seco-Limonoids and Quinoline Alkaloids from Raputia heptaphylla and Their Antileishmanial Activity

Abstract

Regular ArticleThe Rutaceae family, consisting of ca. 150 genera and 1600 species, is mostly distributed throughout tropical regions. Species from this family have important uses in industry such as in food, pharmaceuticals and ornamental purposes, as well as having a wide variety of ethnobotanical uses 1) ; they are studied in terms of obtaining alkaloids and limonoids as bioactive principles.2) Among important plants from Rutaceae, those from the Raputia genus have attracted special attention because of their use in South-America due to their trypanocidal and leishmanicidal properties. 3)Leishmaniasis is an endemic disease which affects nearly 12 million people worldwide in tropical and subtropical regions.4) Clinically, the disease compromises skin, mucosa, and/or visceral organs and its specific action depends on both the species involved and the host's immunological system. Cutaneous and mucocutaneous varieties are often disabling, having high morbidity rates, whereas the visceral type affects a smaller number of people.5) More than 98% cases in Colombia are caused by cutaneous Leishmaniasis, being mostly transmitted by Leishmania (Viannia) panamensis (L. (V.) panamensis) species. 6) At clinical level, 20% of cases are neither reported nor treated; furthermore, nearly 80% of infections are spontaneously resolved due to the host's immunological response against parasites.7) Clinical cases which cannot be immunologically resolved are often treated by first-line drugs (e.g. pentavalent antimonial salts) which have shown higher toxicity and parasite-induced resistance. This had consequently led to the search and development of novel therapeutic agents for controlling this disease. Hence, studying the active principles obtained from traditional medicinal plants still has special importance.8) As part of our research into bioactive compounds from Rutaceae plants, this article thus describes the isolation, elucidation and antileishmanial activity of a novel seco-limonoid (1) and two novel alkaloids (2-3), along with other six known compounds [a seco-limonoid (4) and five alkaloids (5-9)] obtained from Raputia heptaphylla stem bark and leaves. The antileishmanial effect of isolated compounds was evaluated on L. (V.) panamensis (promastigotes and amastigotes). Compounds 1 and 5 revealed important antileishmanial activity at different levels. Results and DiscussionEthanol extract from R. heptaphylla (20 g) stem bark was subjected to an ultrasound-assisted acid-base extraction for alkaloids 9,10) affording an alkaloid extract (1.2 g). Chloroform-soluble extract was purified by repeated CC on silica gel to give compounds 1-4. Alkaloids 5-9 were also isolated using an identical procedure on ethanol extract from R. heptaphylla leaves (50 g). Structures were established on the basis of full spectroscopic data analysis compared to data from the pertinent literature (Fig. 1).Compound 1 was obtained as colorless crystals (mp 220-222°C, MeOH). Its high resolution-electrospray ionization mass spectra (HR-ESI-MS) showed a pseud...

<i>Seco</i>-limonoid 11<i>α</i>,19<i>β</i>-dihydroxy-7-acetoxy-7- deoxoichangin promotes the resolution of <i>Leishmania panamensis</i> infection

“…When developing in vitro screens to study bioactive molecules for the control of this microorganism, there is a necessity for developing assays to evaluate possible antiparasitic activities against parasites of the genus Leishmania at the different life cycle stages of this pathogen. It is particularly important to develop antiparasitic therapies against the form of the pathogen responsible for the disease in the vertebrate host during the clinical manifestations of the disease [34,35], and is in this way, that in the present study we confirmed the efficacy of a seco-limonoid (triterpene) [18] which exhibits activity against only the intracellular form of the parasite, leading to a decrease and subsequent resolution of the infection in treated infected cells. We demonstrated that this activity is related to an immunomodulatory mechanism of action in which the compound induces an apparent "reactivation" of the "paralyzed" APC caused by the survival mechanisms developed by the pathogen.…”

“…of a seco-limonoid (11α,19β-dihydroxy-7-acetoxy-7-deoxoichangin), which was isolated from the bark of Raputia heptaphylla (Rutaceae family), which was previously described by Coy and colleagues [18]. We suggest here a possible mechanism for the antiparasitic activity of this compound that is related to the immunomodulatory effect on APCs.…”

“…Briefly, to obtain the crude ethanolic extract, the dried plant material was subjected to extraction by percolation in 96% ethanol at room temperature, and the organic solvent was removed by distillation under reduced pressure in a rotavapor. Next, the metabolites were extracted from the ethanolic extract, and the purification of the seco-limonoid was performed using conventional chromatographic methods [18]. To elucidate the structure of this seco-limonoid compound (Figure 1(a)), spectroscopic methods were used (including ultraviolet, infrared (IR), nuclear magnetic resonance (NMR) of hydrogen and carbon, circular dichroism, and nuclear Overhauser enhancement spectroscopy (NOESY) experiments), as also data reported in the literature of related seco-limonoid.…”

“…Recently, the study of compounds derived from plant species has become in a major tool for the developed of novel therapeutic agents against several infectious diseases, such as leishmaniasis [13][14][15], and in this regard, several research groups have screened a large number of natural compounds, with the aim of find potential chemical entities (prototypes) that can be used for the development of more effective and safer alternative therapies against these pathogens [16][17][18].…”

The Chemistry and Pharmacology of Citrus Limonoids

“…Section 3). Ichangin (8) (from C. ichangensis) has also been recently isolated from the stem bark and leaves of the South-Americaan plant, Raputia heptaphylla [141]. It may be considered as the product of hydrolytic cleavage of the oxygen-containing portion of the isobenzofuran nucleus of 1 (A' ring).…”