Ursane Type Research Articles

Pentacyclic triterpenoids from spikes of Prunella vulgaris L. with thyroid tumour cell cytostatic bioactivities

Five new triterpenoids, including four ursane types (1–4) and one oleanane type (5), together with 15 known ursane types pentacyclic triterpenoids (6–20) were isolated from the fruit spikes of Prunella vulgaris L., a traditional Chinese herbal medicine. Their structures were elucidated based on IR, HR-ESI-MS, and NMR spectroscopic data. The SW579 cell line was used to evaluate anti-thyroid cancer activities of (1–20). The results indicated that (7–9), (16), and (19) exhibited apparent inhibitory activity with IC50 values of 25.73–71.41 μM (cisplatin as positive control, IC50 14.49 ± 0.97 μM). Network pharmacology and molecular docking were also used for the prediction of the synergistic actions and the underlying mechanisms. Accordingly, four potential targets have been characterized.

New pentacyclic triterpene from Potentilla atrosanguinea Lodd. as anticancer agent for breast cancer targeting estrogen receptor-α

One new (compound 3) along with two previously known ursane type triterpenoids (compounds 1 and 2) were purified by chromatographic techniques from ethyl acetate extract of aerial parts of Potentilla atrosanguniea and characterized by HRMS, 1 D and 2 D-NMR. Compounds 1 (ursolic acid), 2 (euscaphic acid) and 3 (3α,20α-dihydroxy 2-oxo-urs-12-en-28-oic acid) were tested for their antiproliferative activity along with standard bazedoxifene. Compounds 1 and 3 were found to be of higher activity (3.71 and 6.05 μg/mL) as compared to compound 2 and bazedoxifene (IC50: 24.53 and 17.87 μg/mL). Anti-estrogenic activity of three compounds on breast cancer (BC) were studied in vitro by accessing their antiproliferative activity and binding with estrogen receptor alpha (ER-α). All three compounds have effective binding affinity towards ER-α and decreased cell growth by downregulating the expression of mRNA and its translational protein as tested by semi-qRT-PCR and western blotting. In terms of effectiveness compounds 1 and 3 were found more active due to their antiproliferative, and antiestrogenic activity as compared to standard bazedoxifene.

Biocompatible madecassoside encapsulated alginate chitosan nanoparticles, their anti-proliferative activity on C6 glioma cells

Madecassoside (MAD), an ursane type pentacyclic triterpenoid saponin, isolated from Centella asiatica (CA) possesses various pharmacological activities. The aim of this study was to evaluate therapeutic potential of MAD encapsulated alginate chitosan nanoparticles (MACNPs) on C6 glioma cells. Synthesized nanoparticles were characterized by Thermogravimetric analysis (TGA), Differential thermal analysis (DTA), Differential scanning calorimetry (DSC), Scanning electron microscopy (SEM), Transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). Cell viability and compatibility of both MAD and MACNP were observed on primary astrocytes. Cytotoxicity and anti-proliferative effect of MACNPs were studied on C6 glioma cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and 5′-ethynyl-2′-deoxyuridine (Edu) assays. MACNPs showed 90% cytotoxicity, and depicted anti-proliferative activity against C6 cells. Annexin V-Alexa flour-488/propidium iodide (PI) staining followed by flow cytometry revealed that MACNPs induced necrosis in C6 glioma cells. Cell death was also observed using acridine orange/ethidium bromide (AO/EtBr) and Hoechst staining. 2′,7′-Dichlorodihydrofluorescein diacetate (DCFDA) assay by flow cytometry showed an increase in reactive oxygen species (ROS) production in MACNP treated C6 glioma cells. MACNPs showed a greater uptake and distribution in C6 glioma cells and inhibited the proliferation of C6 cells via increased intracellular ROS production. Our findings suggest MACNP as a promising drug delivery carrier for the management of glioma and shed new insights to brain malaises.

Chemical components from Sambucus adnata wall

Sambucus adnata Wall. belongs to Caprifoliaceae family. Phytochemical investigation on the aerial parts of S. adnata led to the isolation and identification of 17 known compounds (1–17) including triterpenoids and sterols. Compounds 1 and 8 are isolated from Sambucus adnata for the first time, and it is the first report that compounds 2, 5–6, 9–10, 12–15, and 17 are isolated from the plants of genus Sambucus. Importantly, three types of abundant components: (3β)-urs-12-en-3-yl stearate (0.33 g/kg, ursane type), (3β)-olean-12-en-3-yl stearate (0.17 g/kg, oleanane type), and lupenyl palmitate (0.52 g/kg, lupinane type) could be used as potential chemotaxonomic markers to distinguish among species of Sambucus.

11-Keto-α-Boswellic Acid, a Novel Triterpenoid from Boswellia spp. with Chemotaxonomic Potential and Antitumor Activity against Triple-Negative Breast Cancer Cells.

Boswellic acids, and particularly 11-keto-boswellic acids, triterpenoids derived from the genus Boswellia (Burseraceae), are known for their anti-inflammatory and potential antitumor efficacy. Although boswellic acids generally occur as α-isomers (oleanane type) and β-isomers (ursane type), 11-keto-boswellic acid (KBA) was found only as the β-isomer, β-KBA. Here, the existence and natural occurrence of the respective α-isomer, 11-keto-α-boswellic acid (α-KBA), is demonstrated for the first time. Initially, α-KBA was synthesized and characterized by high-resolution mass spectrometry (HR-MS) and nuclear magnetic resonance (NMR) spectroscopy, and a highly selective, sensitive, and accurate high-performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) method was developed by Design of Experiments (DoE) using a pentafluorophenyl stationary phase. This method allowed the selective quantification of individual 11-keto-boswellic acids and provided evidence for α-KBA in Boswellia spp. oleogum resins. The contents of α-KBA as well as further boswellic acids and the composition of essential oils were used to chemotaxonomically classify 41 Boswellia oleogum resins from 9 different species. Moreover, α-KBA exhibited cytotoxicity against three treatment-resistant triple-negative breast cancer (TNBC) cell lines in vitro and also induced apoptosis in MDA-MB-231 xenografts in vivo. The respective β-isomer and the acetylated form demonstrate higher cytotoxic efficacies against TNBC cells. This provides further insights into the structure-activity relationship of boswellic acids and could support future developments of potential anti-inflammatory and antitumor drugs.

UPLC-PDA-Q Exactive Orbitrap-MS profiling of the lipophilic compounds product isolated from Eucalyptus viminalis plants

The lipophilic compounds product (LCP), which was isolated and purified from Eucalyptus viminalis plants, has shown earlier broad antimicrobial and anti-inflammatory activities. To study secondary compounds responsible for the pharmacological activities, chemical composition of the LCP was studied with application of ultra-performance liquid chromatography combined with photodiode array detector and high-resolution Q Exactive Orbitrap mass spectrometer (UPLC-PDA-HRMS/MS). There were found thirty two compounds: twenty phloroglucinol derivatives (isopentyl diformyl phloroglucinol, macrocarpals, sideroxylonals, etc.), eight ursane type triterpenoids (loxanic acid, dehydroursolic acid lactone, dehydroursolic acid lactone acetate, two isomers of p-coumaroyl-dehydroursolic acid lactone and two isomers of feruloyl-dehydroursolic acid lactone), sequiterpenoid (S)-β-macrocarpene and three unknown phenolics. The major compounds of the LCP were pharmacologically active macrocarpals A and B, dehydroursolic acid lactone and its derivatives. It is supposed that previously discovered antimicrobial and anti-inflammatory activities of the LCP is due to the high contents of these secondary compounds.

New Anti-inflammatory Triterpene Esters and Glycosides from Alstonia scholaris.

Phytochemical studies on the ethanolic extract of aerial parts of Alstonia scholaris lead to the isolation of two new triterpenoid of the lanostanetype, lanosta 5ene,24-ethyl-3-O-β-D-glucopyranoside (1), lanosta,5ene,24-ethyl-3-O-β-D-glucopyranosideester (2) and new ursane type triterpenoidmethylester, 12-ursene-2,3,18,19-tetrol,28 acetate (nighascholarene) (3), together with seven known triterpenes, betuline, triterpene of the lupane type, alstoprenyol (4), 3β-hydroxy-28-β-acetoxy-5-olea triterpene (5),α-amyrin acetate (6), α-amyrin (7), lupeol acetate (8), 3β-hydroxy-24-nor-urs-4,12,28-triene triterpene (9) and ursolic acid (l0). The triterpenoid structures of these colorless compounds were deduced from the 1H and 13C-NMR data, and in particular from the application of two-dimensional 1H, 13C correlation experiments as well as by comparison with reported literature data. This study deals with isolation and structural elucidation of natural new triterpenoidesters and glycosides with anti-inflammatory activity.

Antidiabetic and cytotoxic polyhydroxylated oleanane and ursane type triterpenoids from Salvia grossheimii

Two polyhydroxylated oleanane and seven ursane triterpenoids were isolated from aerial parts of Salvia grossheimii. The chemical structures of the undescribed triterpenoids (1–6) were characterized using 1 and 2 D NMR and ESI-MS spectral data as; 2α, 3β, 11α –trihydroxy-olean-12- ene (1), 2α, 3β, 11α-trihydroxy-olean-18-ene (2), 2α- acetoxy-urs-12-ene-3β, 11α, 20β-triol (3), 3-keto-urs-12-ene-1β, 11α, 20β -triol (4), 2α, 3β-diacetoxy-urs-12-ene-1β, 11α, 20β -triol (5), and 3β-acetoxy-urs-12-ene-1β, 11α, 20β –triol (6). All compounds were evaluated for the in vitro α-glucosidase inhibitory and cytotoxic activities against MCF-7 human cancer cell line. Compounds 1, 2, 4, and 6 showed in vitro α-glucosidase inhibitory activity with IC50 = 43.6–198.4 µM, which were more potent than the antidiabetic medicine, acarbose. The remaining compounds; 3, and 7–9 showed potent cytotoxic activity (IC50 = 6.2–31.9 µM) against the cancerous cell line, while the potent α-glucosidase inhibitors were inactive. Molecular docking analysis and kinetic studies were applied to investigate the structure activity relationships and mechanisms of the human and Saccharomyces cerevisiae α-glucosidase inhibitory of the purified compounds. Comparing the high cytotoxicity and α-glucosidase inhibitory of the oleanane and ursane type triterpenoids suggest them as potential lead compounds for further research in anticancer and antidiabetic research.

Synthesis and cholinesterase inhibiting potential of A-ring azepano- and 3-amino-3,4-seco-triterpenoids

In this study, a series of A-ring azepano- and 3-amino-3,4-seco-derivatives were synthesized from betulin, oleanolic, ursolic and glycyrrhetinic acids aiming to develop new cholinesterase inhibitors. Azepanobetulin, azepanoerythrodiol and azepanouvaol were modified to give amide and tosyl derivatives, while azepano-anhydrobetulines and azepano-glycyrrhetols were obtained for the first time. Oleanane and ursane type 3-amino-3,4-seco-4(23)-en triterpenic alcohols were synthesized by reducing the corresponding 2-cyano-derivatives accessible from Beckmann type 2 rearrangements. The compounds were screened in colorimetric Ellman’s assays to determine their ability to act as inhibitors for the enzymes acetylcholinesterase (AChE, from electric eel) and butyrylcholinesterase (BChE, from equine serum). While most of these compounds were only moderate inhibitors for AChE, several of them were shown to be inhibitors for BChE acting as mixed-type inhibitors. Azepanobetulin 1, its C28-amide derivatives 7 and 8, azepano-11-deoxo-glycyrrhetol 12 and azepanouvaol 18 held inhibition constants Ki ranging between 0.21 ± 0.06 to 0.68 ± 0.19 μM. Thus, they were approximately 4 to 10 times more active than standard galantamine hydrobromide. For all of the compounds reasonably high docking scores for BChE were obtained being in good agreement with the experimental results from the enzymatic studies. As a result, A-ring azepano-triterpenoids were found to be new scaffolds for the development of BChE inhibitors.

The chemistry of the West and Central African Penianthus zenkeri Diels (Menispermaceae)

A phytochemical investigation of the roots and twigs of Penianthus zenkeri Diels led to the identification of twenty four compounds including one previously undescribed C-28 ecdysteroid (1) and previously described phytosteroids (2–5, 20, 22, 23), phenolic compounds (6–8, 12), diterpenoids (9–11), alkaloids (13,14, 18, 19), a dipeptide (15), ursane type triterpenoids (16–17), a carbohydrate (21) and a fatty alcohol (24). Three semi-synthetic derivatives (5b, 5a, 17a) obtained from acetylation and acetonidation of rubrosterone (5), and allylation of ursolic acid (17), respectively, are also reported. The chemical structures of the compounds were determined using 1D and 2D NMR spectral data, mass spectrometry and by comparison with the data reported in the literature. The absolute configuration of compound 9 was established using X-Ray and ECD analysis. Different extracts of the twigs and roots, compounds 2–4, 6–11, 15, and 17–21 were evaluated for their antibacterial, and cytotoxic activities. The twigs extract showed an antibacterial activity with an MIC of 62.5 μg/mol against Staphylococcus aureus ATCC 4300, while ursolic acid exhibited a moderate cytotoxicity with an IC50 of 50.9 μM. The chemotaxonomic relevance of the isolated compounds is discussed.

The Introduction of Hydrazone, Hydrazide, or Azepane Moieties to the Triterpenoid Core Enhances an Activity Against M. tuberculosis.

Triterpenoids exhibit a wide spectrum of antimicrobial activity. The objective of this study was to synthesize a series of nitrogen derivatives based on lupane, oleanane, and ursane triterpenoids with high antitubercular activity. Isonicotinoylhydrazones were prepared via the reaction of 3-oxotriterpenic acids or betulonic aldehyde with isoniazid (INH) in yields of 54-72%. N-Acylation of betulonic or azepanobetulinic acids led to lupane C28 hydrazides and dihydrazides. The derivatives were evaluated for their in vitro antimycobacterial activities against Mycobacterium tuberculosis (MTB) H37RV and single-drug resistance (SDR)-TB in the National Institute of Allergy and Infectious Diseases, USA. Molecular docking was performed to evaluate the possible binding modes of investigated compounds in the active site of Diterpene synthase (Rv3378c). The obtained compounds are represented by C3 or C28 conjugates with hydrazine hydrate or INH. Some compounds demonstrated from high minimum inhibitory concentration (MIC ≤ 10 μg/mL) to excellent (MICs from 0.19 to 1.25 μg/mL) activity against MTB H37RV. Two lupane conjugates with INH were the leading compounds against MTB H37RV and some SDR-strains with MICs ranged from 0.19 to 1.70 μg/mL. Molecular docking of active compounds to diterpene synthase showed that these moieties accommodate the active site of the enzyme. It was revealed that the conjugation of lupanes with INH at C3 is more effective than at C28 and the lupane skeleton is preferable among oleanane and ursane types. The replacement of native hexacarbocyclic A ring to seven-member azepane ring is favorably for inhibition of both MTB H37RV and SDR-strains. These data could possibly mean that the antitubercular activity against INH-resistant strains (INH-R) came from both triterpenoid and isoniazid parts of the hybrid molecules. Azepanobetulin showed the highest activity against both INH-R strains in comparison with other triterpenoids and INH. Thus, the introduction of hydrazone, hydrazide (dihydrazide), or azepane moieties into the triterpenoid core is a promising way for the development of new anti-tubercular agents.

Medicinal properties of a naturally occurring pentacyclic dihydroxy triterpenoid uvaol

Uvaol is a 6-6-6-6-6 pentacyclic ursane type dihydroxy triterpenoid. It is present in various plants such as Plumeria rubra, Olea europaea, Nerium oleander and Malus domestica. One step conversion of ursolic acid, a 6-6-6-6-6 pentacyclic triterpenic acid having an identical triterpenoid backbone, to uvaol has also been reported. A variety of pharmaceutical properties, including antimicrobial, hepatoprotective, anti-inflammatory, anti-tumour, anti-cancer, cardiovascular effects and healing of cutaneous wounds etc. have been reported. In this review, various plant sources of uvaol and its pharmaceutical properties have been reported.

Organo-petrographic and geochemical characteristics of Gurha lignite deposits, Rajasthan, India: Insights into the palaeovegetation, palaeoenvironment and hydrocarbon source rock potential

The sedimentary sequence containing lignite deposits in Gurha quarry of the Bikaner-Nagaur Basin (Rajasthan) has been investigated. The samples from lignite and allied shale horizons were evaluated for petrographical, palynological, palynofacies and organic geochemical inferences, to depict the source flora and to reconstruct the palaeodepositional conditions prevailed during the sedimentation. An assessment for the hydrocarbon generation potential of these deposits has also been made. The results revealed the dominance of huminite macerals and phytoclasts organic matter (OM) indicating the existence of forested vegetation in the vicinity of the depositional site. A relatively high terrigenous/aquatic ratio (TAR) and the carbon preference index (CPI) are also suggesting the contribution of higher plants in the peat formation. However, the n-alkane distributions, maximizing at n-C17 and n-C29, showed inputs from the algal communities along with the higher plant derived organic matters. Recovered palynomorphs of the families Onagraceae, Meliaceae, Arecaceae, Rhizophoraceae, Rubiaceae, Ctenolophonaceae, etc. together with oleanene and ursane types of triterpenoids suggest the contribution from angiosperms source vegetation. Interestingly, the presence of Araucareaceae and Podocarpaceae pollen grains shows the existence of gymnosperms vegetation. Further, the presence of tetracyclic diterpanes; demethylated ent-beyerane, sandaracopimarane, pimarane, and Kaurane type of compounds confirms the contribution of conifers. The variation in the values of the coefficient of non-equality (H: 0.68%–7.56%), the standard deviation (δ: 0.04%–0.16%) and the coefficient of variability (V: 16.10%–46.47%), also shows the heterogeneity in the source organic matter.The various petrographical indices, palynological entities, and geochemical parameters indicate that the peat-forming vegetation was accumulated under a mixed environment and fluctuating hydrological settings. The interpretation of palynofacies data on APP (Amorphous organic matter-Phytoclast-Palynomorphs) diagram suggests that the accumulation of organic matter occurred in a dysoxic-suboxic condition in a proximal (to land) setting with the shift to an anoxic condition in distal setting towards the termination of sedimentation. The huminite (ulminite) reflectance (Rr) values (av. 0.28%) showed a good relationship with average Tmax value (414 ​°C), suggesting the immaturity. The TOC content ranges of 13–59 ​wt.%, and HI values vary between 101 and 546 ​mg HC/g TOC in the studied samples. Collectively, the studied lignite and shale samples have the admixed kerogens (Type III–II) and exhibit the ability to generate the gaseous to oil hydrocarbons upon maturation.

A-Ring-Modified Triterpenoids and Their Spermidine–Aldimines with Strong Antibacterial Activity

Synthesis of A-ring-modified lupane, oleanane and ursane type triterpenoid conjugates with spermidine through an aldimine linkage or diethylentriamine via an amide bond is described. These derivatives were evaluated for their in vitro antimicrobial properties against human pathogens. Except for derivatives 1 and 7, all compounds have moderate to weak minimum inhibitory concentrations (MICs) against Gram-positive Staphylococcus aureus bacteria, with MICs varying from 3.125 to 200 µM. Compound 11 is efficient against Escherichia coli and Pseudomonas aeruginosa, with MICs of 25 and 50 µM, respectively, while all other derivatives do not possess important antimicrobial activities against these Gram-negative bacteria.

High throughput identification of pentacyclic triterpenes in Hippophae rhamnoides using multiple neutral loss markers scanning combined with substructure recognition (MNLSR)

A fast and simple analytical method was developed to fully understand the chemical diversity of pentacyclic triterpenes: lupane, oleanane and ursane type, using multiple neutral loss markers scanning combined with substructure recognition (MNLSR). This procedure was performed on ultra-high performance liquid chromatography coupled to electrospray ionization quadrupole Orbitrap high resolution mass spectrometry (UHPLC/ESI Q-Orbitrap). Hippophae rhamnoides was used as an example. This approach includes three systematic workflows: (i) targeted identification of 25 reference standards in order to deduce the mechanism of fragmentation in both positive and negative modes. (ii) statistical analysis for neutral loss markers and structural fragment markers of pentacyclic triterpenes by fragmentation mechanism information. (iii) untargeted identification using multiple neutral loss markers scanning technique to discover new compounds and then confirming structural characterization by structural fragment markers. This mass spectra data analysis approach was successful to identify and confirm 15 new compounds from Hippophae rhamnoides samples. This study extended the application of mass spectrometry to satisfy the requirements of high-throughput identification for pentacyclic triterpenes in new medicine or food resources and could help chemists rapidly discover novel similar substructure compounds from a complex matrix.

Triterpenoids and triterpenoid saponins from Dipsacus asper and their cytotoxic and antibacterial activities

Phytochemical investigation of the ethyl acetate soluble part, generated from the ethanol extract of the roots of Dipsacus asper, led to the separation and identification of three undescribed triterpenoids including one arborinane type, one ursane type and one oleanane type, two unreported oleanane type triterpenoid arabinoglycosides, and 18 known analogues. Structures of these compounds were determined by comprehensive spectroscopic analyses, with the absolute configurations of 25-acetoxy-28-dehydroxyrubiarbonone E and 2α,3β-dihydroxy-23-norurs-4(24),11,13(18)-trien-28-oic acid being established by evaluation of their experimental and calculated ECD spectra. 25-Acetoxy-28-dehydroxyrubiarbonone E features an oxygenated C-25 that is the first case among arborinane type triterpenoids, while 2α,3β,24-trihydroxy-23-norurs-12-en-28-oic acid incorporates a sp3 C-24 that is a rare structural feature of 23-norursane type triterpenoids. Of these isolates, 2′,4′-O-diacetyl-3-O-α-l-arabinopyranosyl-23-hydroxyolea-12-en-28-oic acid and hederagonic acid exhibited moderate antibacterial activity against Staphylococcus aureus with IC50 values of 12.3 and 10.3 μM, respectively, while those with either a feruloyloxy group or an arabinosyl moiety at C-3 displayed potent cytotoxic activities against four tumor cell lines A549, H157, HepG2 and MCF-7.

Influence of tree height on the hydrophilic and lipophilic composition of bark extracts from Eucalyptus globulus and Eucalyptus nitens

Abstract The influence of tree height on the composition of bark extractives from Eucalyptus globulus and Eucalyptus nitens was investigated for its potential in the sourcing of valuable compounds. The bark of these trees was extracted at different heights to obtain lipophilic and hydrophilic compounds, which were chemically characterized. The extraction yield of lipophilic compounds was higher for E. globulus than for E. nitens. The type and proportion of the compounds changed with the tree variety and height. The main compounds detected were triterpenic acid derivatives, such as lupane, oleanane and ursane types, followed by fatty acids. The yield extraction of the hydrophilic compounds was higher for E. nitens than E. globulus. The total phenolic content, proanthocyanidins and antioxidant activity of the extracts increased with the tree height in both cases. However, the E. globulus extracts [half maximal inhibitory concentration (IC50) = 13.8 ± 0.2 μg ml−1] showed higher antioxidant activity than did the E. nitens extracts (IC50 = 22.8 ± 0.2 μg ml−1). Differences in the extract composition and the spatial conformation of the molecules (steric effect) could also help to obtain a higher antioxidant capacity from E. globulus extracts. These results show that differentiation by tree height can contribute to the selective enrichment of these valuable compounds.

Pharmacological Properties, Molecular Mechanisms, and Pharmaceutical Development of Asiatic Acid: A Pentacyclic Triterpenoid of Therapeutic Promise.

Asiatic acid (AA) is a naturally occurring aglycone of ursane type pentacyclic triterpenoids. It is abundantly present in many edible and medicinal plants including Centella asiatica that is a reputed herb in many traditional medicine formulations for wound healing and neuropsychiatric diseases. AA possesses numerous pharmacological activities such as antioxidant and anti-inflammatory and regulates apoptosis that attributes its therapeutic effects in numerous diseases. AA showed potent antihypertensive, nootropic, neuroprotective, cardioprotective, antimicrobial, and antitumor activities in preclinical studies. In various in vitro and in vivo studies, AA found to affect many enzymes, receptors, growth factors, transcription factors, apoptotic proteins, and cell signaling cascades. This review aims to represent the available reports on therapeutic potential and the underlying pharmacological and molecular mechanisms of AA. The review also also discusses the challenges and prospects on the pharmaceutical development of AA such as pharmacokinetics, physicochemical properties, analysis and structural modifications, and drug delivery. AA showed favorable pharmacokinetics and found bioavailable following oral or interaperitoneal administration. The studies demonstrate the polypharmacological properties, therapeutic potential and molecular mechanisms of AA in numerous diseases. Taken together the evidences from available studies, AA appears one of the important multitargeted polypharmacological agents of natural origin for further pharmaceutical development and clinical application. Provided the favorable pharmacokinetics, safety, and efficacy, AA can be a promising agent or adjuvant along with currently used modern medicines with a pharmacological basis of its use in therapeutics.

Synthesis and antimycobacterial activity of triterpenic A-ring azepanes

A series of A-ring azepanones and azepanes derived from betulonic, oleanonic and ursonic acids was synthesized and evaluated for their in vitro antimycobacterial activities against M. tuberculosis (MTB) H37Rv and SDR-TB in the National Institute of Allergy and Infectious Diseases. Triterpenic A-azepano-28-hydroxy-derivatives were synthesized by the reduction with LiAlH4 of triterpenic azepanones available from the Beckmann rearrangement of the corresponding C3-oximes. Modification of azepanes at NH-group and atoms С12, C20, C28 and C29 of triterpenic core led to the derivatives with oxo, epoxy, aminopropyl, oximino and acyl substituents. The primary assay of tested triterpenoids against MTB H37Rv demonstrated their MIC values ranged from 3.125 to >200 μM. Ursane type A-azepano-28-cinnamoates were the most active being 2 and 4 times more efficient than the initial 28-hydroxy-derivative. The follow-up testing revealed A-azepano-28-cinnamoyloxybetulin as a leader compound with MIC 2 and MBC 4 μM against MTB H37Rv and MICs 4, 1 and 1 μM against INH, RIF and OFX resistant strains, respectively. Five oleanane and ursane azepanes pronounced better activity than isoniazid against INH-R1 and rifampicin against INH-R2 strains. This work opens a new direction in the design and synthesis of new antitubercular agents basing on azepanotriterpenoids.

Impact of Mistletoe Triterpene Acids on the Uptake of Mistletoe Lectin by Cultured Tumor Cells.

Complementary treatment possibilities for the therapy of cancer are increasing in demand due to the severe side effects of the standard cytostatics used in the first-line therapy. A common approach as a complementary treatment is the use of aqueous extracts of Viscum album L. (Santalaceace). The therapeutic activity of these extracts is attributed to Mistletoe lectins which are Ribosome-inactivating proteins type II. Besides these main constituents the extract of Viscum album L. comprises also a mixture of lipophilic ingredients like triterpene acids of the oleanane, lupane and ursane type. However, these constituents are not contained in commercially available aqueous extracts due to their high lipophilicity and insolubility in aqueous extraction media. To understand the impact of the extract ingredients in cancer therapy, the intracellular uptake of the mistletoe lectin I (ML) by cultured tumor cells was investigated in relation to the mistletoe triterpene acids, mainly oleanolic acid. Firstly, these hydrophobic triterpene acids were solubilized using cyclodextrins (“TT” extract). Afterwards, the uptake of either single compounds (isolated ML and the aqueous “viscum” extract) or in combination with the TT extract (ML+TT, viscumTT), was analyzed. The uptake of ML was studied inTHP-1-, HL-60-, 143B- and Ewing TC-71-cells and determined after 30, 60 and 120 minutes by an enzyme linked immunosorbent assay which quantifies the A-chain of the hololectin. It could be shown that the intracellular uptake after 120 minutes amounted to 20% in all cell lines after incubation with viscumTT. The studies further revealed that the uptake in THP-1-, HL-60- and Ewing TC-71-cells was independent of the addition of TT extract. Interestingly, the uptake of ML by 143B-cells could only be measured after addition of triterpenes pointing to resistance to mistletoe lectin.