Chemosensitization of a Multidrug-Resistant Leishmania tropica Line by New Sesquiterpenes from Maytenus magellanica and Maytenus chubutensis

Abstract

Parasite resistance to drugs has emerged as a major problem in current medicine, and therefore, there is great clinical interest in developing compounds that overcome these resistances. In an intensive study of South American medicinal plants, herein we report the isolation, structure elucidation, and biological activity of dihydro-beta-agarofuran sesquiterpenes from the roots of Maytenus magellanica (1-14) and M. chubutensis (14-17). This type of natural products may be considered as privileged structures. The structures of 10 new compounds, 1, 3, 6-9, and12-15, were determined by means of (1)H and (13)C NMR spectroscopic studies, including homonuclear (COSY and ROESY) and heteronuclear correlation experiments (HMQC and HMBC). The absolute configurations of eight hetero- and homochromophoric compounds, 1, 3,6-9, 12, and 13, were determined by means of CD studies. Fourteen compounds, 1-3 and 6-16, have been tested on a multidrug-resistant Leishmania tropica line overexpressing a P-glycoprotein-like transporter to determine their ability to revert the resistance phenotype and to modulate intracellular drug accumulation. From this series, 1, 2, 3, 14, and 15 showed potent activity, 1 being the most active compound. The structure-activity relationships of the different compounds are discussed.

Celastraceae Sesquiterpenes as a New Class of Modulators That Bind Specifically to Human P-Glycoprotein and Reverse Cellular Multidrug Resistance

“…Among the active compounds identified in those extracts are sesquiterpenes, which constitute a wide family of natural compounds with a considerable range of bioactive properties and with potential clinical applications as anticancer drugs, and MDR reversal agents in cancer cells (16) and in the protozoan parasite Leishmania (17,18). Because of these previous findings, we have initiated research to determine the cellular target(s) for sesquiterpenes and to characterize their molecular mechanism of action to rationally design new, more efficient modulators based on their chemical structure.…”

Combination of Suboptimal Doses of Inhibitors Targeting Different Domains of LtrMDR1 Efficiently Overcomes Resistance of Leishmania spp. to Miltefosine by Inhibiting Drug Efflux

“…The modulation of alkyl-lysophospholipid (ALP) resistance and the sensitization to 150 M DNM by reversal agents were monitored as described in reference 38 after a 72-h incubation period. Parasite viability after shorter miltefosine treatments was determined by the colorimetric MTT assay as previously described (21). Mammalian cell lines used in the cytotoxic assays were NIH 3T3, provided by I. Pastan (National Cancer Institute, National Institutes of Health, Bethesda, MD); epithelial MDCKII (25); epithelial-cell-like MCF-7 and MDA-MB-23 (4,45); Vero (Cercopithecus aethiops ATCC CRL-1586); and mouse macrophage J774 (ATCC HB-197).…”

“…Some flavonoid derivatives bind to a purified recombinant NBD from LtrMDR1 and interact with both the ATP-binding site and a vicinal hydrophobic region (7,11,34) with an affinity that correlates with their abilities to modulate drug accumulation and to reverse the resistance phenotype of a Leishmania tropica MDR line (34,37). On the other hand, some sesqui-terpenes efficiently overcome the Leishmania MDR phenotype (21,38,39) by increasing drug accumulation (21,38); their binding to the TMDs of human Pgp has been suggested recently (27).…”

Neuroleptic-Like Properties of the Chloroform Extract of Maytenus obtusifolia MART. Roots

“…1,4) Maytenus obtusifolia MART. is a plant found in many states of the Northeast and South-east of Brazil, which is used in traditional medicine for the treatment of ulcer.…”

“…[1][2][3] Sesquiterpenes, triterpenes, quinone-methide and sesquiterpene pyridine alkaloids have been identified in these species. 1,4) Maytenus obtusifolia MART. is a plant found in many states of the Northeast and South-east of Brazil, which is used in traditional medicine for the treatment of ulcer.…”