Biologically active vallesamine, strychnan, and rhazinilam alkaloids from Alstonia: Pneumatophorine, a nor-secovallesamine with unusual incorporation of a 3-ethylpyridine moiety

doi:10.1016/j.phytochem.2015.06.024

Phytochemistry

Volume 117, September 2015, Pages 317-324

https://doi.org/10.1016/j.phytochem.2015.06.024 Get rights and content

Highlights

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Thirty-six alkaloids, four previously unknown, were isolated from two Alstonia species.
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Pneumatophorine is notable for the incorporation of a 3-ethylpyridine moiety.
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The alkaloids showed antiproliferation and vasorelaxation effects.

Abstract

Four alkaloids comprising two vallesamine, one strychnan, and one pyranopyridine alkaloid, in addition to 32 other known alkaloids were isolated from two Malayan Alstonia species, Alstonia pneumatophora and Alstonia rostrata. The structures of these alkaloids were determined using NMR and MS analyses, and in one instance, confirmed by X-ray diffraction analysis. The nor-6,7-secovallesamine alkaloid, pneumatophorine, is notable for an unusual incorporation of a 3-ethylpyridine moiety in a monoterpenoid indole. The rhazinilam-type alkaloids (rhazinicine, nor-rhazinicine, rhazinal, and rhazinilam) showed strong cytotoxicity toward human KB, HCT-116, MDA-MB-231, and MRC-5 cells, while pneumatophorine, the uleine alkaloid undulifoline, and the strychnan alkaloids, N4-demethylalstogustine and echitamidine, induced concentration dependent relaxation in phenylephrine-precontracted rat aortic rings.

Graphical abstract

Four alkaloids comprising two vallesamine, one strychnan, and pyranopyridine alkaloid were isolated from two Malayan Alstonia species, A. pneumatophora and A. rostrata. Several of the isolated alkaloids show antiproliferative (e.g., rhazinicine) and vasorelaxation (e.g., pneumatophorine, undulifoline) effects.

Introduction

Plants of the genus Alstonia are distributed over the tropical regions of Central America, Africa, and Asia (Markgraf, 1974, Sidiyasa, 1998). These plants are typically shrubs or trees and are usually rich in alkaloids (Kam, 1999, Kam and Choo, 2006). About seven species (local name Pulai) occur in Peninsular Malaysia (Middleton, 2011), some of which are used in traditional medicine (Burkill, 1966, Perry and Metzger, 1980). A number of the Alstonia bisindole alkaloids have been shown to possess antiproliferative and antimalarial properties (Kam et al., 2008, Keawpradub et al., 1999, Wright et al., 1993). As part of our systematic study of the Malaysian members (Ku et al., 2011, Lim et al., 2011, Lim et al., 2012, Lim et al., 2013, Tan et al., 2010a, Tan et al., 2014), we investigated the alkaloid content of two species, viz., Alstonia pneumatophora Backer ex Den Berger and Alstonia rostrata C.E.C. Fisch, and herein report the results. Plants belonging to the former species are usually encountered in swampy areas (Middleton, 2011).

Section snippets

Results and discussion

The basic fraction from the EtOH extract of A. pneumatophora yielded a total of 22 alkaloids, of which three (1, 4, 5) are new, while a total of 21 alkaloids were isolated from A. rostrata, of which one, the monoterpene alkaloid 6 is new (Fig. 1).

Compound 1 (pneumatophorine) was isolated as a light yellowish oil with [α]²⁵_D −41 (CHCl₃, c 0.57). The IR spectrum showed bands due to NH/OH (3380 cm⁻¹) and ester carbonyl functions (1725 cm⁻¹), while the UV spectrum showed characteristic indole

Concluding remarks

The present investigation of A. rostrata resulted in the isolation of 21 alkaloids including one new monoterpene alkaloid. The known alkaloids include corynanthean (1 isolation), aspidospermatan (1), uleine (1), akuammiline (1), vallesamine (1), rhazinilam-leuconoxine (6), strychnan (4), vallesiachotaman (2) and monoterpene alkaloids (3). This result differs from that of a previous study of the same plant (A. undulifolia) collected in the same general area but at a different time where only

General

Melting points were determined on a Mel-Temp melting point apparatus and are uncorrected. Optical rotations were determined on a JASCO P-1020 digital polarimeter. IR spectra were recorded on a Perkin–Elmer RX1 FT-IR spectrophotometer. UV spectra were obtained on a Shimadzu UV-3101PC spectrophotometer. ¹H and ¹³C NMR spectra were recorded in CDCl₃ using TMS as internal standard on JEOL 400, or Bruker 400 and 600 MHz spectrometers. ESIMS and HRESIMS were obtained on an Agilent 6530 Q-TOF and JEOL

Acknowledgments

We thank the University of Malaya and MOHE Malaysia (HIR-F005) for financial support.

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Ethanol-water (1:1) extracts were tested (1–100 μg/mL) against a panel of cancer cell lines according to their respective traditional use. Selected extracts with relevant cytotoxicity in this screening were also tested against common pediatric malignancies (leukemias (HL-60, REH) and Ewing sarcoma (RD-ES and CADO-ES1)). Bioassay-guided fractionation of the hydroalcoholic extract from Alstonia boonei was performed by liquid-liquid chromatography and preparative HPLC. Preliminary mechanistic studies on the mode of action were performed by flow cytometric cell cycle analysis as well as apoptosis and necrosis staining.
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A. pneumatophora derived indole alkaloids alpneumines E and G, vincamine, and apovincamine exhibited antimelanogenesis effects against B16 mouse melanoma cells [8]. Malayan A. pneumatophora and A. rostrata derived alkaloids rhazinicine, nor-rhazinicine, rhazinal, and rhazinilam showed significant cytotoxicty toward human KB (a subline of the ubiquitous KERATIN-forming tumor cell line HeLa), human colon cancer cells (HCT-116), MDA-MB-231 (a breast cancer cell line), and Medical Research Council cell strain 5 (MRC-5) cells with IC50 (μg/mL) values of 5.10, 19, 6.30, 12.20 (nor-rhazinicine); 1, 4.20, 1.80, 4.10 (rhazinicine); 0.08, 0.20, 0.15, 0.16 (rhazinal), and 0.17, 0.55, 0.38, 0.58 (rhazinilam) against KB/S, MRC-5, HCT-116, and MDA-MB-231, respectively [9]. Angustilobine C from A. angustiloba exhibited moderate cytotoxicity against KB cells [10].
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Biologically active vallesamine, strychnan, and rhazinilam alkaloids from Alstonia: Pneumatophorine, a nor-secovallesamine with unusual incorporation of a 3-ethylpyridine moiety

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Concluding remarks

General

Acknowledgments

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