Betulin, a Newly Characterized Compound in Acacia Auriculiformis Bark, is a Multi-target Protein Kinase Inhibitor (original) (raw)
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Constituents of Acacia nilotica (L.) Delile with Novel Kinase Inhibitory Activity
Planta Medica International Open
Acacia nilotica (L.) Delile belongs to the genus Acacia, which includes about 1400 species in subtropical and tropical Africa including Nigeria, Senegal, Egypt, and Mozambique as well as Asia from India to Burma. This plant is traditionally used to treat several pathologies such as mouth, ear, and bone cancer. Moreover, it possesses many other biological activities (antidiarrheal, anti-inflammatory, antimicrobial, and antifungal). We report here the extraction, purification, and identification of two known compounds [ethylgallate and (+)-catechin] from the bark of the tree that were further tested for their inhibitory activities against a panel of disease-related protein kinases. Both compounds were active, and (+)-catechin showed the best activity by inhibiting nine out of fourteen protein kinases with an IC50 value in the µg/mL range. This compound gave the highest activity against CLK1 with an IC50 of 2.1 µg/mL. The ethyl acetate extract and its components, such as catechins and ...
Pharmacognosy Journal
Background: The decoctions of the bark of Acacia auriculiformis are used in folkloric medicine to relieve pain and inflammation and as remedy for cancer. Objective: The aim of this work is to screen the extract and fractions of Acacia auriculiformis for protein kinase inhibitory activity and also to isolate and characterize chemical entities from this plant and evaluate their protein kinase inhibitory activity. Materials and Methods: Kinase inhibitory activity were assayed in appropriate buffer, with either protein or peptide as substrate in the presence of 15µM (33-P) ATP (3,000Ci/mmol; 10mCi/ml) in a final volume of 30µL. Controls were performed with appropriate dilutions of dimethyl sulphoxide. A portion of the Chloroform extract, ethylacetate and n-butanol soluble fractions of the stem bark of Acacia auriculiformis were screened against a panel of disease-related protein kinases and the active fractions was tested over a wide range of concentrations from 0.016 to 50µg/ml and the IC 50 values were determined from the dose response curve. The most active fraction was subjected to chromatographic separation using Silica gel G column chromatography and sephadex LH-20 to give compound I. The structure of the isolated compound was elucidated using NMR and LC-MS. Results: The Primary screening of the extract and fractions showed that the chloroform extract was inactive against all the protein kinases investigated, while the ethylacetate and n-butanol soluble fractions inhibited all the protein kinases tested. Compound I also inhibited all the kinases tested. The IC 50 of the active fractions and compound were also evaluated. Ethylacetate fraction inhibited all the kinases tested with the highest activity against Haspine kinase with IC 50 of 1.0 µg/ml, while n-butanol also gave the highest activity against Haspine kinase with 1C 50 of 1.3 µg/ml. From the active ethylacetate fractions 3, 4', 7, 8-tetrahydroxy flavone was isolated. The Compound exhibited the maximal activity against DYRK1A kinase with an IC 50 of 2.05 µg/ml followed by CDK9 with an IC 50 of 2.28 µg/ml. Conclusion: 3, 4',7, 8-tetrahydroxy flavone was isolated was found to be a DYRK1A and CDK9 inhibitor which might justify the anticancer potential of this plant.
Cancer Management and Research, 2019
Background: Globally, the prevalence and mortality rates of lung cancer have been escalated with the increasing trend of tobacco smoking. The toxicity and irresponsive nature of the available drugs for lung cancer treatment demands an alternative approach. Methods: In this study, four known compounds namely, cirsimaritin (4′,5,-dihydroxy-6,7-dimethoxyflavone) (1), eupatorin (5,3′-dihydroxy-6,7,4′-trimethoxyflavone) (2), betulin (Lup-20 (29)-ene-3, 28-diol) (3), and b-amyrin acetate (12-Oleanen-3yl acetate) (4) have been isolated from the leaves extract of Quercus incana. Preliminary screening of these natural compounds (1-4) was performed against non-small cell lung carcinoma (NCI-H460) and normal mouse fibroblast (NIH-3T3) cell lines. Results: The compounds were found to be antiproliferative against cancer cells with wide therapeutic index in comparison to the normal cells. Effects of betulin (3) on cell migration, invasion, apoptosis, and expression of important apoptosis-and metastasis-related markers were observed at different concentrations. The results showed significant dose-dependent induction of apoptosis after the treatment with betulin (3) followed by increased expression of the caspases family (ie, caspase-3,-6, and-9), proapoptotic genes (BAX and BAK), and inhibiting antiapoptotic genes (BCL-2L1 and p53). Furthermore, wound healing and transwell invasion assays suggested that betulin (3) could also regulate metastasis by inhibiting MMP-2/-9. Osteopontin, a central regulator of apoptosis and metastasis was also inhibited in a dose-dependent manner. Conclusion: The present findings suggest that betulin (3) can be an attractive chemotherapeutic target for treating resistant lung cancers.
Separations, 2020
The cytotoxic effects of the crude extract of Loranthus acaciae Zucc. and its n-hexane, chloroform, and n-butanol fractions were assessed against three cancer cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay. Cell apoptosis was determined using an annexin V-phycoerythrin/7-aminoactinomycin kit. We observed that the L. acaciae n-hexane extract (LAHE) could inhibit cancer cell growth, particularly of MCF7 and A549 cells. Chromatographic purification of LAHE and nuclear magnetic resonance analysis led to the identification of two compounds from this plant species, namely, betulinic acid and β-sitosterol, for the first time. Flow cytometry study suggested that betulinic acid induced cell death via apoptosis, as a distinguished marked enhancement in the early and late apoptosis of human lung (A549) and breast (MCF-7) cancer cell lines. The isolated compounds were further estimated concurrently in LAHE using a validated high-performance thin-layer c...
Plant-Derived Protein Tyrosine Kinase Inhibitors as Anticancer Agents
Current medicinal chemistry, 2004
Protein tyrosine kinases play a fundamental role in signal transduction pathways regulating a number of cellular functions such as cell growth, differentiation and cell death. Tyrosine kinases are, therefore attractive targets for the design of new therapeutic agents, not only against cancer, but also against many other diseases. Numerous tyrosine kinase inhibitors have been discovered by screening of plant extracts based on ethnopharmacological and chemotaxonomical knowledge. Specific screening approaches have led to the isolation of structurally distinct classes of inhibitors, including phenylpropanes, chalcones, flavonoids, coumarins, styrenes, quinones and terpenes. These natural inhibitors have served as valuable leads for further design and synthesis of more active analogues. Many of these inhibitors have also been used in probing the molecular and cellular mechanisms involved in the protein tyrosine kinase mediated signal transduction. In this review, plant-derived protein tyrosine kinase inhibitors and their synthetic analogues were systematically evaluated based on their plant origin, structureactivity relationship and anticancer efficacy.
Natural Product Communications, 2007
The chemical content of outer birch bark extractive from the North American birches Betula papyrifera Marshall (paper birch) and B. neoalaskana Sargent (Alaskan paper birch) has been evaluated by GC/MS, HPLC and NMR spectroscopy. The comparative antiproliferative activity of the extractive and major triterpenoid components was studied using a number of human and murine malignant (P19, N2/D1, K1735-M2, PC-3 and CaOV3) and normal (BJ) cell lines. Betulin 3-caffeate was found to exhibit the highest antiproliferative activity among all triterpenoid components, including betulinic acid. Synthesis of betulin 3-caffeate from betulin has been developed.
Betula utilis, also known as Himalayan silver birch has been used as a traditional medicine for many health ailments like inflammatation, HIV, renal and bladder disorders as well as many cancers from ages. Here, we performed bio-guided fractionation of Betula utilis Bark (BUB), in which it was extracted in methanol and fractionated with hexane, ethyl acetate, chloroform, n-butanol and water. All six fractions were evaluated for their in-vitro anticancer activity in nine different cancer cell lines and ethyl acetate fraction was found to be one of the most potent fractions in terms of inducing cytotoxic activity against various cancer cell lines. By utilizing column chromatography, six triterpenes namely betulin, betulinic acid, lupeol, ursolic acid (UA), oleanolic acid and β-amyrin have been isolated from the ethyl acetate extract of BUB and structures of these compounds were unraveled by spectroscopic methods. β-amyrin and UA were isolated for the first time from Betula utilis. Isolated triterpenes were tested for in-vitro cytotoxic activity against six different cancer cell lines where UA was found to be selective for breast cancer cells over non-tumorigenic breast epithelial cells (MCF 10A). Tumor cell selective apoptotic action of UA was mainly attributed due to the activation of extrinsic apoptosis pathway via up regulation of DR4, DR5 and PARP cleavage in MCF-7 cells over non-tumorigenic MCF-10A cells. Moreover, UA mediated intracellular ROS generation and mitochondrial membrane potential disruption also play a key role for its anti cancer effect. UA also inhibits breast cancer migration. Altogether, we discovered novel source of UA having potent tumor cell specific cytotoxic property, indicating its therapeutic potential against breast cancer.
International Journal of Pharmacy and Pharmaceutical Sciences, 2021
In developing and developed countries, cancer is a significant health problem in people. Cancer becomes the second greatest cause of death in human after cardiovascular disease. However, significant advancements in modern cancer therapies have a beneficial impact on survival, chemotherapy and radiation therapy. Plants fulfill our basic needs to continue life and provide natural products that help to cure disease. The medicinal plants are readily available and have no toxicity as compared to modern drugs. Phytochemicals act on metabolic pathways and inhibit tumor growth, the development of cancerous cells, and replication by different mechanisms. Apigenin's chemo-preventive and anticancer activities have been demonstrating in numerous studies. Curcumin is a polyphenolic compound isolated from the Curcuma longa plant. EGCG, a polyphenol in black, white, and green tea is a chemo-preventive effect against many cancers by targeting multiple pathways. Normal cell growth and cell proliferation are closely regulated processes. The JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway controls gene expression during different processes, including proliferation, initiation, and apoptosis. The transcription factors are associated with the growth of cancer cells and control a cellular function in the disease. Mitogen-activated protein kinase (MAPK) is a class of serine and threonine kinase that includes ERK (extracellular regulated kinase), JNK (c-Jun N-terminal kinases), and p38. This review paper describes natural phytochemical compounds, their molecular targets and mechanisms of action.
TJPRC, 2013
Cancer is a complex disease which is associated with cell signaling, DNA damage and cell cycle. Cancer is a multifactorial in origin .Cancer causes for 12.5% of deaths worldwide. Cancer treatment methods in cancer therapy like radiation and chemotherapy and using synthetic drugs leading to side effects. Therefore, there is a lot of demand to identify and develop effective novel therapeutic agents to treat many diseases. Plants are richest and unique source of energy, oxygen, metabolites and therapeutic agents. Many compounds of plant derivatives are very active against many dreadful diseases including cancer. Humans benefit from using many of the plants as medicinal purposes to combat diseases and microbes. Since plants are the natural, safe and best source in providing these active components especially anticancer drugs. Hence it is very essential to study about natural products and their potential role in therapeutic use. This review paper focuses mainly on achievements in cancer therapy using plant products and the potential clinical applications of medicinal plants and the role of their products, especially as anticancer drugs.