Ursolic Acid Derivatives Research Articles

Synthesis and antitumor activity evaluation of ursolic acid derivatives

Eighteen uronic acid derivatives were designed and synthesized, and the cytotoxicities in vitro of two cancer cell lines (BEL7402 and SGC7901) were evaluated by MTT assay. The results showed that the inhibitory rate of the compounds on both cell lines was significantly higher than the parent compound. The IC50 of compounds II4, II6, III4, and III6 are comparable or stronger than the positive control drug, the interactions between compounds II4, II6, III4, III6, and NF-κB were also studied by docking simulations.

Inhibitory potency of ursolic acid derivatives on osteoporosis target tryptophan hydroxylase 1 (Tph1)

Phytocompounds offer the wide range of parent molecules to study in different disease conditions. Natural plant compounds most often ex-hibit poor biological activity; nevertheless, facilitate good leads for the unlimited derivatives. The derivatives of the chemical molecules emerged from one particular class of chemical parent group display varying biological function. The phytochemical ursolic acid, a pentacyclic triterpenoid, has been explored in osteoporosis, anti-microbial, anti-inflammation, and anti-cancer. Osteoporosis is due to loss of bone mineral density and results in fragile bones. However, the problem is addressed with several chemotherapeutic drugs but the problem persists. Gut tryptophan hydroxylase 1 (Tph1) produces sero-tonin that promotes osteoporosis therefore targeting Tph1 is interesting in osteoporosis treatment. Ursolic acid and its derivatives were found to inhibit the Tph1 in mice models such that bone mineral density was restored. Therefore, deciphering efficient ursolic acid derivative for Tph1 inhibition is essential in osteoporosis studies. Known derivatives of ursolic acid, targeting Tph1 and other proteins in different diseases, were collected and sketched three dimensional structures to dock on to the Tph1. Molecular docking study produced free energy based interaction strength of the ursolic acid derivatives. Compound 12 displayed strong binding affinity in the Tph1 active site by forming H-bonds via bridge water molecules. This study is useful in shortlisting the challenges faced during a large number of derivatives if at all available for a particular class of compound.

Synthesis and biological evaluation of ursolic acid derivatives bearing triazole moieties as potential anti-Toxoplasma gondii agents

Ursolic acid (UA), a plant-derived compound, has many properties beneficial to health. In the present study, we synthesised three series of novel UA derivatives and evaluated their anti-Toxoplasma gondii activity both in vitro and in vivo. Most derivatives exhibited an improved anti-T. gondii activity in vitro when compared with UA (parent compound), whereas compound 3d exhibited the most potent anti-T. gondii activity in vivo. Spiramycin served as the positive control. Additionally, determination of biochemical parameters, including the liver and spleen indexes, indicated compound 3d to effectively reduce hepatotoxicity and significantly enhance anti-oxidative effects, as compared with UA. Furthermore, our molecular docking study indicated compound 3d to possess a strong binding affinity for T. gondii calcium-dependent protein kinase 1 (TgCDPK1). Based on these findings, we conclude that compound 3d, a derivative of UA, could act as a potential inhibitor of TgCDPK1.

Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors

In this article, a series of novel quinoline derivatives of ursolic acid (UA) bearing hydrazide, oxadiazole, or thiadiazole moieties were designed, synthesised, and screened for their in vitro antiproliferative activities against three cancer cell lines (MDA-MB-231, HeLa, and SMMC-7721). A number of compounds showed significant activity against at least one cell line. Among them, compound 4d exhibited the most potent activity against three cancer cell lines with IC50 values of 0.12 ± 0.01, 0.08 ± 0.01, and 0.34 ± 0.03 μM, respectively. In particular, compound 4d could induce the apoptosis of HeLa cells, arrest cell cycle at the G0/G1 phase, elevate intracellular reactive oxygen species level, and decrease mitochondrial membrane potential. In addition, compound 4d could significantly inhibit MEK1 kinase activity and impede Ras/Raf/MEK/ERK transduction pathway. Therefore, compound 4d may be a potential anticancer agent and a promising lead worthy of further investigation.

Synthesis and Antibacterial Activity of Ursolic Acid Derivatives

To obtained natural products with remarkable antibacterial activities, three 3-amino substituted (UA) derivatives 2, 3 and 4 were designed and synthesized, and their antibacterial activity were assayed using broth microdilution method. Compared to UA, there three derivatives present higher antimicrobial activities against methicillin-resistant Staphylococcus aureus (MRSA) with the minimum inhibitory concentrations of 16 to 32 μg/mL. Furthermore, their cytotoxicities to human hepatoma cell (BEL-7402) were evaluated using MTT method, and the results indicated that their derivatives had no toxicity (IC50 value was larger than 10 μM), while UA presented a certain cytotoxicity.

Ursolic Acid Derivatives Induced Apoptosis and Reduces the NF-<i>κ</i>B in Human Lung Adenocarcinoma Cells

Lung cancer is the major cause of death in the neoplastic diseases. In spite of the advances in the chemotherapy, the lung cancer treatments are still complex and costly, being necessary the seeking of new drugs. In this context, the ursolic acid (UA) becomes the target of studies that investigate its antitumor potential and, thus, structural modifications can enhance its biological activities. Eight UA semisynthetic derivative compounds (UAD1-8) were synthesized and evaluated their cytotoxic activity against human alveolar adenocarcinoma cells (A549). UAD1, UAD3, UAD5, UAD6 and UAD8 were able to reduce the viability of the A549 cells. Only UAD1 and UAD6 reduced the viability at 24 h, and only UAD3 didn’t reduce the NF-κB expression. The compound UAD1 showed the greater apoptosis induction. Moreover, the compound UAD1 showed better results than UA in all assays. The present study shows, for the first time, the action of these compounds in the apoptotic effect, in the expression of NF-κB and in the A549 cell line. The ursolic acid derivatives showed substantial results in the apoptosis, cytotoxicity and NF-κB inhibition of A549 cells, and further studies are necessary for the development of possible new therapeutic drugs.

3D-QSAR and docking studies on ursolic acid derivatives for anticancer activity based on bladder cell line T24 targeting NF-kB pathway inhibition

Bladder cancer is the common reason for mortality worldwide, and its increasing rate announces as a significant area of research in drug designing. The side effects and toxicity of existing drugs and the consequence of gradual cancer cell resistance against the available therapy make the treatment poor. Globally, there is a continuous high demand to develop new, more potent, and easily affordable drugs against cancer. The current research article illustrates the application of developed three-dimensional quantitative structure-activity relationship (3D-QSAR) based on human bladder cancer cell line T24 in vitro anticancer activity. The derived QSAR model has been used for prediction of natural compounds and analogs with 80% similarity of the most active compound of the dataset. The developed model describes the structure-activity relationship for terpenes and their derivatives at the molecular level. The developed comparative molecular field analysis (CoMFA) model shows a satisfactory cross-validation correlation coefficient (q2) of 0.54 and a regression correlation coefficient (r2) of 0.86. In order to evaluate the compliance with electronic pharmacokinetic parameters, Lipinski’s rule of five filter, absorption, distribution, metabolism, and excretion (ADME) and toxicity of predicted compounds have been calculated. Furthermore, molecular-docking study has been performed to prioritize these predicted compounds based on their docking score and binding pocket similarity through the identified potential anticancer targets. Finally, two compounds T9 and B42 have been identified as the best hit because these two fall within the standard limits of all filters and show a good binding affinity. Conclusively, all satisfactory results strongly suggest that the derived 3D-QSAR model and obtained candidate’s binding structures are reasonable in the prediction of a new antagonist’s activity. The strategy adopted in the present research is expected to be of immense importance and a great support in the identification and optimization of lead in the early and advance drug discovery.

Design, synthesis, and screening of novel ursolic acid derivatives as potential anti-cancer agents that target the HIF-1α pathway

The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumor angiogenesis, growth, and metastasis and is recognized as an important potential therapeutic target for cancer. Here, we designed and synthesized three novel series of ursolic acid derivatives containing an aminoguanidine moiety and evaluated them as HIF-1α inhibitors and anti-cancer agents using human cancer cell lines. Most of the compounds exhibited significant inhibition of HIF-1α transcriptional activity, as measured using a Hep3B cell-based luciferase reporter assay. Among these compounds, 7b was the most potent inhibitor of HIF-1α expression under hypoxic conditions (IC50 4.0 µM) and did not display significant cytotoxicity against any cell lines tested. The mechanism of action of 7b was investigated, we found that 7b downregulated HIF-1α protein expression, possibly by suppressing its synthesis, reduced production of vascular endothelial growth factor, and inhibited the proliferation of cancer cells.

Ursolic and oleanolic acid derivatives with cholinesterase inhibiting potential

Triterpenoids are in the focus of scientific interest, and they were evaluated for many pharmacological applications among them their ability to act as inhibitors of cholinesterases. These inhibitors are still of interest as drugs that improve the life quality of patients suffering from age-related dementia illnesses especially of Alzheimer’s disease. Herein, we prepared several derivatives of ursolic and oleanolic acid and screened them in Ellman’s assays for their ability to inhibit acetylcholinesterase and/or butyrylcholinesterase, and for each of the active compounds the type of inhibition was determined. As a result, several compounds were shown as good inhibitors for acetylcholinesterase and butyrylcholinesterase even in a micromolar range. An ursolic acid derived hydroxyl-propinyl derivative 10 was a competitive inhibitor for butyrylcholinesterase with an inhibition constant of Ki = 4.29 μM, and therefore being twice as active as gold standard galantamine hydrobromide. The best inhibitor for acetylcholinesterase, however, was 2-methyl-3-oxo-methyl-ursoloate (18), acting as a mixed-type inhibitor showing Ki = 1.72 µM and Ki′ = 1.28 μM, respectively.

Construction and biological evaluation of different self-assembled nanoarchitectures of FZU-03,010

Chemotherapy is currently one of the promising therapeutic methods for non-small-cell lung cancer (NSCLC), but the emergence of multidrug resistance (MDR) is the greatest obstacle to efficient drug delivery for successful chemotherapy. Nanotechnology-based drug delivery holds great promise to promote intracellular drug delivery to reverse MDR. In this work, we used our previously synthesized ursolic acid (UA) derivative, FZU-03,010 (F3), to prepare nanodrugs of F3 with different architectures and study the role of the structure on the physiochemical properties and the biological effects against A549 and its PTX-resistant A549/PTX lung cancer cells. Using different preparation methods, amphiphilic F3 could self-assemble into different structures such as nanoaggregates (F3-NA), vesicles (F3-VC), or nanoparticles (F3-NP) with different physiochemical properties. The self-assembled nanodrugs could be utilized for the entrapment of fluorophores and showed different cellular uptake efficiencies. The cytotoxicity results demonstrated that compared with UA, F3-NA and F3-NP could suppress A549 and A549/PTX cells viability more potently at lower concentration. In addition, F3-NA and F3-NP could induce G1 cell cycle arrest, cell apoptosis and caspase-3 activation more efficiently than that of UA. Furthermore, F3-NA and F3-NP could effectively inhibit PI3K/Akt pathway and decrease the expression of Bcl-2 and the cell cycle-dependent kinase inhibitors p-ERK1/2 and Cyclin D1 in both A549 and A549/PTX cells. In conclusion, our results suggest that the UA derivative F3 is more potent in inhibiting cancer cell proliferation, and F3-NA and F3-NP have the potential to be developed as a therapeutic agent for resistant NSCLC cells.

Discovery of antitumor ursolic acid long-chain diamine derivatives as potent inhibitors of NF-κB

A series of inhibitors of NF-κB based on ursolic acid (UA) derivatives containing long-chain diamine moieties were designed and synthesized as well as evaluated the antitumor effects. These compounds exhibited significant inhibitory activity to the NF-κB with IC50 values at micromolar concentrations in A549 lung cancer cell line. Among them, compound 8c exerted potent activity against the test tumor cell lines including multidrug resistant human cancer lines, with the IC50 values ranged from 5.22 to 8.95 μM. Moreover, compound 8c successfully suppressed the migration of A549 cells. Related mechanism study indicated compound 8c caused cell cycle arrest at G1 phase and triggered apoptosis in A549 cells through blockage of NF-κB signalling pathway. Molecular docking study revealed that key interactions between 8c and the active site of NF-κB in which the bulky and strongly electrophilic group of long-chain diamine moieties were important for improving activity.

Design, synthesis, evaluation, and molecular docking of ursolic acid derivatives containing a nitrogen heterocycle as anti-inflammatory agents

Ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were synthesized in an attempt to develop potent anti-inflammatory agents. Structures of the synthesized compounds were elucidated by 1H NMR, 13C NMR, and HRMS. Most of the synthesized compounds showed pronounced anti-inflammatory effects at 100 mg/kg. In particular, compound 11b, which displayed the most potent anti-inflammatory activity of all of the compounds prepared, with 69.76% inhibition after intraperitoneal administration, was more potent than the reference drugs indomethacin and ibuprofen. The cytotoxicity of the compounds was also assessed by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50 >100 μmol/L). Furthermore, molecular docking studies of the synthesized compounds were performed to rationalize the obtained biological results. Overall, the results indicate that compound 11b could be a therapeutic candidate for the treatment of inflammation.

Anti-Trichomonas vaginalis activity of ursolic acid derivative: a promising alternative.

Trichomonas vaginalis is an extracellular parasite that binds to the epithelium of the human urogenital tract and causes the sexually transmitted infection, trichomoniasis. In view of increased resistance to drugs belonging to the 5-nitroimidazole class, new treatment alternatives are urgently needed. In this study, eight semisynthetized triterpene derivatives were evaluated for in vitro anti-T. vaginalis activity. Ursolic acid and its derivative, 3-oxime-urs-12-en-28-oic-ursolic acid (9), presented the best anti-T. vaginalis activity when compared to other derivatives, with minimum inhibitory concentration (MIC) at 25μM. Moreover, 9 was active against several T. vaginalis fresh clinical isolates. Hemolysis assay demonstrated that 9 presented a low hemolytic effect. Importantly, 25μM 9 was not cytotoxic against the Vero cell lineage. Finally, we demonstrated that compound 9 acts synergistically with metronidazole against a T. vaginalis metronidazole-resistant isolate. This report reveals the high potential of the triterpenoid derivative 9 as trichomonicidal agent.

Ursolic acid derivatives as potential antidiabetic agents: In vitro, in vivo, and in silico studies.

Hit, Lead & Candidate Discovery Protein tyrosine phosphatase 1B (PTP-1B) has attracted interest as a novel target for the treatment of type 2 diabetes, this because its role in the insulin-signaling pathway as a negative regulator. Thus, the aim of current work was to obtain seven ursolic acid derivatives as potential antidiabetic agents with PTP-1B inhibition as main mechanism of action. Furthermore, derivatives 1-7 were submitted in vitro to enzymatic PTP-1B inhibition being 3, 5, and 7 the most active compounds (IC50 =5.6, 4.7, and 4.6μM, respectively). In addition, results were corroborated with in silico docking studies with PTP-1B orthosteric site A and extended binding site B, showed that 3 had polar and Van der Waals interactions in both sites with Lys120, Tyr46, Ser216, Ala217, Ile219, Asp181, Phe182, Gln262, Val49, Met258, and Gly259, showing a docking score value of -7.48Kcal/mol, being more specific for site A. Moreover, compound 7 showed polar interaction with Gln262 and Van der Waals interactions with Ala217, Phe182, Ile219, Arg45, Tyr46, Arg47, Asp48, and Val49 with a predictive docking score of -6.43kcal/mol, suggesting that the potential binding site could be localized in the site B adjacent to the catalytic site A. Finally, derivatives 2 and 7 (50mg/kg) were selected to establish their in vivo antidiabetic effect using a noninsulin-dependent diabetes mice model, showing significant blood glucose lowering compared with control group (p<.05).

Synthesis, Characterization and Cytotoxic Activity of Novel Oleanolic Acid and Ursolic Acid Derivatives

Synthesis, Characterization and Cytotoxic Activity of Novel Oleanolic Acid and Ursolic Acid Derivatives

Semisynthesis, cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives

In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC50 = 3.4 µM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC50 > 400 µM), showing selectivity towards parasites (selectivity index > 117.47). In combination with artemisinin, compound 7b showed an additive effect (CI = 1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of −7.02 kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC50 = 93 µM) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3β-butanoyl betulinic acid on Plasmodium may be related to other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources.

A novel synthetic ursolic acid derivative inhibits growth and induces apoptosis in breast cancer cell lines.

The present study investigated the anticancer functions of ursolic acid (UA) and its novel derivatives, with a nitrogen-containing heterocyclic scaffold and the privileged fragment at the C-28 position on apoptosis induction, cell proliferation and cell cycle in human BC lines. UA was chemically modified in the present study to increase its antitumor activity and bioavailability. A novel UA derivative, FZU3010, was synthesized using a nitrogen-containing heterocyclic scaffold and a privileged fragment at the C-28 position. Sulforhodimine B assays were used to measure the effect of UA and different concentrations of FZU3010 on the viability of breast cancer (BC) SUM149PT and HCC1937 cells. FZU3010 significantly repressed the proliferation of the two cancer cell lines in a dose-dependent manner, with a half-maximal inhibitory concentration of 4–6 µM, and exhibited decreased cytotoxicity compared with vehicle-treated cell lines. The effect of FZU3010 on cell cycle distribution and cellular apoptosis was also investigated. The results of this investigation indicated that FZU3010 significantly increased the number of SUM149PT and breast cancer HCC1937 cells in the G0/G1 phase in a dose-dependent manner. Additionally, at a concentration of 5 µM, the capability of FZU3010 to induce BC apoptosis was significantly higher than the capability of UA. Thus, the results of the current study indicated that FZU3010 induced apoptosis in BC cells, together with induction of cell cycle arrest at the S and G0/G1 phase. FZU3010 may therefore be considered as a potential therapeutic agent for the treatment of BC.

Design, synthesis, and evaluation of novel ursolic acid derivatives as HIF-1α inhibitors with anticancer potential

Hypoxia-inducible factor-1α (HIF-1α), a key mediator in tumor metastasis and angiogenesis, is associated with poor patient prognosis and has been recognized as an important cancer drug target. In this work, four novel series of ursolic acid derivatives containing oxadiazole, triazolone, and piperazine moieties were designed, synthesized, and evaluated for anti-tumor activity as HIF-1α inhibitors. The majority of the compounds showed an excellent ability to inhibit the expression of HIF-1α. In particular, 11b inhibited HIF-1α transcriptional activity under hypoxic conditions with IC50=36.9μM. The cytotoxicity of these compounds was also assessed in human colon cancer cell HCT116 cells by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and no compounds showed any appreciable cytotoxic activity (IC50>100μmol/L), which was lower than that of ursolic acid (IC50=23.8μmol/L). The mechanism of action of the representative compound 11b was also investigated.

Design, synthesis and in vitro anticancer activity of novel quinoline and oxadiazole derivatives of ursolic acid

A series of new quinoline derivatives of ursolic acid were designed and synthesized in an attempt to develop potential anticancer agents. The structures of these compounds were identified by 1H NMR, 13C NMR, IR and ESI-MS spectra analysis. The target compounds were evaluated for their in vitro cytotoxicity against three human cancer cell lines (MDA-MB-231, Hela and SMMC-7721). From the results, compounds 3a–d displayed significant antitumor activity against three cancer cell lines. Especially, compound 3b was found to be the most potent derivative with IC50 values of 0.61±0.07, 0.36±0.05, 12.49±0.08μM against MDA-MB-231, HeLa and SMMC-7721 cells, respectively, stronger than positive control etoposide. Furthermore, the Annexin V-FITC/PI dual staining assay revealed that compound 3b could significantly induce the apoptosis of MDA-MB-231 cells in a dose-dependent manner. The cell cycle analysis also indicated that compound 3b could cause cell cycle arrest of MDA-MB-231 cells at G0/G1 phase.

Structure-Activity Relationships of Pentacyclic Triterpenoids as Potent and Selective Inhibitors against Human Carboxylesterase 1.

Human carboxylesterase 1 (hCE1), one of the most important serine hydrolases distributed in liver and adipocytes, plays key roles in endobiotic homeostasis and xenobiotic metabolism. This study aimed to find potent and selective inhibitors against hCE1 from phytochemicals and their derivatives. To this end, a series of natural triterpenoids were collected and their inhibitory effects against human carboxylesterases (hCEs) were assayed using D-Luciferin methyl ester (DME) and 6,8-dichloro-9,9-dimethyl-7-oxo-7,9-dihydroacridin-2-yl benzoate (DDAB) as specific optical substrate for hCE1, and hCE2, respectively. Following screening of a series of natural triterpenoids, oleanolic acid (OA), and ursolic acid (UA) were found with strong inhibitory effects on hCE1 and relative high selectivity over hCE2. In order to get the highly selective and potent inhibitors of hCE1, a series of OA and UA derivatives were synthesized from OA and UA by chemical modifications including oxidation, reduction, esterification, and amidation. The inhibitory effects of these derivatives on hCEs were assayed and the structure-activity relationships of tested triterpenoids as hCE1 inhibitors were carefully investigated. The results demonstrated that the carbonyl group at the C-28 site is essential for hCE1 inhibition, the modifications of OA or UA at this site including esters, amides and alcohols are unbeneficial for hCE1 inhibition. In contrast, the structural modifications on OA and UA at other sites, such as converting the C-3 hydroxy group to 3-O-β-carboxypropionyl (compounds 20 and 22), led to a dramatically increase of the inhibitory effects against hCE1 and very high selectivity over hCE2. 3D-QSAR analysis of all tested triterpenoids including OA and UA derivatives provide new insights into the fine relationships linking between the inhibitory effects on hCE1 and the steric-electrostatic properties of triterpenoids. Furthermore, both inhibition kinetic analyses and docking simulations demonstrated that compound 22 was a potent competitive inhibitor against hCE1-mediated DME hydrolysis. All these findings are very helpful for medicinal chemists to design and develop highly selective and more potent hCE1 inhibitors for biomedical applications.