Triterpenoid Derivatives Research Articles

Oleanane and Stigmasterol-Type Triterpenoid Derivatives from the Stem Bark of Albizia gummifera and Their Antibacterial Activities

Chromatographic separation of methanol extract of stem bark of Albizia gummifera led to the isolation of two oleanane-type triterpenoids (1 and 2), a stigmasterol derivative (3), and stigmasterol (4). The structures of the compounds were elucidated based on 1D and 2D NMR spectroscopic data and comparing with reported literature values. The crude extract and the isolated compounds were evaluated for their antibacterial activities against five bacterial strains. Compounds 1, 2, and 4 showed marginal antibacterial activity with the growth inhibition zone ranging from 6.8 to 13.2 mm against the tested bacterial strains, with compounds 2 and 4 showing significant inhibition (13.0 and 13.2 mm) against S. flexneri and S. typhimurium, respectively. While, the standard drug, gentamycin showed inhibition zone 20.0 and 24.0 mm against S. flexneri and S. typhimurium, respectively.

Discovery of triterpenoids as potent dual inhibitors of pancreatic lipase and human carboxylesterase 1

Pancreatic lipase (PL) is a well-known key target for the prevention and treatment of obesity. Human carboxylesterase 1A (hCES1A) has become an important target for the treatment of hyperlipidaemia. Thus, the discovery of potent dual-target inhibitors based on PL and hCES1A hold great potential for the development of remedies for treating related metabolic diseases. In this study, a series of natural triterpenoids were collected and the inhibitory effects of these triterpenoids on PL and hCES1A were determined using fluorescence-based biochemical assays. It was found that oleanolic acid (OA) and ursolic acid (UA) have the excellent inhibitory effects against PL and hCES1A, and highly selectivity over hCES2A. Subsequently, a number of compounds based on the OA and UA skeletons were synthesised and evaluated. Structure–activity relationship (SAR) analysis of these compounds revealed that the acetyl group at the C-3 site of UA (compound 41) was very essential for both PL and hCES1A inhibition, with IC50 of 0.75 µM and 0.014 µM, respectively. In addition, compound 39 with 2-enol and 3-ketal moiety of OA also has strong inhibitory effects against both PL and hCES1A, with IC50 of 2.13 µM and 0.055 µM, respectively. Furthermore, compound 39 and 41 exhibited good selectivity over other human serine hydrolases including hCES2A, butyrylcholinesterase (BChE) and dipeptidyl peptidase IV (DPP-IV). Inhibitory kinetics and molecular docking studies demonstrated that both compounds 39 and 41 were effective mixed inhibitors of PL, while competitive inhibitors of hCES1A. Further investigations demonstrated that both compounds 39 and 41 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. Collectively, we found two triterpenoid derivatives with strong inhibitory ability on both PL and hCES1A, which can be served as promising lead compounds for the development of more potent dual-target inhibitors targeting on PL and hCES1A.

New iridal-type triterpenoid analogues with 6/5/6-fused carbon skeleton from the rhizomes of Belamcanda chinensis

Five new iridal-type triterpenoid derivatives with 6/5/6 tricyclic ring skeleton (1–5) were obtained from the rhizomes of Belamcanda chinensis. Their structures were determined on the basis of detailed spectroscopic data and ECD calculation. Compounds 1–5 possessed the same 6/5/6-fused carbon skeleton as Belamchinenin A, which further enriched this kind of iridals. In vitro bioassay, compounds 2 and 3 exhibited 51.95 and 54.52% inhibitory activities, respectively, against Fe2+/cysteine-induced liver microsomal lipid peroxidation at a concentration of 10 μM. A putative biogenetic pathway for compounds 1–5 was proposed.

Triterpenoids From Kadsura coccinea With Their Anti-inflammatory and Inhibited Proliferation of Rheumatoid Arthritis-Fibroblastoid Synovial Cells Activities.

One new 3,4-seco-17,13-friedo-lanostane triterpenoid heilaohuacid A (1), one new 3,4-seco-17,14-friedo-lanostane triterpenoid heilaohuacid B (2), five new 3,4-seco-lanostane triterpenoids heilaohuacids C-D (3–4) and heilaohumethylesters A-C (7–9), one new 3,4-seco-cycloartane triterpenoid heilaohuacid E (5), and one new intact-lanostane triterpenoid heilaohuacid F (6), together with twenty-two known analogues (10–31), were isolated from heilaohu. Their structures were determined using HR-ESI-MS data, 1D and 2D NMR spectra, 13C NMR calculations, and electronic circular dichroism (ECD) calculations. Heilaohuacids A and B (1 and 2) contain a 3,4-seco ring A and unprecedented migration of Me-18 from C-13 to C-17 or C-14 to C-18. This type of lanostane triterpenoid derivatives was rarely reported so far. More importantly, all compounds against inflammatory cytokines IL-6 and TNF-α levels on LPS-induced RAW 264.7 macrophages were evaluated, and compounds 4 and 31 significantly inhibited the release level of IL-6 with IC50 values of 8.15 and 9.86 μM, respectively. Meanwhile, compounds 17, 18, and 31 significantly inhibited proliferation of rheumatoid arthritis-fibroblastoid synovial (RA-FLS) cells in vitro with IC50 values of 7.52, 8.85, and 7.97 μM, respectively.

Synthesis of 2-Aminoethanesulfonamides of Betulinic and Betulonic Acids.

New potentially biologically active sulfonamide derivatives of pentacyclic lupane-type triterpenoids, the sulfonamide group of which was bonded to C-17 of the triterpene skeleton through an amidoethane spacer, were synthesized via conjugation of 2-aminoethanesulfonamides to betulinic and betulonic acids in the presence of Mukaiyama reagent (2-bromo-1-methylpyridinium iodide).

Chemical modifications of ergostane-type triterpenoids from Antrodia camphorata and their cytotoxic activities

In order to discover potential antitumor agents from natural products, chemical modifications of ergostane-type triterpenoids from Antrodia camphorata yielded ten new compounds. They include nine C-26 amide derivatives of antcin G (1) and a methyl antcin B (4) derivative with hydroxyamino groups at C-3 and C-7. Chemical structures of the new compounds were elucidated by NMR and MS analyses. Furthermore, cytotoxicities of the triterpenoid derivatives were evaluated using four human cancer cell lines (HL60, U251, SW480, and MCF-7). As a result, 1a, 1g, and 4a exhibited potent cytotoxic activities against HL60, U251, and SW480 with IC50 values of 0.7 ± 0.9, 2.9 ± 1.3, and 2.2 ± 0.6 μM, respectively. Molecular docking indicates that 1a, 1g, and 4a have strong binding affinity with DNA topoisomerase IIα (−9.3, −7.9, and −7.4 kcal/mol, respectively), and that they could be potent topoisomerase IIα inhibitors.

Pentacyclic Triterpenoids with Nitrogen-Containing Heterocyclic Moiety, Privileged Hybrids in Anticancer Drug Discovery.

Pentacyclic triterpenoids are well-known phytochemicals with various biological activities commonly found in plants as secondary metabolites. The wide range of biological activities exhibited by triterpenoids has made them the most valuable sources of pharmacological agents. A number of novel triterpenoid derivatives with many skeletal modifications have been developed. The most important modifications are the formation of analogues or derivatives with nitrogen-containing heterocyclic scaffolds. The derivatives with nitrogen-containing heterocyclic compounds are among the most promising candidate for the development of novel therapeutic drugs. About 75% of FDA-approved drugs are nitrogen-containing heterocyclic moieties. The unique properties of heterocyclic compounds have encouraged many researchers to develop new triterpenoid analogous with pharmacological activities. In this review, we discuss recent advances of nitrogen-containing heterocyclic triterpenoids as potential therapeutic agents. This comprehensive review will assist medicinal chemists to understand new strategies that can result in the development of compounds with potential therapeutic efficacy.

Synthesis and biological evaluation of pentacyclic triterpenoid derivatives as potential novel antibacterial agents

A series of ursolic acid (UA), oleanolic acid (OA) and 18β-glycyrrhetinic acid (GA) derivatives were synthesized by introducing a range of substituted aromatic side-chains at the C-2 position after the hydroxyl group at C-3 position was oxidized. Their antibacterial activities were evaluated in vitro against a panel of four Staphylococcus spp. The results revealed that the introduction of aromatic side-chains at the C-2 position of GA led to the discovery of potent triterpenoid derivatives for inhibition of both drug sensitive and resistant S. aureus, while the other two series derivatives of UA and OA showed no significant antibacterial activity even at high concentrations. In particular, GA derivative 33 showed good potency against all four Staphylococcus spp. (MIC = 1.25–5 μmol/L) with acceptable pharmacokinetics properties and low cytotoxicity in vitro. Molecular docking was also performed using S. aureus DNA gyrase to rationalize the observed antibacterial activity. This series of GA derivatives has strong potential for the development of a new type of triterpenoid antibacterial agent.

Triterpene glycosides and phenylpropane derivatives from Staurogyne concinnula possessing anti-angiogenic activity

After anti-angiogenic activity screening, the potential n-butanol layer partitioned from the ethanol extract of Staurogyne concinnula was conducted. Further purification by Diaion HP20 column and preparative HPLC chromatography, four undescribed triterpenoid saponin derivatives, along with the known baptisiasaponin I, and four known phenylpropanoid glycosides were isolated and characterized from n-butanol layer. The structures of isolated compounds were elucidated by ESI-MS, 1D, and 2D MNR data. Biological evaluation revealed that baptisiasaponin I possessed significant anti-angiogenic effects (IC50 4.0 ± 0.2 μM). Further mechanism of action of baptisiasaponin I by inhibition of integrin/FAK/paxillin signaling pathway and its downstream effectors as MMP2 and MMP9 are also presented.

Synthesis of C(28)-linker derivatives of betulinic acid bearing phosphonate group

A convenient method for the synthesis of C(28)-linker derivatives of triterpenoids containing a phosphonate group is presented. The method is based on the reaction of triterpenic acids (using betulinic acid as an example) with O, O-dialkyl-ω-bromoalkane phosphonates in DMF in the presence of K2CO3. The target phosphonates are synthesized in a yield of about 80%. The structures and compositions of the synthesized compounds were confirmed by NMR spectroscopy, IR spectroscopy, and elemental analysis.

Biological and Pharmacological Effects of Synthetic Saponins.

Saponins are amphiphilic molecules consisting of carbohydrate and either triterpenoid or steroid aglycone moieties and are noted for their multiple biological activities—Fungicidal, antimicrobial, antiviral, anti-inflammatory, anticancer, antioxidant and immunomodulatory effects have all been observed. Saponins from natural sources have long been used in herbal and traditional medicines; however, the isolation of complexed saponins from nature is difficult and laborious, due to the scarce amount and structure heterogeneity. Chemical synthesis is considered a powerful tool to expand the structural diversity of saponin, leading to the discovery of promising compounds. This review focuses on recent developments in the structure optimization and biological evaluation of synthetic triterpenoid and steroid saponin derivatives. By summarizing the structure–activity relationship (SAR) results, we hope to provide the direction for future development of saponin-based bioactive compounds.

The Novel Synthetic Triterpene Methyl 3β-O-[4-(2-Aminoethylamino)-4-oxo-butyryl]olean-12-ene-28-oate Inhibits Breast Tumor Cell Growth in Vitro and in Vivo.

Oleanolic and ursolic acids were used as lead compounds to synthesize a series of pentacyclic triterpenoid derivatives bearing ethylenediamine, butanediamine, or hexanediamine groups at the C-3 position. The potential antiproliferative activity of these compounds was examined in A549 (human non-small cell lung cancer cells), MCF-7 (human breast cancer cells), and HeLa (human cervical carcinoma cells) cells. Methyl 3β-O-[4-(2-aminoethylamino)-4-oxo-butyryl]olean-12-ene-28-oate (DABO-Me) was identified as a promising antiproliferative agent in vitro and in vivo. DABO-Me strongly suppressed the proliferation of A549, MCF-7, and HeLa cells (IC50 = 4-7 µM). In MCF-7 cells, DABO-Me upregulated the pro-apoptotic protein Bax, downregulated the anti-apoptotic protein Bcl-2, promoted the release of cytochrome c, and activated caspase-3/9. Transwell and flow cytometry assays showed that DABO-Me inhibited MCF-7 cell proliferation, migration, and invasion, and induced apoptosis and S phase arrest. In vitro and in vivo experiments indicated that DABO-Me inhibited MCF-7 cell proliferation and suppressed tumor growth. Taken together, these results indicate that DABO-Me could be developed as an effective antitumor drug.

Synthesis of new fatty acid derivatives of oleanane and ursane triterpenoids and investigation of their in vitro cytotoxic effects on 3T3 fibroblast and PC3 prostate cancer cell linesLines

Synthesis of new fatty acid derivatives of oleanane and ursane triterpenoids and investigation of their in vitro cytotoxic effects on 3T3 fibroblast and PC3 prostate cancer cell linesLines

Synthesis of new fatty acid derivatives of oleanane and ursane triterpenoids and investigation of their in vitro cytotoxic effects on 3T3 fibroblast and PC3 prostate cancer cell linesLines

Synthesis of new fatty acid derivatives of oleanane and ursane triterpenoids and investigation of their in vitro cytotoxic effects on 3T3 fibroblast and PC3 prostate cancer cell linesLines

Design, Synthesis, and Cytotoxic Evaluation of Novel Lupane Triterpenoid Derived Hydroxamates

A series of new hydroxamate derivatives of lupane triterpenoids has been designed and successfully synthesized. The synthesized compounds were evaluated for their in vitro antitumor activity using the 3-[4,5-dimethylthiazol-2-yl]−2,5-diphenyltetrazolium bromide-based assay against the human cancer cell lines KB and HepG2. Most of these derivatives possess at least moderate cytotoxic activity and the hydroxamate derivative compounds 3c, 3e, 7a, and 15b could be lead compounds for further optimization to develop novel anticancer agents.

Single- and repeated-dose toxicity studies on the novel HIV maturation inhibitor QF-036 in Sprague-Dawley rats

QF-036 is a novel human immunodeficiency virus (HIV) maturation inhibitor that is a lupine triterpenoid derivative. The objective of this study was to evaluate the safety of QF-036. A single oral toxicity and a 4-week repeated oral toxicity were investigated in Sprague-Dawley (SD) rats. The single oral toxicity study of QF-036 in SD rats showed that no mortality or visible pathological changes were noted at doses of 100, 300, and 1000 mg/kg. QF-036 exhibited a non-linear toxicokinetic profile over the dose range of 100–1000 mg/kg in the single dose study, and a saturation trend appeared at doses of 100 and 300 mg/kg. In the 4-week oral toxicity and toxicokinetic study, SD rats were given 0, 50, 100, and 200 mg/kg QF-036 once daily for 4 weeks, followed by a 4-week recovery period. No mortality or significant effects on food consumption, body weight, or behavior were observed. In addition, there were no test article-related changes in hematology, clinical biochemistry and histopathology. The no observed adverse effect level (NOAEL) was 200 mg/kg. The toxicokinetic study demonstrated a dose-dependent increase in the systemic exposure to QF-036 after 4 weeks of oral administration. There were no marked sex differences or drug accumulation observed for repeated doses of QF-036.

Application of Relay C−H Oxidation Logic to Polyhydroxylated Oleanane Triterpenoids

Summary Although clinical applications of abundant feedstock triterpenoids such as oleanolic acid are limited because of poor solubility and bioavailability, synthetic access to higher hydroxylated oleanane terpenoids is challenging. We now report the use of relay C−H oxidation logic to mimic the processes carried out in nature by P450 monooxygenase enzymes. To this end, we used the C-23-OH as natural handle for a hydrogen-atom transfer to access C-6, enabling the first syntheses of highly oxidized natural products uncargenin C and protobassic acid as well as uncovering the anti-leukemic activity of a synthetic intermediate.

The synthetic oleanane triterpenoid CDDO-Me binds and inhibits pyruvate kinase M2.

The M2 isoform of the glycolytic enzyme pyruvate kinase (PKM2) is one of the key components in the Warburg effect, and an important regulator of cancer cell metabolism. Elevated PKM2 expression is a hallmark of numerous tumor types, making it a promising target for cancer therapy. Migration of H1299 lung tumor cells treated with synthetic oleanane triterpenoid derivatives CDDO-Me and CDDO-Im was monitored using scratch and transwell assays. Direct binding and inhibition of PKM2 activity by CDDO-Me was demonstrated by pull-down and activity assays. PKM2 localization in the absence and presence of CDDO-Me or CDDO-Im was determined by subcellular fractionation and immunofluorescence microscopy. Involvement of PKM2 in tumor cell migration was assessed using a stable PKM2 knockdown cell line. We demonstrate that migration of H1299 lung tumor cells is inhibited by CDDO-Me and CDDO-Im in scratch and transwell assays. CDDO-Me binds directly and specifically to recombinant PKM2, leading to a reduction of its catalytic activity. PKM2 knockdown cells exhibit significantly lower migration compared to control cells when subjected to glucose and oxygen deprivation, but not under regular conditions. The results suggest that PKM2 expression in a tumor-like environment contributes to cell migration, and that PKM2 activity can be down regulated by synthetic triterpenoid derivatives.

Application of tandem biotransformation for biosynthesis of new pentacyclic triterpenoid derivatives with neuroprotective effect

Tandem whole-cell biotransformation was applied successfully to deliver novel pentacyclic triterpenoid derivatives for the first time. In this process, the starting substrate oleanolic acid (1) was biotransformed into a hydroxylated metabolite 1a by Rhizopus chinensis CICC 40335 and then was further glycosylated to 1b by Bacillus subtilis ATCC 6633. Moreover, metabolite 1a was furtherly oxidized by Streptomyces griseus ATCC 13273 and generated two new derivatives as 1c and 1d. To validate the feasibility, tandem biotransformation of 18β-glycyrrhetinic acid (2) by R. chinensis and B. subtilis was also conducted and offered a glycosylated derivative (2c). Finally, the neuroprotective effects of the derivatives were assessed on neural injury PC12 cell model induced by cobalt chloride.

Design, synthesis and biological evaluation of novel ocotillol-type triterpenoid derivatives as antibacterial agents

Design, synthesis and biological evaluation of novel ocotillol-type triterpenoid derivatives as antibacterial agents