- Catalytic oxidative transformation of betulin to its valuable oxo-derivatives over gold supported catalysts: Effect of support nature
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Liquid-phase oxidation of betulin extracted from birch bark was studied over gold catalysts supported on a range of supports (hydrotalcite, ZrO2, ZnO, MgO, CeO2, La2O3, HMS and various alumina) with different morphology and properties. Gold catalysts as well as the corresponding supports were characterized by XRD, BET, ICP-OES, XPS and TEM. It was found that the nature of the support plays a decisive role in betulin oxidation over gold-based catalysts, expressed in the influence on the average size and distribution of gold nanoparticles and, thereby, on their catalytic performance (activity and selectivity) in betulin oxidation. Moreover, it was revealed that betulin oxidation catalyzed by gold is a structure sensitive reaction, requiring an optimal size of gold nanoparticles of ca. 3.3 nm. The most suitable support for gold was found to be alumina. Kinetic studies allowed determination of reaction orders and conditions favorable for selective formation of a particular oxo-derivative of betulin (betulone, betulinic and betulonic aldehydes, betulinic acid).
- Kolobova,M?ki-Arvela,Grigoreva,Pakrieva,Carabineiro,Peltonen,Kazantsev,Bogdanchikova,Pestryakov,Murzin, D.Yu.
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- Pyrazine-Fused Triterpenoids Block the TRPA1 Ion Channel in Vitro and Inhibit TRPA1-Mediated Acute Inflammation in Vivo
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TRPA1 is a nonselective cation channel, most famously expressed in nonmyelinated nociceptors. In addition to being an important chemical and mechanical pain sensor, TRPA1 has more recently appeared to have a role also in inflammation. Triterpenoids are natural products with anti-inflammatory and anticancer effects in experimental models. In this paper, 13 novel triterpenoids were created by synthetically modifying betulin, an abundant triterpenoid of the genus Betula L., and their TRPA1-modulating properties were examined. The Fluo 3-AM protocol was used in the initial screening, in which six of the 14 tested triterpenoids inhibited TRPA1 in a statistically significant manner. In subsequent whole-cell patch clamp recordings, the two most effective compounds (pyrazine-fused triterpenoids 8 and 9) displayed a reversible and dose- and voltage-dependent effect to block the TRPA1 ion channel at submicromolar concentrations. Interestingly, the TRPA1 blocking action was also evident in vivo, as compounds 8 and 9 both alleviated TRPA1 agonist-induced acute paw inflammation in mice. The results introduce betulin-derived pyrazine-fused triterpenoids as promising novel antagonists of TRPA1 that are potentially useful in treating diseases with a TRPA1-mediated adverse component.
- M?ki-Opas, Ilari,H?m?l?inen, Mari,Moilanen, Lauri J.,Haavikko, Raisa,Ahonen, Tiina J.,Alakurtti, Sami,Moreira, Vania M.,Muraki, Katsuhiko,Yli-Kauhaluoma, Jari,Moilanen, Eeva
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- Oxidation of betulin and its monoacetates by "activated" DMSO
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The oxidation of betulin and its 3-O- and 28-O-acetates by "activated" dimethylsulfoxide was investigated.
- Ashavina,Flekhter,Galin,Kabalnova,Baltina,Tolstikov
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Read Online
- Structural modifications of 2,3-indolobetulinic acid: Design and synthesis of highly potent α-glucosidase inhibitors
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A series of nineteen nitrogen-containing lupane triterpenoids was obtained by modification of C2, C3, C20 and C28 positions of betulonic acid and their α-glucosidase inhibiting activity was investigated. Being a leader compound from our previous study, 2,3-indolo-betulinic acid was used as the main template for different modifications at C-(28)-carboxyl group to obtain cyano-, methylcyanoethoxy-, propargyloxy- and carboxamide derivatives. 20-Oxo- and 29-hydroxy-20-oxo-30-nor-analogues of 2,3-indolo-betulinic acid were synthesized by ozonolysis of betulonic acid followed by Fischer indolization reaction. To compare the influence of the fused indole or the seven-membered A-ring on the inhibitory activity, lupane A-azepanones with different substituents at C28 were synthesized. The structure-activity relationships revealed that the enzyme inhibition activity dramatically increased (up to 4730 times)when the carboxylic group of 2,3-indolo-betulinic acid was converted to the corresponding amide. Thus, the IC50 values for glycine amide and L-phenylalanine amides were 0.04 and 0.05 μM, respectively. This study also revealed that 2,3-indolo-platanic acid is 4.5 times more active than the parent triterpenoid with IC50 of 0.4 μM. Molecular modeling suggested that improved potency is due to additional polar interactions formed between C28 side chain and a sub-pocket of the α-glucosidase allosteric site.
- Khusnutdinova, Elmira F.,Petrova, Anastasiya V.,Thu, Ha Nguyen Thi,Tu, Anh Le Thi,Thanh, Tra Nguyen,Thi, Cham Ba,Babkov, Denis A.,Kazakova, Oxana B.
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- Chemical transformations of betulonic aldehyde
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Chemical transformations of 3-oxolup-20(29)-en-28-al in oxidation, reduction, reductive amination, aldol crotonic condensation, cyclopropanation, Grignard, and Wittig reactions were investigated. The structure of reaction products was established by X-ray diffraction (XRD) analysis.
- Semenenko,Babak,Eremina,Gella,Shishkina,Musatov,Lipson
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- Alkylidene branched lupane derivatives: Synthesis and antitumor activity
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Several novel alkylidene branched lupane derivatives have been prepared. Many of these compounds showed a significant cytotoxicity. The most active compound, 2-methylene-betulonic acid, showed IC50 values between 0.2 and 0.6 μM for 15 different human cancer cell lines. Cytotoxicity can be improved by encapsulation in liposomes. These compounds act by triggering apoptotic cell death as shown by DNA-laddering experiments and acridine orange/ethidium bromide staining.
- Csuk, Rene,Stark, Sebastian,Nitsche, Christoph,Barthel, Alexander,Siewert, Bianka
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- Enhancement of the antioxidant and skin permeation properties of betulin and its derivatives
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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.
- Duchnik, Wiktoria,Günther, Andrzej,Klimowicz, Adam,Kucharski, ?ukasz,Makuch, Edyta,Nowak, Anna,Pe?ech, Robert
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- Synthesis of α,ω-Diketodiesters from Betulin
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A new synthesis of 3-oxo-28-hydroxylup-20(29)-ene from the available natural triterpenoid betulin was developed. α,ω-Diketodiesters were prepared for the first time by different methods from 3-oxo-28-hydroxylup-20(29)-ene and a series of natural dicarboxylic acids. Steglich reaction conditions gave the highest yields. One of the synthesized α,ω-diketodiesters was moderately active in vitro against A-549 lung carcinoma.
- Ishmuratov, G. Yu.,Sayakhov, R. R.,Talipov, R. F.,Vydrina, V. A.,Yakovleva, M. P.,Zileeva, Z. R.
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p. 706 - 711
(2021/07/31)
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- Anti-tumor betulinol derivative and preparation method thereof
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The invention discloses an anti-tumor betulin derivative and a preparation method thereof. The preparation method comprises the following steps: adding betulin into a reactor, oxidizing hydroxyl by using a mixed solution of sodium dichromate and sulfuric acid, carrying out acylating chlorination on thionyl chloride, carrying out aminolysis under an alkaline condition, and finally crystallizing by using ethanol to obtain the betulin derivative with a novel structure. Pathological experiments show that compared with cis-platinum which is commonly used at present, the betulin derivative has remarkable inhibitory activity on breast cancer cells, human ovarian cancer cells, human lung cancer cells and human liver cancer cells. The method is simple in route, simple to operate and high in yield, the used reagents are common reagents, and particularly, the preparation cost of the technical route of the preparation method is obviously reduced, and the reaction conditions are mild.
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Paragraph 0006; 0026-0027
(2021/07/28)
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- Oxidation of a wood extractive betulin to biologically active oxo-derivatives using supported gold catalysts
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Betulin (90-94%) was extracted from birch with a non-polar solvent and recrystallized from 2-propanol. Liquid-phase oxidation of betulin aimed at obtaining its biologically active oxo-derivatives (betulone, betulonic and betulinic aldehydes), exhibiting e.g. antitumor, anti-inflammatory, antiparasitic, anticancer and anti-HIV properties, was demonstrated for the first time over gold-based catalysts. Gold was deposited on pristine TiO2 and the same support modified with ceria and lanthana, followed by pretreatment with a H2 or O2 atmosphere. The catalysts were characterized by XRD, BET, ICP, TEM, XPS, DRIFT CO, TPD of NH3 and CO2 methods. The nature of the support, type of modification and the pretreatment atmosphere through the metal-support interactions significantly influenced the average particle size of gold, its distribution and the electronic state of gold, as well as the acid-base properties and, thereby, the catalytic performance (activity and selectivity) in betulin oxidation. Au/La2O3/TiO2 pretreated in H2 displayed the highest catalytic activity in betulin oxidation among the studied catalysts with selectivities to betulone, betulonic and betulinic aldehydes of 42, 32 and 27%, respectively, at 69% conversion. Side reactions resulting in oligomerization/polymerization products occurred on the catalyst surface with the participation of strong acid sites, diminishing the yield of the desired compounds. The latter was improved by adding hydrotalcite with the basic properties to the reaction mixture containing the catalyst. Kinetic modelling through numerical data fitting was performed to quantify the impact of such side reactions and determine the values of rate constants.
- Kolobova, Ekaterina N.,Pakrieva, Ekaterina G.,Carabineiro, Sónia A. C.,Bogdanchikova, Nina,Kharlanov, Andrey N.,Kazantsev, Sergey O.,Hemming, Jarl,M?ki-Arvela, P?ivi,Pestryakov, Alexey N.,Murzin, Dmitry Yu.
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p. 3370 - 3382
(2019/06/24)
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- Design, Synthesis, and SAR of C-3 Benzoic Acid, C-17 Triterpenoid Derivatives. Identification of the HIV-1 Maturation Inhibitor 4-((1 R,3a S,5a R,5b R,7a R,11a S,11b R,13a R,13b R)-3a-((2-(1,1-Dioxidothiomorpholino)ethyl)amino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1 H-cyclopenta[ a]chrysen-9-yl)benzoic Acid (GSK3532795, BMS-955176)
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GSK3532795, formerly known as BMS-955176 (1), is a potent, orally active, second-generation HIV-1 maturation inhibitor (MI) that advanced through phase IIb clinical trials. The careful design, selection, and evaluation of substituents appended to the C-3 and C-17 positions of the natural product betulinic acid (3) was critical in attaining a molecule with the desired virological and pharmacokinetic profile. Herein, we highlight the key insights made in the discovery program and detail the evolution of the structure-activity relationships (SARs) that led to the design of the specific C-17 amine moiety in 1. These modifications ultimately enabled the discovery of 1 as a second-generation MI that combines broad coverage of polymorphic viruses (EC50 15 nM toward a panel of common polymorphisms representative of 96.5% HIV-1 subtype B virus) with a favorable pharmacokinetic profile in preclinical species.
- Regueiro-Ren, Alicia,Swidorski, Jacob J.,Liu, Zheng,Chen, Yan,Sin, Ny,Sit, Sing-Yuen,Chen, Jie,Venables, Brian L.,Zhu, Juliang,Nowicka-Sans, Beata,Protack, Tricia,Lin, Zeyu,Terry, Brian,Samanta, Himadri,Zhang, Sharon,Li, Zhufang,Easter, John,Beno, Brett R.,Arora, Vinod,Huang, Xiaohua S.,Rahematpura, Sandhya,Parker, Dawn D.,Haskell, Roy,Santone, Kenneth S.,Cockett, Mark I.,Krystal, Mark,Meanwell, Nicholas A.,Jenkins, Susan,Hanumegowda, Umesh,Dicker, Ira B.
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p. 7289 - 7313
(2018/09/06)
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- COMPOSITIONS COMPRISING TRITERPENOIDS AND USES THEREOF FOR TREATING OPTIC NEUROPATHY
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The invention relates to compositions and formulations comprising at least one triterpenoic acid and at least one neutral triterpenoid and uses thereof for treating optic neuropathy conditions.
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- Synthesis of Conjugates of Lupane-Type Pentacyclic Triterpenoids with 2-Aminoethane- and N-Methyl-2-Aminoethanesulfonic Acids. Assessment of in vitro Toxicity
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Conjugates of betulin and betulinic and betulonic acids with 2-aminoethane- and N-methyl-2-aminoethanesulfonic acids were synthesized for the first time and were interesting as potential biologically active compounds. Experiments in vitro in MDCK cell culture using the MTT assay found that betulin and betulinic-acid derivatives with aminoethanesulfonic acid bound to triterpene C-3 or C-28 through an ester linker were less toxic than the native compounds.
- Komissarova,Dubovitskii,Shitikova,Vyrypaev,Spirikhin,Eropkina,Lobova,Eropkin, M. Yu.,Yunusov
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p. 907 - 914
(2017/10/16)
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- Synthesis of HIV-Maturation Inhibitor BMS-955176 from Betulin by an Enabling Oxidation Strategy
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A concise and scalable second generation synthesis of HIV maturation inhibitor BMS-955176 is described. The synthesis is framed by an oxidation strategy highlighted by a CuI mediated aerobic oxidation of betulin, a highly selective PIFA mediated dehydrogenation of an oxime, and a subsequent Lossen rearrangement which occurs through a unique reaction mechanism for the installation of the C17 amino functionality. The synthetic route proceeds in 7 steps with 47% overall yield and begins from the abundant and inexpensive natural product betulin.
- Ortiz, Adrian,Soumeillant, Maxime,Savage, Scott A.,Strotman, Neil A.,Haley, Matthew,Benkovics, Tamas,Nye, Jeffrey,Xu, Zhongmin,Tan, Yichen,Ayers, Sloan,Gao, Qi,Kiau, Susanne
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p. 4958 - 4963
(2017/05/12)
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- COMPOSITIONS COMPRISING TRITERPENOIDS
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The invention relates to compositions and formulations comprising at least one triterpenoic acid and at least one neutral triterpenoid and uses thereof for treating stroke or trauma and side effects related thereto.
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- COMPOSITIONS COMPRISING TRITERPENOIDS
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The invention relates to compositions and formulations comprising at least one triterpenoic acid and at least one neutral triterpenoid and uses thereof for treating for use in treating a condition selected from Alzheimer's disease (AD), Parkinson's Diseases (PD) and vascular dementia (VD).
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- Development of an azanoradamantane-type nitroxyl radical catalyst for class-selective oxidation of alcohols
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The development of 1,5-dimethyl-9-azanoradamantane N-oxyl (DMN-AZADO; 1,5-dimethyl-Nor-AZADO, 2) as an efficient catalyst for the selective oxidation of primary alcohols in the presence of secondary alcohols is described. The compact and rigid structure of the azanoradamantane nucleus confers potent catalytic ability to DMN-AZADO (2). A variety of hindered primary alcohols such as neopentyl primary alcohols were efficiently oxidized by DMN-AZADO (2) to the corresponding aldehydes, whereas secondary alcohols remained intact. DMN-AZADO (2) also has high catalytic efficiency for one-pot oxidation from primary alcohols to the corresponding carboxylic acids in the presence of secondary alcohols and for oxidative lactonization from diols.
- Doi, Ryusuke,Shibuya, Masatoshi,Murayama, Tsukasa,Yamamoto, Yoshihiko,Iwabuchi, Yoshiharu
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supporting information
p. 401 - 413
(2016/10/12)
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- 9-azanoradamantane N—oxyl compound and method for producing same, and organic oxidation catalyst and method for oxidizing alcohols using 9-azanoradamantane N—oxyl compound
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An organocatalyst for oxidizing alcohols in which a primary alcohol is selectively oxidized in a polyol substrate having a plurality of alcohols under environmentally-friendly conditions. The organic oxidation catalyst has an oxygen atom bonded to a nitrogen atom of an azanoradamantane skeleton and at least one alkyl group at positions 1 and 5. The oxidation catalyst has higher activity than TEMPO, which is an existing oxidation catalyst, in the selective oxidation reaction of primary alcohols, and better selectivity than AZADO and 1-Me-AZADO. This DMN-AZADO can be applied to the selective oxidation reaction of primary alcohols that contributes to shortening the synthesizing process for pharmaceuticals, pharmaceutical raw materials, agricultural chemicals, cosmetics, organic materials, and other such high value-added organic compounds.
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Page/Page column 27-28
(2015/09/23)
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- Isolation, structural modification, and HIV inhibition of pentacyclic lupane-type triterpenoids from cassine xylocarpa and maytenus cuzcoina
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As a part of our investigation into new anti-HIV agents, we report herein the isolation, structure elucidation, and biological activity of six new (1-6) and 20 known (7-26) pentacyclic lupane-type triterpenoids from the stem of Cassine xylocarpa and root bark of Maytenus cuzcoina. Their stereostructures were elucidated on the basis of spectroscopic and spectrometric methods, including 1D and 2D NMR techniques. To gain a more complete understanding of the structural requirements for anti-HIV activity, derivatives 27-48 were prepared by chemical modification of the main secondary metabolites. Sixteen compounds from this series displayed inhibitory effects of human immunodeficiency virus type 1 replication with IC50 values in the micromolar range, highlighting compounds 12, 38, and 42 (IC50 4.08, 4.18, and 1.70 μM, respectively) as the most promising anti-HIV agents.
- Callies, Oliver,Bedoya, Luis M.,Beltrán, Manuela,Mu?oz, Alejandro,Calderón, Patricia Obregón,Osorio, Alex A.,Jiménez, Ignacio A.,Alcamí, José,Bazzocchi, Isabel L.
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p. 1045 - 1055
(2015/06/02)
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- C-3 ALKYL AND ALKENYL MODIFIED BETULINIC ACID DERIVATIVES
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Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, alkyl and alkenyl C-3 modified betulinic acid derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formulas I, II, III and IV: a compound of Formula I a compound of Formula II a compound of Formula III and a compound of Formula IV These compounds are useful for the treatment of HIV and AIDS.
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Paragraph 0217
(2014/09/03)
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- Heterocycle-fused lupane triterpenoids inhibit Leishmania donovani amastigotes
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The synthesis of heterocyclic betulin derivatives and their activity against Leishmania donovani is reported. Betulonic acid was used as a versatile intermediate. Several different fused heterocycles were introduced at the 2,3-position of the lupane skeleton including isoxazole, pyrazine, pyridine, indole and pyrazole rings. Also the 28-position was modified. Three compounds, 5, 8 and 25, showed low micromolar activity with IC50 values of 13.2, 4.3 and 7.2 μM, respectively. Compound 8 showed the best activity and selectivity, and its activity was tested on infected macrophages using a concentration, 5 μM, where no macrophage toxicity was exhibited. Interestingly, the activity of compound 8 on axenic amastigotes and Leishmania-infected macrophages was similar.
- Haavikko, Raisa,Nasereddin, Abedelmajeed,Sacerdoti-Sierra, Nina,Kopelyanskiy, Dmitry,Alakurtti, Sami,Tikka, Mari,Jaffe, Charles L.,Yli-Kauhaluoma, Jari
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supporting information
p. 445 - 451
(2014/04/17)
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- METHOD FOR PREPARATION OF BETULINIC ACID
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The present invention relates to a method for preparation of betulinic acid from betulin. The method comprises oxidizing betulin to betulinic and/or betulonic aldehyde with a ruthenium based catalyst catalyzed oxidation process in the presence of an oxidant, and further converting the betulinic and/or betulonic aldehyde to betulinic acid.
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Page/Page column 22
(2013/03/28)
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- METHOD FOR PREPARATION OF BETULINIC ACIDcla
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The invention relates a method for preparation of betulonic acid or betulinic acid from betulin wherein the method comprises a stage for oxidizing betulin to betulonic aldehyde and/or betulinic aldehyde with Pd(ll)-catalyst catalyzed oxidation process in the presence of dioxygen.
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(2013/03/28)
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- C-3 CYCLOALKENYL TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY
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Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, C-3 cycloalkenyl triterpenoids that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formulas I, II, III and IV: wherein X can be a C4-8 cycloalkyl, C4-8 cycloalkenyl, C4-9 spirocycloalkyl, C4-9 spirocycloalkenyl, C4-8 oxacycloalkyl, C4-8 dioxacycloalkyl, C6-8 oxacycloalkenyl, C6-8 dioxacycloalkenyl, C6-9 oxaspirocycloalkyl, or C6-9 oxaspirocycloalkenyl ring. These compounds are useful for the treatment of HIV and AIDS.
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Paragraph 0417-0419
(2013/08/28)
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- C-17 BICYCLIC AMINES OF TRITERPENOIDS WITH HIV MATURATION INHIBITORY ACTIVITY
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Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, C-17 bicyclic amines of triterpenoids that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formulas I, II and III: These compounds are useful for the treatment of HIV and AIDS.
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Paragraph 0378-0379
(2013/11/19)
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- Synthesis of betulonic aldehyde derivatives
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Selective functionalization of betulonic aldehyde (the oxidation product of betulin) was studied with the aim of obtaining new physiologically active substances. We developed a method for the synthesis of azomethine derivatives at the C-28 aldehyde group
- Kurbatov,Kostrub,Kurbatov
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p. 740 - 742
(2013/07/19)
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- 23-Substituted Derivatives of Lupane-type Pentacyclic Triterpenoids
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The present invention comprises small molecule inhibitors of cell proliferative conditions, in particular cancer and conditions associated with cancer. For example, associated malignancies include ovarian cancer, cervical cancer, breast cancer, colorectal cancer, and glioblastomas, among others. Accordingly, the compounds of the present invention are useful for treating, preventing, and/or inhibiting these diseases. Thus, the present invention also comprises pharmaceutical formulations comprising the compounds and methods of using the compounds and formulations to inhibit cancer and treat, prevent, or inhibit the foregoing diseases.
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Page/Page column 18-19
(2010/06/19)
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- Betulin-derived compounds as inhibitors of alphavirus replication
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This paper describes inhibition of Semliki Forest virus (SFV) replication by synthetic derivatives of naturally occurring triterpenoid betulin (1). Chemical modifications were made to OH groups at C-3 and C-28 and to the C-20-C-29 double bond. A set of heterocyclic betulin derivatives was also assayed. A free or acetylated OH group at C-3 was identified as an important structural contributor for anti-SFV activity, 3,28-di-O-acetylbetulin (4) being the most potent derivative (IC50 value 9.1 μM). Betulinic acid (13), 28-O-tetrahydropyranylbetulin (17), and a triazolidine derivative (41) were also shown to inhibit Sindbis virus, with IC50 values of 0.5, 1.9, and 6.1 μM, respectively. The latter three compounds also had significant synergistic effects against SFV when combined with 3′-amino-3′-deoxyadenosine. In contrast to previous work on other viruses, the antiviral activity of 13 was mapped to take place in virus replication phase. The efficacy was also shown to be independent of external guanosine supplementation.
- Pohjala, Leena,Alakurtti, Sami,Ahola, Tero,Yli-Kauhaluoma, Jari,Tammela, Paeivi
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supporting information; experimental part
p. 1917 - 1926
(2010/04/29)
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- Synthesis and evaluation of A-seco type triterpenoids for anti-HIV-1protease activity
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2,3-Seco-dioic acids derived from four different triterpene skeletons were prepared and evaluated for their anti-HIV-1 protease activity. Two A-seco derivatives showed potent inhibitory activity against HIV-1 protease (3c and 3e, IC50 5.7 and 3.9 μM, respectively), while four other derivatives showed moderate to weak inhibition (3a, 3b, 3d and 3f, IC50 15.7-88.1 μM). The combination of a 2,3-seco-2,3-dioic acid functional group in ring A and a free acid group at C-28 or C-30 significantly enhanced HIV-1 protease inhibitory activity (3a, 3c-3e, IC50 3.9-17.6 μM). On the other hand, all A-seco derivatives were found to be very weak inhibitors of HCV, renin and trypsin proteases (IC50 > 80 μM). These findings indicate that A-seco triterpenes with a carboxyl group at C-28 or C-30 are novel and highly selective HIV-1 protease inhibitors.
- Wei, Ying,Ma, Chao-Mei,Hattori, Masao
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experimental part
p. 4112 - 4120
(2009/12/24)
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- SYNTHESIS OF BETULONIC AND BETULINIC ALDEHYDES
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The present invention provides for methods of selectively converting betulin to betulonic aldehyde. The present invention also provides for methods of selectively converting 3-substituted triterpen-28-ols to the corresponding 3-substituted triterpen-28-carboxaldehydes. Additionally, the present invention provides for methods of preparing betulonic aldehyde, betulonic acid, betulinic acid, and corresponding 3-substituted triterpenes.
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Page/Page column 8
(2009/05/28)
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- Oxidative transformations of betulinol
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Starting from commercially available betulinol by a combination of several selective oxidation procedures betutinal, betulinic acid, betulonal as well as betulonic acid were obtained in high yields on a multi-gram scale.
- Barthel, Alexander,Stark, Sebastian,Csuk, René
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p. 9225 - 9229
(2008/12/21)
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- BETULONIC AND BETULINIC ACID DERIVATIVES
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The present invention relates to betulonic and betulinic acid derivatives and, in particular, to C-28 and C-3 derivatives. The present invention relates to betulonic acid esters, dihydro-betulonic acid esters, PAG-modified betulinic acid derivatives, and PAG-modified dihydro-betulinic acid derivatives. Betulinic acid and derivatives thereof may be bound to a poly(alkylene glycol) (PAG) such as poly(ethylene glycol). Binding may be via a linker, such as a diamine, an amino acid, a peptide, an ester or a carbonate. The compounds of the present invention may be used for the treatment of cancer or a viral infection. The present invention also provides pharmaceutical compositions comprising the compounds of the present invention. The present invention further provides processes for the preparation of the compounds of the present invention, for example, from betulin.
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Page/Page column 33-34
(2008/06/13)
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- BETULIN DERIVED COMPOUNDS USEFUL AS ANTIBACTERIAL AGENTS
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The invention relates to compouns derived from betulin, and to the use thereof as antibacterial agents in pharmaceutical and cosmetic applications.
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Page/Page column 79-80
(2008/06/13)
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- Synthetic pentacyclic triterpenoids and derivatives of betulinic acid and betulin
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The present invention comprises small molecule inhibitors of cell proliferative conditions, in particular cancer and conditions associated with cancer. For example, associated malignancies include ovarian cancer, cervical cancer, breast cancer, colorectal cancer, and glioblastomas, among others. Accordingly, the compounds of the present invention are useful for treating, preventing, and/or inhibiting these diseases. Thus, the present invention also comprising pharmaceutical formulations comprising the compounds and methods of using the compounds and formulations to inhibit cancer and treat, prevent, or inhibit the foregoing diseases.
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Page/Page column 68
(2010/11/28)
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- ANTI-HIV-1 ACTIVITY OF BETULINOL DERIVATIVES
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The present invention relates to a method of inhibiting HIV-1 activity in a cell. This method involves providing a cell infected with HIV-1 and contacting the cell with a compound of Formula (I) where R1 is -CH3, =O, -OH, -OCH3, or -OC(O)CH3, and R2 is -H, -CH3, -CHO, -CH2OH, -CH2OCH3, -CH2OC(O)CH3, -COCH3, or -COOH, or a pharmaceutically acceptable salt or derivative thereof, under conditions effective to inhibit HIV-1 activity in the cell. A method of treating HIV-1 infection in a subject is also disclosed. This method involves administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or derivative thereof, under conditions effective to treat the subject for HIV-1 infection.
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Page/Page column 21
(2008/06/13)
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- Selective oxidation of betulin for the preparation of betulinic acid, an antitumoral compound
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This paper describes a semisynthetic approach for the preparation of betulinic acid from betulin. The main step of this synthetic approach is the selective oxidation of primary alcohol function of betulin. This reaction is accomplished with chromic oxide adsorbed on silica gel to obtain betulinal in an adequate yield. Betulinal is then almost quantitatively oxidized to betulinic acid by potassium permanganate action.
- Pichette, Andre,Liu, Hongyan,Roy, Christian,Tanguay, Steve,Simard, Francois,Lavoie, Serge
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p. 3925 - 3937
(2007/10/03)
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- Synthesis of betulin derivatives and their protective effects against the cytotoxicity of cadmium
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The protecting effect of betulin against cadmium toxicity was investigated using 11 inds of analogues. It was elucidated by analyzing the analogue activities that both hydroxyl groups on C-3 and C-28 and the isopropenyl group on C-19 played important roles for expressing efficient activities. In addition, the cytotoxicity of betulin was also reduced by being functionalized using the above functional group. Copyright
- Hiroya, Kou,Takahashi, Taisuke,Miura, Nobuhiko,Naganuma, Akira,Sakamoto, Takao
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p. 3229 - 3236
(2007/10/03)
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- Differentiation- and apoptosis-inducing activities by pentacyclic triterpenes on a mouse melanoma cell line
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In a study to investigate the relationship between the chemical structure and the differentiation-inducing activity of pentacyclic triterpenes, several lupane, oleanane, and ursane triterpenes were prepared and their effects on B16 2F2 melanoma cell differentiation and growth were examined. Eleven lupane triterpenes used in this study acted on the melanoma cells as a melanogen, but no induction of melanogenesis of B16 2F2 cells by oleanane and ursane was detected. The differences at C-17 of the lupane series and acetylation of the OH group at C-3 did not markedly influence their activities. However, the ED50 value for up-regulation of melanin biosynthesis was markedly decreased by the oxidation of the OH group at C-3 of lupeol (1). Betulinic acid (11), its methyl ester (12), lup-28-al-20(29)-ene-3β-ol (9), and lup-28-al-20(29)-en-3-one (10) inhibited B16 2F2 cell proliferation by induction of apoptosis. These findings suggested that the carbonyl group at C-17 might be essential for the apoptotic effects of these compounds on B16 2F2 cells.
- Hata, Keishi,Hori, Kazuyuki,Takahashi, Saori
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p. 645 - 648
(2007/10/03)
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- Selective oxidation of betulin by Cr(VI) reagents
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Oxidation of betulin by pyridinium dichromate, pyridinium chlorochromate, and K2Cr2O7 - H2SO4 in the presence of tetrabutylammonium bromide was studied. Products of regioselective C-3, C-28-, and exha
- Komissarova,Belenkova,Spirikhin,Shitikova,Yunusov
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- Synthesis of betulinic acid derivatives with activity against human melanoma
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Betulinic acid has been modified at C-3, C-20, and C-28 positions and the toxicity of the derivatives has been evaluated against cultured human melanoma (MEL-2) and human epidermoid carcinoma of the mouth (KB) cell lines. This preliminary investigation demonstrates that simple modifications of the parent structure of betulinic acid can produce potentially important derivatives, which may be developed as antitumor drugs.
- Kim, Darrick S. H. L.,Pezzuto, John M.,Pisha, Emily
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p. 1707 - 1712
(2007/10/03)
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- Anti-AIDS agents. 34. Synthesis and structure-activity relationships of betulin derivatives as anti-HIV agents
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Succinyl and 3'-substituted glutaryl betulin derivatives showed stronger anti-HIV activity and higher therapeutic index (TI) values than their dihydrobetulin counterparts, with ratios of 1.2:1 to 15:1 (cf. 7 and 15, 9 and 17, 10 and 18, 11 and 19, and 12 and 20). For various 3'-substituted glutaryl compounds, the order of anti-HIV effects, from strong to weak inhibition, was 3',3'-dimethyl, 3'-methyl, 3'-ethyl-3'-methyl, followed by 3',3'-tetramethylene glutaryl derivatives (10 > 9 > 11 > 12, 18 > 17 > 19 > 20). The most potent compound, 10, has two 3',3'-dimethylglutaryl groups and displays significant anti-HIV potency with an EC50 value of 0.000 66 μM and a TI of 21 515. Results for compounds (22 and 23) without a C-3 acyl group confirmed the importance of the C-3 acyl group to the anti-HIV effect. With 3',3'-tetramethylene glutaryl derivatives, triacyl 29 showed stronger inhibition than diacyl 12; in contrast, 3',3'-dimethylglutaryl compounds displayed opposite results. 3-Keto compounds (35 and 36) and 2,3-dihydro compounds (39 and 40) had EC50 values in the range of 4.3-10.0 μM, suggesting that A ring modification led to decreased potency. The reduced activity of amide (33 and 34), ester (41), and oxime (42) analogues suggested that the orientation and linkage of the C-3 acyl side chain play crucial roles in the potent anti-HIV activity. Finally, replacing the C-28 acyl group with a bulky non-carboxylic group produced a less potent compound (44). In the study of mechanism of action, our results indicated that fusion is not the primary target for the anti-HIV activity of 10. It appears to inhibit HIV replication at a late stage of the viral life cycle, i.e., after viral protein synthesis.
- Sun, I.-Chen,Wang, Hui-Kang,Kashiwada, Yoshiki,Shen, Jing-Kang,Cosentino, L. Mark,Chen, Chin-Ho,Yang, Li-Ming,Lee, Kuo-Hsiung
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p. 4648 - 4657
(2007/10/03)
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