1721-69-3Relevant articles and documents
Molecular structure, in vitro anticancer study and molecular docking of new phosphate derivatives of betulin
B?benek, Ewa,Boryczka, Stanis?aw,Chrobak, Elwira,Jastrz?bska, Maria,Kadela-Tomanek, Monika,Kusz, Joachim,Latocha, Ma?gorzata,Marciniec, Krzysztof,Wrzalik, Roman
, (2021)
A series of 30-diethylphosphate derivatives of betulin were synthesized and evaluated for their in vitro cytotoxic activity against human cancer cell lines, such as amelanotic melanoma (C-32), glioblastoma (SNB-19), and two lines of breast cancer (T47D, MDA-MB-231). The molecular structure and activities of the new compounds were also compared with their 29-phosphonate analogs. Compounds 7a and 7b showed the highest activity against C-32 and SNB-19 cell lines. The IC50 values for 7a were 2.15 and 0.91 μM, and, for 7b, they were 0.76 and 0.8 μM for the C-32 and SNB-19 lines, respectively. The most potent compounds, 7a and 7b, were tested for their effects on markers of apoptosis, such as H3, TP53, BAX, and BCL-2. For the whole series of phosphate derivatives, a lipophilicity study was performed, and the ADME parameters were calculated. The most active products were docked to the active site of the EGFR protein. The relative binding affinity of selected phosphate betulin derivatives toward EGFR was compared with standard erlotinib on the basis of ChemScore and KDEEP score. Positively, all derivatives docked inside the cavity and showed significant interactions. Moreover, a molecular dynamics study also reveals that ligands 7a,b form stable complexes and the plateau phase started after 7 ns.
Enhancement of the antioxidant and skin permeation properties of betulin and its derivatives
Duchnik, Wiktoria,Günther, Andrzej,Klimowicz, Adam,Kucharski, ?ukasz,Makuch, Edyta,Nowak, Anna,Pe?ech, Robert
, (2021)
This study investigated the antioxidant activity DPPH, ABTS, and Folin–Ciocalteu methods of betulin (compound 1) and its derivatives (compounds 2–11). Skin permeability and accumulation associated with compounds 1 and 8 were also examined. Identification of the obtained products (compound 2–11) and betulin isolated from plant material was based on the analysis of1H-NMR and13C-NMR spectra. The partition coefficient was calculated to determine the lipophilicity of all compounds. In the next stage, the penetration through pig skin and its accumulation in the skin were evaluated of ethanol vehicles containing compound 8 (at a concentration of 0.226 mmol/dm3), which was characterized by the highest antioxidant activity. For comparison, penetration studies of betulin itself were also carried out. Poor solubility and the bioavailability of pure compounds are major constraints in combination therapy. However, we observed that the ethanol vehicle was an enhancer of skin permeation for both the initial betulin and compound 8. The betulin 8 derivative showed increased permeability through biological membranes compared to the parent betulin. The paper presents the transformation of polycyclic compounds to produce novel derivatives with marked antioxidant activities and as valuable intermediates for the pharmaceutical industry. Moreover, the compounds contained in the vehicles, due to their mechanism of action, can have a beneficial effect on the balance between oxidants and antioxidants in the body, minimizing the effects of oxidative stress. The results of this work may contribute to knowledge regarding vehicles with antioxidant potential. The use of vehicles for this type of research is therefore justified.
Amino(oxo)acetate moiety: A new functional group to improve the cytotoxicity of betulin derived carbamates
Heller, Lucie,Perl, Vincent,Wiemann, Jana,Al-Harrasi, Ahmed,Csuk, René
, p. 2852 - 2854 (2016)
While 3-O-acetylated betulin derivatives carrying a carbamate moiety at position C-28 are of rather low cytotoxicity for human tumor cell lines, the corresponding C-3 amino(oxo) acetates show good cytotoxicity. For example, an EC50 as low as 2.0 μM was found for (3β) 28-{[(hexylamino)carbonyl]oxy}lup-20(29)-en-3-yl amino(oxo)acetate (16) employing the ovarian cancer cell line A2780.
Selective inhibition of the interaction of C1q with immunoglobulins and the classical pathway of complement activation by steroids and triterpenoids sulfates
Bureeva, Svetlana,Andia-Pravdivy, Julian,Symon, Andrey,Bichucher, Anna,Moskaleva, Vera,Popenko, Vladimir,Shpak, Alexey,Shvets, Vitaly,Kozlov, Leonid,Kaplun, Alexander
, p. 3489 - 3498 (2007)
Since undesirable activation of the complement system through the classical pathway is associated with tissue damage and other pathologic proinflammatory consequences at ischemia/reperfusion injury, autoimmune diseases, and rejection of allo- and xenografts, creation of selective inhibitors of the classical pathway leaving the alternative pathway intact is of great importance. Classical pathway is triggered by binding of its recognizing unit, protein C1q, to a number of targets like antibodies, pentraxins, apoptotic cells, and others. In order to obtain inhibitors blocking the first step of the classical cascade, synthesis of sulfates of steroids (Δ5-3β-hydroxycholenic, Δ5-3β-hydroxyetiocholenic, deoxycholic, and cholic acids) and triterpenoids (betulin, 20,29-dihydro-20,29-dichloromethylenbetulin, betulinic, ursolic, and oleanolic acids) has been performed. Testing of the compounds in classical pathway inhibition assay has displayed derivatives of triterpenoid betulin (betulin disulfate and betulinic acid sulfate) to be the most potent inhibitors. Further studies of the two compounds established that their activity to inhibit the classical pathway had been due to their capability to block the interaction of C1q with antibodies. Betulin disulfate and betulinic acid sulfate have shown weak inhibition of the alternative route of activation, what makes them promising inhibitors for the selective suppression of the classical complement pathway at the earliest possible level as well as perspective agents for blocking the interaction of C1q with its other targets.
Synthesis and structure-activity relationship study of novel cytotoxic carbamate and N-acylheterocyclic bearing derivatives of betulin and betulinic acid
Santos, Rita C.,Salvador, Jorge A.R.,Marin, Silvia,Cascante, Marta,Moreira, Joao N.,Dinis, Teresa C.P.
, p. 4385 - 4396 (2010)
Chemical transformation studies were conducted on betulin and betulinic acid, common plant-derived lupane-type triterpenes. The concise synthesis, via a stepwise approach, of betulin and betulinic acid carbamate and N-acylheterocyclic containing derivatives is described. All new compounds, as well as betulinic acid were tested in vitro for their cytotoxic activity. Most of the compounds have shown a better cytotoxic profile than betulinic acid, including the synthesized betulin derivatives. Compounds 25 and 32 were the most promising derivatives, being up to 12-fold more potent than betulinic acid against human PC-3 cell lines (IC50 values of 1.1 and 1.8 μM, respectively).
Synthesis of terminal acetylenes using POCl3 in pyridine as applied to natural triterpenoids
Kazakova, Oxana B.,Medvedeva, Natalya I.,Tolstikov, Genrikh A.,Kukovinets, Olga S.,Yamansarov, Emil Y.,Spirikhin, Leonid V.,Gubaidullin, Aidar T.
, p. 234 - 236 (2010)
Four new triterpenoids with alkyne moieties have been synthesized by the proposed procedure; among them, 3β,28-dihydroxy-29-norlup-20(30)-yne has demonstrated antiviral activity against papilloma virus and HCV replicon.
New 30-substituted derivatives of pentacyclic triterpenes: preparation, biological activity, and molecular docking study
B?benek, Ewa,Boryczka, Stanis?aw,Chrobak, Elwira,Kadela-Tomanek, Monika,Latocha, Ma?gorzata,Marciniec, Krzysztof,Siudak, Szymon
, (2021)
A series of 30-substituted derivatives of 3,28-O,O′-diacetylbetulin 4-19 were prepared and assessed for anticancer activities in vitro against five human cancer cell lines (SNB-19, C-32, SKOV-3, MCF-7, and T47D). The triterpene 14, containing the butyryloxycarbonyl group at the C-30 position, showed the highest cytotoxicity, with IC50 values within the range of 1.24 to 6.03 μM towards applied cancer cells. The ADME study of the betulinines 4-19 were performed by determination of molecular weight (M), hydrogen bond acceptors (nHBA), hydrogen bond donors (nHBD), lipophilicity (cLogP), rotatable bonds (nROTB) and topological polar surface area (TPSA). Molecular docking was applied to examine the probable interaction between the new synthesized compounds and the Akt1 kinase. The analysis showed that triterpenes 13-16 formed numerous hydrophobic interactions inside the binding pocket of Akt1.
Fluorinated betulinic acid derivatives and evaluation of their anti-HIV activity
Li, Jizhen,Goto, Masuo,Yang, Xiaoming,Morris-Natschke, Susan L.,Huang, Li,Chen, Chin-Ho,Lee, Kuo-Hsiung
, p. 68 - 71 (2016)
Several fluorinated derivatives of the anti-HIV maturation agent bevirimat (1) were synthesized and evaluated for anti-HIV replication activity. The modified positions were the C-2, C-3, C-28, and C-30 positions, either directly on the betulinic acid (2) skeleton or in the attached side chains. Compound 18, which has a trifluoromethyl group added to C-30 of its isopropenyl group, exhibited similar potency to 1 against HIV-1NL4-3. In total, our current studies support our prior conclusion that C-30 allylic modification is unlikely to be a pharmacophore for anti-HIV activity, but could be a meaningful route to manipulate other properties of 2-related compounds.
Antineoplastic Agents. 606. the Betulastatins
Pettit, George R.,Melody, Noeleen,Chapuis, Jean-Charles
, p. 458 - 464 (2018)
The medicinal potential of the plant pentacyclic triterpene betulin has generated long-term interest focused on various SAR research avenues. The present approach was based on producing further analogues (chimeras) arising from a studied modification of betulin bonded to the Dov-Val-Dil-Dap unit of the powerful anticancer drug dolastatin 10, which provided betulastatins 1 (7b), 2 (11b), 3 (16b), and 4 (18b). Betulastatin 1, 2, and 4 exhibited modest levels of cancer cell growth inhibition against six cancer cell lines. Betulastatin 3 proved to be the most potent cancer cell growth inhibitor (GI50 0.01 μg/mL) and seems worthy of further development, as the presumed mixture of anticancer mechanisms of action may prove to be useful.
Synthesis and antitumor activity of cyclopropane derivatives of betulinic and betulonic acids
Symon,Veselova,Kaplun,Vlasenkova,Fedorova,Lyutik,Gerasimova,Shvets
, p. 286 - 291 (2005)
New cyclopropane derivatives of betulin were synthesized by attachment of dichlorocarbenes or dibromocarbenes to the double bond of betulin diacetate, followed by the deprotection of hydroxyl groups. The betulin cyclopropane derivative was obtained from 20,29-dihydro-20,29-dichloromethylenebetulin by treatment with lithium in tert-butanol. These compounds were converted into the corresponding derivatives of betulonic acid by oxidation with chromium trioxide. The reduction of oxo group with sodium borohydride led to the corresponding derivatives of betulinic acid. 20,29-Dihydro-20,29-dichloromethylenebetulinic acid proved to be the most cytotoxic toward human melanoma of the Colo 38 and Bro lines and human ovarian carcinoma of the CaOv line (IC50 10 μM). 20,29-Dihydro-20,29-dibromomethylenebetulinic acid inhibited the growth of the Bro melanoma cell line and the CaOv carcinoma cell line practically by 50% at a concentration of 10 μM. The other derivatives of betulinic and betulonic acids were active toward all of the three cancer cell lines at concentrations higher than 10 μM.
