New terpenoids from Maytenus apurimacensis as MDR reversal agents in the parasite Leishmania

doi:10.1016/j.bmc.2007.10.071

Bioorganic & Medicinal Chemistry

Volume 16, Issue 3, 1 February 2008, Pages 1425-1430

https://doi.org/10.1016/j.bmc.2007.10.071 Get rights and content

Abstract

Two new sesquiterpenes (1–2) and one new lupane triterpene (3) have been isolated from the roots of Maytenus apurimacensis. The novel β-dihydroagarofurans are the first sesquiterpenes with a basic polyhydroxy skeleton of 15-deoxyalatol and 4,15-dideoxyalatol that show high MDR reversing activity in the protozoan parasite Leishmania tropica.

Graphical abstract

Introduction

Chemical substances derived from animals, plants, and microbes have been used to treat human disease since the dawn of medicine. The investigation of natural products as a source of novel human therapeutics reached its peak in the Western pharmaceutical industry in the period 1970–1980, which resulted in a pharmaceutical landscape heavily influenced by non-synthetic molecules. Of the 1184 small-molecules New Chemical Entities (NCEs) introduced between 1981 and 2006, roughly half (48%) were natural products, semi-synthetic natural product analogues or synthetic compounds based on natural product pharmacophores.¹ The remarkable chemical diversity encompassed by natural products continues to be of relevance to drug discovery. According to WHO report, leishmaniasis is one of the 10 more important infectious diseases. Despite recent scientific and technological advances, infectious diseases continue to affect poor and marginalized people throughout the world. At least three key factors contribute to the emergence and re-emergence of such diseases: 1-failure to use properly existing tools effectively; 2-failure or non-existence of tools to control the disease, and 3-insufficient knowledge of the disease.² Leishmaniasis is the most important emerging and uncontrolled infectious disease and the second cause of death among parasitic diseases, after Malaria. Numerous plant-derived natural products from different structural classes have been investigated as antileishmanial candidates, including various alkaloids, terpenoids, flavonoids, and quinonoids.³ One of the main problems concerning the control of infectious diseases is the increased resistance to usual drugs. Overexpression of P-glycoprotein (Pgp)-like transporters represents a very efficient mechanism to reduce the intracellular accumulation of drugs in cancer cells and parasitic protozoans, thus conferring a multidrug resistance (MDR) phenotype. Pgps are active pumps belonging to the ATP-binding cassette (ABC) superfamily of proteins. The inhibition of the activity of these proteins represents an interesting way to control drug resistance both in cancer and in infectious diseases. Most conventional mammalian Pgp-MDR modulators are ineffective in the modulation of Pgp activity in the protozoan parasite Leishmania.⁴ Consequently, there is a necessity to find effective modulators of Pgp-MDR for protozoan parasites.⁵ It has been previously described that natural dihydro-β-agarofuran sesquiterpenes from Celastraceae plants are potent and specific inhibitors of Pgp and devoid of intrinsic toxicity in the concentration range of Pgp inhibition.⁶ As a part of an intensive investigation into active metabolites as reversal agents of the Pgp-dependent MDR phenotype, we have focused our efforts in the characterization of new natural compounds as potential Pgp inhibitors. In this paper, we describe the phytochemical analysis of n-hexane–Et₂O extract of the root bark of Maytenus apurimacensis, which yielded three new terpenoids; one triterpenoid with lupane structure and two sesquiterpenes that present two new polyhydroxylated skeletons (Fig. 1). M. apurimacensis also yielded friedelin,⁷ β-sitosterol,⁸ baruol,⁹ pristimerine,¹⁰ 6′,7′-dihydrocangoronsin αA,¹¹ 3-epiglochidiol,¹² paniculatadiol,¹³ 3β,29-dihidroxy-glut-5-ene,¹⁴ glochidiol,¹⁵ zeylasteral,¹⁶ 6-oxo-pristimerol,¹⁷ tingenone,¹⁸ blepharodol,¹⁹ dispermoquinone,²⁰ and lupeol.²¹ Their structures were elucidated by means of ¹H and ¹³C NMR spectroscopic studies, including homonuclear (COSY and ROESY) and heteronuclear correlation (HSQC and HMBC) experiments. The absolute configuration of the new sesquiterpenes was determined by CD studies. Furthermore, these sesquiterpenes have been tested on a MDR Leishmania tropica line overexpressing a Pgp-like transporter²² to determine their ability to revert the resistance phenotype.

Section snippets

Results and discussion

Repeated chromatography of the n-hexane–Et₂O (1:1) extract of the root bark of M. apurimacensis on silica gel and Sephadex LH-20 yielded two new dihydro-β-agarofuran sesquiterpenes (1–2) and one new lupane triterpenoid (3).

Compound 1 was isolated as an amorphous white solid with the molecular formula C₃₇H₃₉NO₉, established by HR-MS. The IR spectrum showed absorption bands for ester groups (1725 cm⁻¹). The mass spectrum contained fragments attributable to the presence of nicotinate (m/z 124),

Materials and methods

Roots of M. apurimacensis were collected in Santuario de Ampay, Huancavelica (Peru), in November 2001, and were identified by the botanist G. Yarupaitan. A voucher specimen is on file (No. 3020) with the Herbarium of the Museo de Historia Natural, Lima, Peru.

Extraction and isolation

Root bark of M. apurimacensis (0.2 kg) was extracted with n-hexane–Et₂O (1:1) (2 L) in a Soxhlet apparatus for 48 h. Evaporation of the solvent under reduced pressure provided 10 g of a dark extract. This residue was chromatographed on Sephadex

Acknowledgments

This work has been supported by the MCYT (SAF-2003-04200-C02-01, Project SAF2006-66720,) by ICIC (Instituto Canario de Investigación del Cáncer), by RICET Project RD06/0021/0002 and by Plan Andaluz de Investigación (Cod. CVI-130). We also thank to Dr. Trujillo-Vásquez for carrying out the CD spectra. P.D.M. thanks the support of the Universidad de Los Andes Sabbatical Program.

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New terpenoids from Maytenus apurimacensis as MDR reversal agents in the parasite Leishmania

Abstract

Graphical abstract

Introduction

Section snippets

Results and discussion

Materials and methods

Extraction and isolation

Acknowledgments

J. Nat. Prod.

Tetrahedron

Chem. Pharm. Bull.

Fitoterapia

J. Nat. Prod.

EMBO Rep.

Curr. Med. Chem.

Phytother. Res.

Curr. Top. Med. Chem.

J. Med. Chem.

Antimicrob. Agents Chemother.

Clin. Microbiol. Rev.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

J. Med. Chem.

Phytochemistry

Experientia

Tetrahedron Lett.

J. Chem. Soc.

J. Nat. Prod.