Triterpene Derivatives Research Articles

α-Glucosidase and cholinesterase inhibiting potential of a series of semisynthetic nitrogen triterpenic derivatives

α-Glucosidase and cholinesterase inhibiting potential of a series of semisynthetic nitrogen triterpenic derivatives

Triterpene Derivatives from Garcinia oligantha and Their Anti-Cancer Activity.

Phytochemical investigations of leaves and twigs from Garcinia oligantha Merr. resulted in the isolation of five undescribed triterpene derivatives (1-5) and six known analogs (6-11). Their structures were determined based on extensive spectroscopic data and high-resolution mass spectra analyses. Compounds 1-11 were tested for their in vitro cytotoxicity against three human cancer cell lines (HeLa, HepG-2, and MCF-7). Compounds 1, 2, 8, and 11 exhibited broad and significant cytotoxicity against the tested cell lines with IC50 values ranging from 5.04 to 21.55 μM. Compounds 5 and 9 showed cytotoxicity against HeLa and MCF-7 with IC50 values ranging from 13.22 to 19.62 μM. The preliminary structure-activity relationship for the 11 isolated compounds is also discussed.

Human Lung Cancer (A549) Cell Line Cytotoxicity and Anti-Leishmania major Activity of Carissa macrocarpa Leaves: A Study Supported by UPLC-ESI-MS/MS Metabolites Profiling and Molecular Docking.

Lung cancer and cutaneous leishmaniasis are critical diseases with a relatively higher incidence in developing countries. In this research, the activity of Carissa macrocarpa leaf hydromethanolic extract and its solvent-fractions (n-hexane, EtOAc, n-butanol, and MeOH) against the lung adenocarcinoma cell line (A549) and Leishmania major was investigated. The MeOH fraction exhibited higher cytotoxic activity (IC50 1.57 ± 0.04 μg/mL) than the standard drug, etoposide (IC50 50.8 ± 3.16 μg/mL). The anti-L. major results revealed strong growth inhibitory effects of the EtOAc fraction against L. major promastigotes (IC50 27.52 ± 0.7 μg/mL) and axenic amastigotes (29.33 ± 4.86% growth inhibition at 100 μg/mL), while the butanol fraction exerted moderate activity against promastigotes (IC50 73.17 ± 1.62), as compared with miltefosine against promastigotes (IC50 6.39 ± 0.29 μg/mL) and sodium stibogluconate against axenic amastigotes (IC50 22.45 ± 2.22 μg/mL). A total of 102 compounds were tentatively identified using UPLC-ESI-MS/MS analysis of the total extract and its fractions. The MeOH fraction was found to contain several flavonoids and flavan-3-ol derivatives with known cytotoxic properties, whereas the EtOAc fractions contained triterpene, hydroxycinnamoyl, sterol, and flavanol derivatives with known antileishmanial activity. Molecular docking of various polyphenolics of the MeOH fraction with HDAC6 and PDK3 enzymes demonstrates high binding affinity of the epicatechin 3-O-β-D-glucopyranoside and catechin-7-O-β-D-glucopyranoside toward HDAC6, and procyanidin C2, procyanidin B5 toward PDK3. These results are promising and encourage the pursuit of preclinical research using C. macrocarpa's MeOH fraction as anti-lung cancer and the EtOAc fraction as an anti-L. major drug candidates.

Cytotoxic Activities and Fingerprint Analysis of Triterpenes by HPTLC Technique for Distinguishing Ganoderma Species from Vietnam and other Asian Countries.

Ganoderma lucidum (Fr.) P. Karst. (Ganodermataceae), commonly called Linhzhi, is traditionally employed in the treatment of human diseases, including hepatitis, liver disorders, hypercholesterolemia, arthritis, bronchitis, and tumorigenic diseases. In this study, the fingerprint profiles of five different strains of G. lucidum originated from Japan, Korea, China, and Vietnam, five samples of G. lucidum growing on Erythrophloeum fordii Oliv. in Vietnam, and five related Linhzhi species (Ganoderma applanatum, Ganoderma australe, Ganoderma clossum, Ganoderma subresinosu, and Ganoderma sp.) were investigated for triterpene derivatives using high-pressure, thin-layer chromatography (HPTLC). The HPTLC fingerprint profiles demonstrated significant differences between G. lucidum and other related Linhzhi species in the presence of triterpene derivatives. Evaluation for the cytotoxicity of these samples against four cancer cell lines, including A549, MCF7, PC3, and HepG2, displayed various levels of cytotoxic effects, with IC50 values of: 15.6-46.3 µg/mL on the A549 cancer cell line, of 18.4-43.6 µg/mL on the MCF7 cancer cell line, of 10.0-32.1 µg/mL on the PC3 cancer cell line, and of 10.6-27.6 µg/mL on the HepG2 cancer cell line. Conclusively, these data contributed to the literature on the cytotoxic activities and fingerprint analysis of triterpenes by the HPTLC technique for distinguishing Ganoderma species from Vietnam and other Asian countries.

Lupane Triterpene Derivatives Improve Antiproliferative Effect on Leukemia Cells through Apoptosis Induction

Leukemia is one of the most frequent types of cancer. No effective treatment currently exists, driving a search for new compounds. Simple structural modifications were made to novel triterpenes isolated from Phoradendron wattii. Of the three resulting derivatives, 3α-methoxy-24-hydroxylup-20(29)-en-28-oic acid (T1m) caused a decrease in the median inhibitory concentration (IC50) on the K562 cell line. Its mode of action was apparently apoptosis, ROS generation, and loss of mitochondrial membrane potential (MMP). Molecular docking analysis showed T1m to produce lower binding energies than its precursor for the Bcl-2 and EGFR proteins. Small, simple, and viable modifications to triterpenes can improve their activity against leukemia cell lines. T1m is a potentially promising element for future research. Clarifying the targets in its mode of action will improve its applicability.

New triazole-substituted triterpene derivatives exhibiting anti-RSV activity: synthesis, biological evaluation, and molecular modeling.

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infections in infants. Currently, ribavirin, a nucleoside analog containing a 1,2,4-triazole-3-carboxamide moiety, is a first-line drug for its treatment, however, its clinical use has been limited due to its side effects. Here, we designed two new nitroaryl-1,2,3-triazole triterpene derivatives as novel anti-RSV drugs. Their anti-RSV and cytotoxic activity were evaluated in vitro, RSV protein F gene effects by RT-PCR and molecular modeling with inosine monophosphate dehydrogenase (IMPDH) were performed. Compound 8 was the best performing compound, with an EC50 value of 0.053 μM, a TI of 11160.37 and it inhibited hRSV protein F gene expression by approximately 65%. Molecular docking showed a top-ranked solution located in the same region occupied by crystallographic ligands in their complex with IMPDH. The results obtained in this study suggest that compound 8 might be a new anti-RSV candidate.

Semisynthetic Derivatives of Pentacyclic Triterpenes Bearing Heterocyclic Moieties with Therapeutic Potential.

Medicinal plants have been used by humans since ancient times for the treatment of various diseases and currently represent the main source of a variety of phytocompounds, such as triterpenes. Pentacyclic triterpenes have been subjected to numerous studies that have revealed various biological activities, such as anticancer, antidiabetic, anti-inflammatory, antimicrobial, and hepatoprotective effects, which can be employed in therapy. However, due to their high lipophilicity, which is considered to exert a significant influence on their bioavailability, their current use is limited. A frequent approach employed to overcome this obstacle is the chemical derivatization of the core structure with different types of moieties including heterocycles, which are considered key elements in medicinal chemistry. The present review aims to summarize the literature published in the last 10 years regarding the derivatives of pentacyclic triterpenes bearing heterocyclic moieties and focuses on the biologically active derivatives as well as their structure–activity relationships. Predominantly, the targeted positions for the derivatization of the triterpene skeleton are C-3 (hydroxyl/oxo group), C-28 (hydroxyl/carboxyl group), and C-30 (allylic group) or the extension of the main scaffold by fusing various heterocycles with the A-ring of the phytocompound. In addition, numerous derivatives also contain linker moieties that connect the triterpenic scaffold with heterocycles; one such linker, the triazole moiety, stands out as a key pharmacophore for its biological effect. All these studies support the hypothesis that triterpenoid conjugates with heterocyclic moieties may represent promising candidates for future clinical trials.

Isolation of quercetin-3-O-sulfate and quantification of major compounds from Psidium guajava L. from Vietnam

The aim of this study is first to identify the major phenolic compound of a crude ethanol extract of Psidium guajava leaves collected in Vietnam and to develop validated methods for quantification of phenolic and triterpenic components by HPLC-PDA-HRMS. The major phenolic compound was determined as quercetin-3-O-sulfate which is isolated and quantified for the first time in P. guajava. Validated HPLC-DAD quantification methods were developed to quantify the major triterpenic and phenolic derivatives of this extract and found to be accurate in the concentration range of 2–50 μg/mL for phenolic, and 5–100 μg/mL for triterpenic compounds. Four crude ethanol extracts of guava leaves collected at different periods of the year were analyzed using the developed methods and were found to be richer in triterpenic than phenolic derivatives. We also observed that the weather or rainfall influenced the richness in bioactive compounds in guava leaves.

Development of an Enzyme-Based Thin-Layer Chromatographic Assay for the Detection of Cyclooxygenase-2 Inhibitors

The search for new anti-inflammatory drugs with less side effects requires simple, fast and reliable screening methods. In this context, we have developed a sensitive thin-layer chromatographic (TLC) assay on silica gel plates to detect cyclooxygenase-2 (COX-2) inhibition. COX-2 catalyzes two sequential enzymatic reactions: a first oxygenation step that converts arachidonic acid into prostaglandin G2, and a subsequent reduction of prostaglandin G2 into prostaglandin H2. Our test is based on the co-oxidation during this peroxidation step of a co-substrate, N,N,N′,N′-tetramethyl-p-phenylenediamine (TMPD), leading to a blue-grey product. As a consequence, COX-2 inhibitors appear on the TLC plate after revelation as clear spots against the colored background. Parameters such as concentrations of enzyme, substrate, and chromogenic reagent have been optimized. The limit of detection was found to be below the microgram for standard COX-2 inhibitors such as celecoxib or ibuprofen. The developed TLC assay was also conclusive when applied to 60 various natural pure compounds and some complex natural extracts. Results demonstrated a COX-2 inhibitory activity mostly for triterpene and sterol derivatives. This COX-2 TLC assay appears as a suitable low-cost and reliable strategy for the screening of natural extracts to discover new anti-inflammatory compounds.

Seco-Lupane Triterpene Derivatives Induce Ferroptosis through GPX4/ACSL4 Axis and Target Cyclin D1 to Block the Cell Cycle.

In this study, 70 new seco-lupane triterpene derivatives were designed, synthesized, and characterized, and their in vitro anticancer activities were evaluated. Structure-activity relationship studies showed that most compounds inhibited the growth of a variety of tumor cells in vitro. With the extension of alkyl chains, the activity of azole compounds gradually increased while that of indole compounds first increased and then decreased. Moreover, all indole derivatives showed stronger anticancer activity than azole derivatives. In addition, compound 21 showed the strongest inhibitory effect on HepG2 cells with an IC50 value of 0.97 μM. Mechanistic studies showed that compound 21 coregulates the cell death process by inducing ferroptosis and regulating the cell cycle. In conclusion, compound 21 can be used as a ferroptosis inducer and cycle blocker to regulate the HepG2 death process, and it has the potential to become an effective new drug for the treatment of hepatocellular carcinoma.

An improved partial synthesis of corosolic acid and its conversion to highly cytotoxic mitocans

Ursolic acid was used as a convenient starting material for a three-step partial synthesis of corosolic acid. Corosolic acid was acetylated, and an amide linker was attached followed by a rhodamine B unit at the distal end of the linker. Especially compounds holding a piperazinyl or homopiperazinyl linker held exceptional cytotoxicity for several human tumor cell lines. For example, homopiperazinyl spacered 11 showed EC50 ​= ​2 ​nM for A2780 ​cells combined with high tumor cell/non-tumor cell selectivity (compound 11: EC50 ​= ​0.122 ​μM for non-malignant NIH 3T3). Thus, compound 11 currently represents one of the most cytotoxic triterpene derivatives holding both superior cytotoxicity combined with high selectivity (SI A2780 vs NIH 3T3 ​> ​60). Staining experiments showed this compound to act as a mitocan. This makes 11 an interesting compound for further studies or as a lead substance.

Novel β-Cyclodextrin-Based Heptavalent Glycyrrhetinic Acid Conjugates: Synthesis, Characterization, and Anti-Influenza Activity.

In our continuing efforts toward the design of novel pentacyclic triterpene derivatives as potential anti-influenza virus entry inhibitors, a series of homogeneous heptavalent glycyrrhetinic acid derivatives based on β-cyclodextrin scaffold were designed and synthesized by click chemistry. The structure was unambiguously characterized by NMR, IR, and MALDI-TOF-MS measurements. Seven conjugates showed sufficient inhibitory activity against influenza virus infection based on the cytopathic effect reduction assay with IC50 values in the micromolar range. The interactions of conjugate 37, the most potent compound (IC50 = 2.86 μM, CC50 > 100 μM), with the influenza virus were investigated using the hemagglutination inhibition assay. Moreover, the surface plasmon resonance assay further confirmed that compound 37 bound to the influenza HA protein specifically with a dissociation constant of 5.15 × 10−7 M. Our results suggest the promising role of β-cyclodextrin as a scaffold for preparing a variety of multivalent compounds as influenza entry inhibitors.

Insulin mimetic lanostane triterpenes from the cultivated mushroom Ganoderma orbiforme

• Three triterpenes derivatives were isolated from the cultivated fruiting bodies of Ganoderma orbiforme . • The triterpenes induced glucose uptake in a zebrafish-based assay. • The triterpenes also showed an inhibitory effect on nitric oxide production in LPS-induced BV-2 microglia cells. Two new lanostane triterpenes, ganorbifoins A and B ( 1 - 2 ), together with the known compound (25S,3′S)-(+)-12α-hydroxy-3α-(3′-hydroxy-4′-methoxycarbonyl-3′-methylbutiryloxy)-24-methyllanosta-824-(31)-dien-26-oic acid ( 3 ) were isolated from the cultivated fruiting bodies of Ganoderma orbiforme . The structures of isolates were determined by extensive analysis of NMR and HRESIMS. All compounds induced glucose uptake in zebrafish-based system at the concentration of 10 μM. And the best performing compound is ganorbifoin A. Compounds 2 and 3 exhibited an inhibitory effect on nitric oxide production in LPS-induced BV-2 microglia cells at the concentration of 20 μ M.

Semisynthetic triterpenes led to the generation of selective antitrypanosomal lead compounds.

Triterpenes α,β-amyrin are naturally occurring molecules that can serve as building blocks for synthesizing new chemical entities. This study synthesized acyl, carboxyesther, NSAID, and nitrogenous derivatives and evaluated their antimicrobial activity. A cyclodextrin complexation method was developed to improve the solubility of the derivatives. Of the 17 derivatives tested, five exhibited activity against Trypanosoma cruzi, T. brucei, Leishmania infantum, Candida albicans, Staphylococcus aureus, and Escherichia coli. The 9a/9b mixture showed weak activity against the parasites (IC50 24.45-40.32μM). However, it showed no activity for the other microorganisms. Derivatives 14a/14b exhibited potent activity against T. cruzi (IC50 2.0nM) in this tested concentration did not show activity to the other microorganisms and were not cytotoxic. Derivatives 15a/15b and 16a/16b demonstrated relevant activity against the parasites (IC50 2.24-5.44μM), but were also cytotoxic. Derivatives 17a/17b showed low activity against the tested parasites (IC50 21.70-22.79μM), but they were selective since they did not show activity against other microorganisms. In docking studies, in general, all derivatives showed complementarity with the CYP51 binding site of the trypanosomatid mainly by hydrophobic interactions; thus, it is not conclusive that the molecules act by inhibiting this enzyme. Our results showed that triterpenes derivatives with antitrypanosomal activity could be synthesized by an inexpensive and rapid method.

Rhodamine 101 Conjugates of Triterpenoic Amides Are of Comparable Cytotoxicity as Their Rhodamine B Analogs.

Pentacyclic triterpenoic acids (betulinic, oleanolic, ursolic, and platanic acid) were selected and subjected to acetylation followed by the formation of amides derived from either piperazine or homopiperazine. These amides were coupled with either rhodamine B or rhodamine 101. All of these compounds were screened for their cytotoxic activity in SRB assays. As a result, the cytotoxicity of the parent acids was low but increased slightly upon their acetylation while a significant increase in cytotoxicity was observed for piperazinyl and homopiperazinyl amides. A tremendous improvement in cytotoxicity was observed; however, for the rhodamine B and rhodamine 101 conjugates, and compound 27, an ursolic acid derived homopiperazinyl amide holding a rhodamine 101 residue showed an EC50 = 0.05 µM for A2780 ovarian cancer cells while being less cytotoxic for non-malignant fibroblasts. To date, the rhodamine 101 derivatives presented here are the first examples of triterpene derivatives holding a rhodamine residue different from rhodamine B.

Ecofriendly Approach for Steroids, Terpenes, and Alkaloids-based Biosurfactant

In the last decade, the investigation of biosurfactants (BS) has been extensively studied due to the application of BS to remove or minimize the use of toxic synthetic surfactants into the ecosystem. Contaminated soil, air, and water cause a serious hazard to human health and the environment. Usually, biosurfactants exhibited remarkable emulsification with minimum surface tension values less than 16.5 dynes/cm. The BS exhibited significant bioactivities against bacterial and fungal pathogens. The plant-based surfactants have a more than 80% free radical scavenging nature and show potential antioxidant activity. BS are amphiphilic motifs obtained from plants and microorganisms' extract. BS has distinct hydrophilic and hydrophobic properties, leading to micellization formation. BS has a special molecular structure with hydrophilic glycoside linkage and lipophilic (Hydrophobic) triterpene derivative. BS has a broad spectrum of numerous sectors, including food, agriculture, personal care, petroleum, cosmetic, pharmaceutical, textile. The features of BS are low toxicity, environmental capability, biodegradability, multi-functionality, and availability of resources. The biosurfactant is today's need of society because synthetic surfactants have high toxicity and high ecological impact due to carcinogenic and mutagenic effects on human health. The proteins and polysaccharides act as emulsifiers. The chemical composition of this kind of surfactant is protein, glycolipid, carbohydrates, steroids, terpenoids. We focused on the steroids, terpenes, and alkaloids based surfactants. Currently employed plant and microbes-based surfactants, study their production, chemical composition, and effect of synthetic biosurfactant on human health and ecosystem.

3D-QSAR, ADME-Tox, and molecular docking of semisynthetic triterpene derivatives as antibacterial and insecticide agents

In the present work, 27 triterpene derivatives have been subjected to 3D-QSAR, ADME-Tox, and molecular docking for their insecticidal activity. The selected derivatives are previously semi-synthesized based on compounds obtained from Euphorbia resinifera and Euphorbia officinarum latex. The in silico studies were used to predict and to evaluate the antibacterial and insecticidal properties of the 3D structure of triterpene derivatives. The 3D-QSAR models are developed using CoMFA and CoMSIA techniques, and they have showed excellent statistical results (R2 = 0.99; Q2 = 0.672; R2pred = 0.91 for CoMFA and R2 = 0.97; Q2 = 0.61; R2pred = 0.94 for CoMSIA). The results indicate that the built models are able to describe the relationship between the structure of triterpene derivatives and the pLD50 bioactivity. Based on contour maps obtained from CoMFA and CoMSIA models, 38 new molecules are designed and their pLD50 activities are predicted. The drug-like and ADME-Tox properties of the molecule designed are examined and led to the selection of four molecules (55, 56, 59, 64) as promising antibacterial and insecticidal agents. Compounds 55, 56, 59, and 64 are able to inhibit the MurE (PDB code: 1E8C) and EcR (PDB code: 1R20) proteins involved in the process of antibacterial and insecticidal activities. This hypothesis is confirmed by the implementation of a molecular docking test. This test predicted the most important referential interactions that occur between the structure of triterpene derivatives and the targeted receptors. Among the four docked molecules, three molecules (55, 56, and 59) showed greater stability than the reference molecule 16 inside the MurE and EcR receptors pocket. Therefore, the structure of the three new triterpene derivatives can be adopted as reference for the synthesis of antibacterial drugs and also in the development of insecticides.

Seco-Tetracyclic and Seco-Pentacyclic Triterpenoids from Nature: Phytochemistry, Biological Activity: A Review

: Seco-tetracyclic and seco-pentacyclic triterpenoids are a special class of triterpenoids with ring/rings cleaved on the original skeleton structures. A class of important triterpene derivatives, secotetracyclic and seco-pentacyclic triterpenoids, have long stimulated the interest and attention of botanists and natural products chemists. There is no systematic and comprehensive review for them. This review is focused on the phytochemical investigations and biological activities of seco-tetracyclic and seco-pentacyclic triterpenoids from nature, covering the literature from 2000-2019. This review describes 310 seco-tetracyclic and 139 seco-pentacyclic triterpenoids discovered from 154 species belong to 97 genera, which cover the chemical structures, types, sources, and bioactivities of compounds. The literature from 2000-2019 is reviewed and 208 references are cited.

Natural Biosurfactant as Antimicrobial Agent: Strategy to Action Against Fungal and Bacterial Activities.

Natural surfactants have gained importance as the usage of synthetic surfactants shows economical aspects, health, and environmental effect. This study examined the anti-microbial activity of safflower seed waste (Ssw) isolated surfactant against dandruff-causing Malassezia furfur and skin diseases causing bacterial strains. Saponin was the major component and non-ionic surfactants derived from plants, which have a special molecular structure with hydrophilic glycoside backbone and lipophilic triterpene derivative. The antimicrobial activity of isolated surfactants was confirmed by the MIC and kill-time assays. Our results showed that the isolated saponin may interact with the cell wall and membrane first and destroy the cell wall and membranes, which finally results in bacterial death. Besides, isolated saponin penetrates the cytoplasmic membrane or enters inside the cell after the destruction of cell structure, and then inhibits the normal synthesis of DNA and proteins that are required for bacterial growth. These results suggested that the effects of the Ssw isolated saponin on the growth inhibition of selected bacterial strains may be at the molecular level rather than only physical damage. Extraction of Biosurfactant (saponin) from Safflower seed waste and its antimicrobial activity.

A Stereoselective Glycosylation Approach to the Construction of 1,2-trans-β-d-Glycosidic Linkages and Convergent Synthesis of Saponins.

Conventional syntheses of 1,2-trans-β-d- or α-l-glycosidic linkages rely mainly on neighboring group participation in the glycosylation reactions. The requirement for a neighboring participation group (NPG) excludes direct glycosylation with (1→2)-linked glycan donors, thus only allowing stepwise assembly of glycans and glycoconjugates containing this type of common motif. Here, a robust glycosylation protocol for the synthesis of 1,2-trans-β-d- or α-l-glycosidic linkages without resorting to NPG is disclosed; it employs an optimal combination of glycosyl N-phenyltrifluroacetimidates as donors, FeCl3 as promoter, and CH2 Cl2 /nitrile as solvent. A broad substrate scope has been demonstrated by glycosylations with 12 (1→2)-linked di- and trisaccharide donors and 13 alcoholic acceptors including eight complex triterpene derivatives. Most of the glycosylation reactions are high yielding and exclusively 1,2-trans selective. Ten representative, naturally occurring triterpene saponins were thus synthesized in a convergent manner after deprotection of the coupled glycosides. Intensive mechanistic studies indicated that this glycosylation proceeds by SN 2-type substitution of the glycosyl α-nitrilium intermediates. Importantly, FeCl3 dissociates and coordinates with nitrile into [Fe(RCN)n Cl2 ]+ and [FeCl4 ]- , and the ferric cationic species coordinates with the alcoholic acceptor to provide a protic species that activates the imidate, meanwhile the poor nucleophilicity of [FeCl4 ]- ensures an uninterruptive role for the glycosidation.