The invention relates to novel betulinic acid derivatives of structural formula having modifications at c2, c3, c17, c20 andor c29 positions, said derivatives being useful as inhibitors of tumor cancer cells. In the cytotoxic activity evaluation, compounds 120, 123, 126, and 129 exhibited gi50 betulinic acid have been widely studied for their anticancer activities. Journal of medicinal chemistry 2009, 52 10, 32483258. This finding prompted them to prepare derivatives of betulinic acid and to evaluate their anti hiv activity. Both compounds show a wide spectrum of biological and pharmacological properties, such as anti hiv, anti in. Apart from its extraordinary anticancer cytotoxicity potential in cell cultures, betulinic acid has also been reported to be a cancer growth suppressor in xenograft mouse models. Subsequent studies show that betulinic acid induces apoptosis and antiangiogenic responses in tumors derived from multiple tissues. A 3d qsar study of betulinic acid derivatives as antitumor. Mitochondriatargeted betulinic and ursolic acid derivatives. The antitumor cytotoxicity of betulinic acid has been investigated for man. A 3d qsar study of betulinic acid derivatives as anti.
Betulinic acid, a natural compound with potent anticancer ef. Betulinic acid shows anti hiv activities, with an ec50 of 1. Betulinic acid, a phytochemical with antitumor activity. The use of betulinic acid for treatment of colorectal cancer cells resistant to various chemotherapeutic drugs was evaluated. Betulin, betulinic acid, and their derivatives exhibit a multitude of pharmacological properties ranging from antitumor, antiinflammatory, antiparasitic, and anti hiv activities 312. Synthesis, characterization and cytotoxic activity of. It is found in the bark of several species of plants, including the ber tree ziziphus mauritiana, the white birch betula pubescens, and many other. Mitochondriontargeted agents such as betulinic acid may open new perspectives to overcome some forms of drug resistance 4. Optimization of invasionspecific effects of betulin. New derivatives of lupane triterpenoids disturb breast cancer.
Betulinic acid, a natural compound with potent anticancer. Chapter 1 betulinic acid, a natural compound with potent anti cancer effects 7 chapter 2 broad in vitro efficacy of plantderived betulinic acid against cell lines derived from the most prevalent human cancer types 35 chapter 3 betulinic acid delivered in liposomes reduces growth of human lung and colon cancers. New ionic derivatives of betulinic acid as highly potent anti. Herein, we evaluated the anti cancer effect and molecular mechanisms of a novel betulinic acid ba derivative, syk023, by using two mouse models of lung cancer driven by krasg12d or egfrl858r. Betulin and betulinic acid have been widely studied for their anticancer activities. Anticancer properties of ester derivatives of betulin in.
Betulinic acid is a pentacyclic triterpene natural product initially identified as a melanomaspecific cytotoxic agent that exhibits low toxicity in animal models. Betulinic acid also induces morphological changes of mdamb231 cells at 20 m, and leads to ultrastructure changes of mdamb231 cells at 40 m2. Oxidation of a wood extractive betulin to biologically active. Several ba derivatives are potent and highly selective inhibitors of hiv1. Betulinic acid, obtained by betulin oxidation, is also abundantly present in nature.
Research consisting of in vitro and in vivo studies have proved that this betulin derivative killed melanoma cells in mice 17. Abstract of ep0943620 the invention relates to use of betulinic acid andor its derivatives for treating, inhibiting, andor preventing. However, their further development is limited due to low bioavailability, poor aqueous solubility, and limited intracellular accumulation. Betulinic acid, a pentacyclic triterpene, is widely distributed throughout the tropics.
Advertise with us journal and book catalog media pack 2020. Chemistry, biological activity, and chemotherapeutic. Betulin b and betulinic acid ba are natural pentacyclic lupanestructure triterpenoids which possess a wide range of pharmacological activities. Chemistrysynthesis of betulinic acid derivatives 2, 4, 68 79 has been described in scheme 1. Betulin and its derivatives as novel compounds with. Ionic derivatives of betulinic acid as novel hiv1 protease. Betulinic acid and its derivatives as anticancer agent. Novel semisynthetic analogues of betulinic acid with. Betulinic acid beta, a pentacyclic triterpene, is a selective apoptosis. Feb 15, 2012 this compound and its derivatives possess many favorable biological properties such as anti cancer, anti hiv1 human immunodeficiency virus type1, antibacterial, anti malarial, anti inflammatory, and anthelmintic activities. It is found in the bark of several species of plants, principally the white birch betula pubescens from which it gets its name, but also the ber tree. Betulinic acid, betulinic acid derivatives, anticancer, structure act.
Betulinic acid is a naturally occurring pentacyclic triterpenoid which has antiretroviral, antimalarial, and anti inflammatory properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase. Anticancer agents in medicinal chemistry 2020, 20 3, 286300. Betulinic acid derivative ba5, a dual nfkbcalcineurin. Anticancer role of betulinic acid appeared by inducing apoptosis in cells. Pdf betulinic acid and its derivatives as antiangiogenic. Natural plantderived anticancer drugs nanotherapeutics. New derivatives of lupane triterpenoids disturb breast. Us20120237629a1 us512,472 us2010512472a us2012237629a1 us 20120237629 a1 us20120237629 a1 us 20120237629a1 us 2010512472 a us2010512472 a us 2010512472a us 2012237629 a1 us2012237629 a1 us 2012237629a1 authority us united states prior art keywords acid plant dosage extract sickle prior art date 20091 legal status the legal status is an.
Structureactivitystudiesamong several oleanolic and ursolic acid derivatives 11 have identified 2cyano3,12dioxoolean1,9dien28oic acid cddo and related compounds as highly potent anti inflammatory. Betulinic acid is a naturally occurring pentacyclic triterpenoid which has anti retroviral, anti malarial, and anti inflammatory properties, as well as a more recently discovered potential as an anticancer agent, by inhibition of topoisomerase. Jul 25, 2019 the discovery, structure, organic synthesis and derivatives forming were shortly described. Pentacyclic triterpene acid conjugated with mitochondria. Unfortunately, the bioavailability and the biodistribution of betulinic acid and its metabolic precursor, betulin are very low because of poor solubility in aqueous buffers.
In neuroectodermal tumor cells, betulinic acidinduced apoptosis is. A novel derivative of betulinic acid, syk023, suppresses lung. Synergistic activity of sorafenib and betulinic acid. Recent study has revealed that beta inhibits in vitro enzymatic activity of aminopeptidase n apn, ec 3. Biomolecules free fulltext betulinic acid suppresses ovarian. This compound and its derivatives possess many favorable biological properties such as anti cancer, anti hiv1 human immunodeficiency virus type1, antibacterial, anti malarial, anti inflammatory, and anthelmintic activities. Betulinic acid ba is a natural product that exerts its cytotoxicity against various malignant carcinomas without side effects by triggering the mitochondrial pathway to apoptosis.
However, betulinic acid is most highly regarded for its anti hiv1 activity and specific cytotoxicity against a variety of tumor cell lines. Depending on the specific sidechain modification, these compounds function by inhibiting hiv fusion or, as recently demonstrated, by interfering with a specific step in hiv1 maturation. Oxidation of a wood extractive betulin to biologically. The anti cancer activity of betulinic acid and some derivatives has been demonstrated using mouse sarcoma 180 cells. Betulin be, the 28hydroxyl analog of ba, is present in large amounts up to 30% dry weight in the outer bark of birch trees, and shares the same pentacyclic triterpenoid core as ba, yet exhibits no significant. It is found in the bark of several species of plants, principally the white birch from which it gets its name, but also the ber tree, selfheal, the tropical carnivorous plants triphyophyllum peltatum and ancistrocladus heyneanus, diospyros leucomelas, a mem. Herein, we evaluated the anti cancer effect and molecular mechanisms of a novel betulinic acid ba derivative, syk023, by using two mouse models of lung cancer driven by kras g12d or egfr l858r.
Betulinic acid and its designed derivative the diversity centres in betulinic acid are c1, c2, c3, c4, c20 and c28 positions and the derivatives resulted on various structural modifications at these positions screened for their anticancer activity. Design, synthesis, and biological evaluation of betulinic. Dissertation or thesis ddb and betulinic acidderivatives. Betulinic acid derivatives were designed based on the structureactivity relationship of triptolide and evaluated for their cytotoxic effects in cml cells, lymphocytes. New ionic derivatives of betulinic acid as highly potent. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti human immunodeficiency virus hiv agents. Studies show it has all the same benefits of betulin, but better particularly anti cancer, anti tumor, and anti hiv effects. It was found that betulinic acid shows an inhibitory ac tivity against hiv1 replication with an ec.
Betulinic acid inhibits prostate cancer growth through. Betulinic acid 20, 40 m causes decrease in bcl2 expression of mdamb231 cells. Betulinic acid ba derivatives are low molecular weight organic compounds synthesized from a plantderived natural product. Ba derivatives semisynthesized from ba and be have been reported, and their anti tumor bioactivities have been investigated 618. In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid 1 derivatives were investigated. Betulinic acid is a more powerful form of betulin and is found particularly in the chaga mushroom, which creates the triterpene from betulin in birch. The efficacy of betulinic acid in triplenegative breast cancer. In order to achieve the designed derivatives of betulinic. A variety of biological activities have been ascribed to betulinic acid including anti inflammatory and in vitro antimalarial effects.
Nanoformulated drug delivery of potential betulinic acid derivatives. Gomathi periasamy, girma teketelew, mebrahtom gebrelibanos. Both compounds are abundantly present in the outer bark of white birch, with betulin forming up to 34% its dry mass and are known for their valuable biological properties, including anti cancer effect. One of the widely recognized analogs of betulinic acid is bevirimat, which was found to inhibit hiv in a novel mechanism of action known as virus maturation.
Betulinic acid is also cytotoxic against primary cancer cells isolated from tumor. Betulinic acid 1 was converted to 3oxo betulinic acid 2 by joneso oxidation. Effects of betulinic acid against infectious diseases before its discovery as an anti cancer agent beta had already been shown to be effective against hiv via inhibition of replication 37. Dec 18, 2011 furthermore, betulinic acid induced the expression of the ptp shp1 and silencing of the shp1 gene abolished the ability of betulinic acid to inhibit stat3 activation and rescued betulinic acid induced cell death. Furthermore, the ability of betulinic acid to inhibit angiogenesis was also determined. However, betulinic acid is most highly regarded for its anti. A novel derivative of betulinic acid, syk023, suppresses. We found that syk023 inhibits lung tumor proliferation, without side effects in vivo or cytotoxicity in primary lung cells in vitro.
Gebrehiwot and aman karim and gereziher geremedhin, journalarchives of applied science research. Also, the potential molecular mechanisms of action and numerous medical applications of betulin and betulinic acid were presented, including previous studies of anti cancer activity of the compounds, with listed cancer cell types susceptible to therapy. Wo2000046235a1 novel betulinic acid derivatives, processes. Pdf antiprotozoal activity of betulinic acid derivatives. Betulinic acid is a natural product that exhibits potent antitumor activities by triggering the mitochondrial path to apoptosis 4. May 12, 2015 betulinic acid and other betulin derivatives have antiviral, anti inflammatory, anti malarial, and anti cancer effects. An easy and efficient strategy to prepare betulinic acid esters with various anhydrides was used by the enzymatic synthesis method. Fulda s 2008 betulinic acid for cancer treatment and prevention. Methods in this study, we examined the anticancer properties of the ester derivatives of betulin compared. Effect of betulinic acid on anticancer drugresistant. In the cytotoxic activity evaluation, compounds 120, 123, 126, and 129 exhibited gi50 betulinic acid ba derivatives are low molecular weight organic compounds synthesized from a plantderived natural product.
Betulinic acid 3betahydroxylup2029ene28oic acid, is naturally occurring pentacyclic triterpenes discovered in 1995 in the stem bark of the plant melaleuca cajuput. Anticancer activity of 3oacylated betulinic acid derivatives. The efficacy of betulinic acid in triplenegative breast. Therefore, thirteen new betulinic acid derivatives were designed, synthesized, and evaluated for anticancer, cancer prevention, or anti hiv activity. This compound and its derivatives have exhibited a variety of biological properties such as anti hiv1 human immunodeficiency virus type1, anti cancer, anti bacterial, anti malarial, anti inflammatory and anthelmintic activities1. Due to high order safety in betulinic acid, a number of structural modifications carried. Betulinic acid and its derivatives as anticancer agent scholars. Due to high order safety in betulinic acid, a number of structural modifications carried out to improve its potency and efficacy. Betulinic acid for cancer treatment and prevention ncbi nih. Betulinic acid betulin o ho oh 3 28 19 20 29 3 28 19 20 29 ho oh. Betulin and its derivatives as novel compounds with different. Betulinic acid also downregulated the expression of stat3regulated gene products such as bclxl, bcl2, cyclin d1 and survivin. Jan 03, 2017 background betulinic acid and betulin are triterpenes that have anticancer properties in various types of cancer. Betulin and betulinic acid have a wide variety of potentially useful medical applications, including anti inflammatory and anti cancer 45, anti bacterial 1 and anti viral properties 22,36.
One of its derivatives, formed by oxidation, is betulinic acid. Introduction the pentacyclic lupane triterpenoid betulinic acid, 1 3b, hydroxylup2029en28oic acid is one of the first natural products identified from plants in 17881. In a different project, we discovered that c3 modification and c30 modification can increase the anti proteasome activity of ba dramatically. In the present study, a triphenylphosphonium cation moiety was linked to betulin and betulinic acid to specifically target them to cancer cell mitochondria. Betulinic acid, a natural compound with potent anticancer effects mullauer, franziska b. Gebrehiwot and aman karim and gereziher geremedhin, journalarchives of. Mitochondriatargeted lupane triterpenoid derivatives and. This anticancer property is linked to its ability to induce apoptotic cell death in cancer cells by triggering the mitochondrial pathway of apoptosis. In this study, the efficacy of betulinic acid, a naturally abundant phytochemical exhibiting anti inflammatory and anti proliferative activity, has been evaluated for the treatment of triplenegative breast cancer mdamb231 and mdamb468 cell lines. An 34,5dimethylthiazol2yl2,5diphenyltetrazolium bromide mtt assay was employed to assess the anticancer effects of compounds 114 on a2780 cells.
A variety of biological activities have been ascribed to betulinic acid including anti. Betulinic acid derivatives for inhibiting cancer growth. Betulinic acid and its derivatives as potential antitumor agents. These compounds can be found in the bark of the many plants. It possesses several biological properties such as anticancer, anti inflammatory, antiviral, antiseptic, antimalarial, spermicidal, antimicrobial, antileshmanial, antihelmentic and antifeedent activities. The antitumor activity of betulinic acid and its derivatives exhibit a high activity against several tumors and cancers, such as melanoma 2631, leukemia 3235, prostate carcinoma 36, while normal cells are unaffected by betulinic acid, indicating selectivity 37. The in vitro experiments on three human cancer cell lines mcf7, hct116 and tet21n revealed that all the obtained triphenylphosphonium triterpene acid. Betulinic acid beta figure 1, a pentacyclic triterpene discovered in 1995 from the stem bark of the plant zizyphus mauritiana, was initially reported to be a melanomaspecific cytotoxic agent. Recent evidence indicates that b and ba have several properties useful for the treatment of metabolic disorders, infectious diseases, cardiovascular di. Anticancer role of betulinic acid appeared by inducing apoptosis in cells irrespective of their p53 status. The discovery, structure, organic synthesis and derivatives forming were shortly described. Pdf targeting cancer by betulin and betulinic acid researchgate. Here we report for the first time the antiangiogenic activity of betulinic acid 1 and its potent derivatives 2, 4, 68.
In addition, betulinic acid was identified as a selective inducer of apoptosis in melanoma cells 32, triggering a strong interest in triterpenes as anticancer agents. Synthesis of aseco derivatives of betulinic acid with cytotoxic. Betulinic acid, seco betulinic acid, lactone derivatives, ester derivatives, cytotoxicity, cancer. Betulinic aaid for cancer treatment and prevention. Betulinic acid and dihydrobetulinic acid derivatives as. Research progress in the promissing natural productbetulin. Merck column chromatography and a gradient elution chcl 3 meoh article in press contents lists available at. The similar compounds were tested for anticancer activity on various human cancer and healthy.
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