Monoterpene indole alkaloids with diverse skeletons from the stems of Rauvolfia vomitoria and their acetylcholinesterase inhibitory activities
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.
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 (1−9) and eleven known MIAs (10–20) (Fig. 1). The nine unreported MIAs, rauvomitorine A−I (1–9), pertain to an unprecedented framework (1), suaveoline framework (2–3), and yohimbine framework (4–9) 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 (2–3), 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 1–20 are described.
Section snippets
Structural elucidation
Rauvomitorine A (1) was isolated as a colorless oil ( +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 (2–3), and yohimbine framework type alkaloids (4–9), as well as eleven known MIAs (10–20) 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
References (39)
- et al.
The alkaloids of Rauwolfia volkensii
J. Ethnopharmacol.
(1981) - et al.
Alkaloids of Rauwolfia nitida root bark
Phytochemistry
(1981) - et al.
Alkaloids from leaves and root bark of Ervatamia hirta
Phytochemistry
(1991) - et al.
Therapeutic potentials of plant iridoids in Alzheimer's and Parkinson's diseases: a review
Eur. J. Med. Chem.
(2019) - et al.
Structure of suaveoline, a new alkaloid from Rauwolfia suaveolens (Apocynaceae)
Tetrahedron Lett.
(1972) - et al.
Plants of New Caledonia. XXIV. Alkaloids of Rauwolfia suaveolens
Phytochemistry
(1973) - et al.
Stem bark alkaloids of Rauwolfia caffra
J. Ethnopharmacol.
(1984) - et al.
Leaf alkaloids of Rauwolfia caffra
Phytochemistry
(1983) - et al.
Acetylcholinesterase inhibitors as Alzheimer therapy: from nerve toxins to neuroprotection
Eur. J. Med. Chem.
(2013) - et al.
Sarpagan-ajmalan-type indoles: biosynthesis, structural biology, and chemo-enzymatic significance. The alkaloids
Chem. Biol.
(2016)
Engineered mitochondrial production of monoterpenes in Saccharomyces cerevisiae
Metab. Eng.
Nepenthe-like indole alkaloids with antimicrobial activity from Ervatamia chinensis
Org. Lett.
Rauvomines A and B, two monoterpenoid indole alkaloids from Rauvolfia vomitoria
Org. Lett.
Amaryllidaceae alkaloids with new framework types from Zephyranthes candida as potent acetylcholinesterase inhibitors
Eur. J. Med. Chem.
Indole alkaloids from Ervatamia hainanensis with potent acetylcholinesterase inhibition activities
Bioorg. Med. Chem. Lett
The heteroyohimbine mayumbine binds with high affinity to rat brain benzodiazepine receptors in vitro
Nat. Prod. Lett.
Root wood alkaloids of Rauwolfia macrophylla
Planta Med.
Stem bark alkaloids of Rauwolfia macrophylla
Planta Med.
Enantiospecific synthesis of (-)-3-iso-19,20-dehydro-β-yohimbine from secologanin: a route to normal and pseudo stereoisomers of yohimbine
Tetrahedron Lett.
Cited by (19)
Ring-closing metathesis in the synthesis of fused indole structures
2023, Advances in Heterocyclic ChemistryCitation Excerpt :It should be noted that tetracyclic alcohols 28 and 29 are subunits of the sarpagine alkaloid family (Fig. 2). The sarpagine-related macrolines are principally isolated from the Apocynaceae family,69 showing a wide variety of bioactivities, such as antimalarial,70 antiproliferative,71 and acetylcholinesterase inhibitory72 properties. Abarca et al. described the synthesis of the indolo[2,3-a]quinolizinium mesomeric betaine 34 starting from tryptamine 30.
Genus Rauvolfia: A review of its ethnopharmacology, phytochemistry, quality control/quality assurance, pharmacological activities and clinical evidence
2022, Journal of EthnopharmacologyCitation Excerpt :Compound 261 (IC50 = 97.72 ± 9.91 μM), and 271 (IC50 = 49.76 ± 0.88 μM) showed a moderate anti-AChE effect, while, rauvomitorine C (262) (IC50 > 200 μM) did not have significant anti-AChE activities, indicating that the aliphatic chain at C-20 presence of the in sarpagine-type MIAs, It may be a responsible for the anti-AChE activity. Therefore, sarpagine type MIAs may be potent candidates in the discovery of anti-AChE agents (Zhan et al., 2020b). Compound 216 was found to be the most potent inhibitor of both AChE, and BChE among the tested compounds with IC50 values in the range of 8.06–73.23 μM.
Pharmacognostic evaluation of three Apocynaceae plants that share the same West African local names
2022, Phytomedicine PlusCitation Excerpt :From V. africana, several monoterpenoid indole alkaloids (Chen et al., 2015; Babiaka et al., 2020; Li et al., 2021), essential oil components (Ehiabhi et al., 2013), have been isolated and completely characterized. Monoterpenoid indole alkaloids (Zeng et al., 2017; Zhan et al., 2020a), yohimbine-type alkaloids (Zhan et al., 2020b), triterpenes (Fannang et al., 2011) have been previously isolated from R. vomitoria. Other secondary metabolites in lesser quantities in these plants include flavonoids, simple phenolics and lignans (Bhadane et al., 2018) have been reported.
Natural surfactants assisted an efficient synthesis of tetrahydro-β-carbolines
2021, Results in ChemistryCitation Excerpt :Reserpine (A) is used to treat high blood pressure and to treat mental disorder patients[21]. (-)- Suaveoline (B) has nutritional and medicinal applications[22,23]. Moreover, β-carboline derivatives possesses antimalarial[24], antitumor, anti HIV[25] and antibacterial activitites[26], Tadalafil (C) is used to treat male sexual function problems[27].