 (Table 1) exhibited the presence of a 1,2,3,4-tetrasubstituted benzene ring system (δH 6.67, d, J = 8.4 Hz, H-11; 7.15, d, J = 8.4 Hz, H-12), an olefinic proton (δH 5.43, q, J = 6.5 Hz, H-19), two oxymethylene groups (δH 3.50, dd, J = 10.5, 5.7 Hz,

Conclusions

Nine undescribed MIAs, including an unprecedented C-9-methoxymethylene-sarpagine framework alkaloid (1), two rare suaveoline framework type alkaloids (23), and yohimbine framework type alkaloids (49), as well as eleven known MIAs (1020) were isolated from the stems of R. vomitoria. This is also the first study of MIAs from the n-butanol fraction of this plant. Rauvomitorine A (1) with undescribed framework type represents the first example of C-9-methoxymethylene-sarpagine alkaloids and its

General experimental procedures

Melting points were obtained with a Haineng Auto Melting Point System. Optical rotations were measured in methanol on an InsMark FD polarimeter. UV, ECD, and FT-IR spectra were recorded using Agilent Cary 60, JASCO J-815, and Thermo Fisher Niclolet 6700 instruments, respectively. HRESIMS spectra were obtained on a Waters I-Class Vion IMS QTOF spectrometer in the positive ion mode. NMR spectra were recorded on a Bruker Avance III HD-600. After that the residual peaks of methanol-d4 (δH 3.31 and δ

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (No. 31800286), the Fundamental Research Funds for the Central Universities (No. Xjj2018169), Natural Science Foundation of Shaanxi Province (No. 2019JQ-194), China Postdoctoral Science Foundation (No. 2017M623200), Scientific Research Supporting Project for New Teacher of Xi'an Jiaotong University (No. 1191319803). We are grateful to the staff, Gang Chang and Axin Lu, at the Instrumental Analysis Centre of

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