92594-07-5

Upstream product

• 473-98-3 betulin 
• 27570-20-3 betulin monoacetate 
• 1721-69-3 betulin diacetate 
• 59868-82-5 3-O-acetylbetulinic acid chloride 
• 10376-50-8 3-O-acetylbetulinic acid 
• 472-15-1 Betulinic acid 
• 1587722-29-9 3-O-allyl betulinal 
• 212708-99-1 O,O'-bis-(trimethylsilyl)-betulin 
• 1025068-55-6 (3β)-3-acetyloxy-N-methoxy-N-methyl-lup-20(29)-en-28-amide 
• 27570-21-4 3-O-acetylbetulinal 

Downstream Products

• 1025069-19-5 (3β)-3-[4-(2-phenylmethoxycarbonyl)-3,3-dimethyl-1-oxobutoxy]lup-20(29)-en-28-al 
• 545-47-1 lupenol 
• 1025068-98-7 4-fluoro-N-[[(3β)-3-hydroxylup-20(29)-en-28-yl]methyl]phenylacetamide 
• 1025069-18-4 (3β)-28-[[(phenylcarbonyl)amino]methyl]lup-20(29)-en-3-ol; hydrogen 3,3-dimethylpentanedioate 
• 1025068-79-4 [(3β)-3-[4-(phenylmethoxy)carbonyl-3,3-dimethyl-1-oxobutoxy]lup-20(29)-en-28-yl]acetic acid 
• 1025068-78-3 methyl [(3β)-3-[4-(phenylmethoxy)carbonyl-3,3-dimethyl-1-oxobutoxy]lup-20(29)-en-28-yl]acetate 
• 1025069-17-3 (3β)-28-[[(phenylcarbonyl)amino]methyl]lup-20(29)-en-3-ol; methyl 3,3-dimethylpentanedioate 
• 1025069-72-0 (3β)-28-[[[(2-(4-fluorophenyl)-1-oxo)ethyl]amino]methyl]lup-20(29)-en-3-ol; hydrogen 3,3-dimethylpentanedioate 
• 1025070-12-5 [(3β)-N-(2-hydroxy-1,1-dimethylethyl)-3-[4-(phenylmethoxy)carbonyl-3,3-dimethyl-1-oxobutoxy]lup-20(29)-en-28-yl]acetamide 
• 1025068-99-8 (3β)-28-[[[[2-(4-fluorophenyl)-1-oxo]ethyl]amino]methyl]lup-20(29)-en-3-ol; 2-trimethylsilylethyl 3,3-dimethylpentanedioate 
• 1025069-32-2 [(3β)-N-[3-(4-methyl-1-piperazinyl)propyl]-3-[4-(phenylmethoxy)carbonyl-3,3-dimethyl-1-oxobutoxy]lup-20(29)-en-28-yl]acetamide 
• 472-15-1 Betulinic acid 
• 4481-62-3 betulonic acid 
• 1228273-12-8 (R)-4-[3β-hydroxy-28-norlup-20(29)-en-17β-yl]-γ-butyrolactone 

Relevant academic research and scientific papers

Design and synthesis of novel betulin derivatives containing thio-/semicarbazone moieties as apoptotic inducers through mitochindria-related pathways

Two new series of betulin derivatives with semicarbazone (7a–g) or thiosemicarbazone (8a–g) groups at the C-28 position were synthesized. All compounds were evaluated for their in vitro cytotoxicities in human hepatocellular carcinoma cells (HepG2), human breast carcinoma cells (MCF-7), human lung carcinoma cells (A549), human colorectal cells (HCT-116) and normal human gastric epithelial cells (GES-1). Among these compounds, 8f displayed the most potent cytotoxicity with an IC50 value of 5.86 ± 0.61 μM against MCF-7 cells. Furthermore, the preliminary mechanism studies in MCF-7 cells showed that compound 8f could trigger the intracellular mitochondrial-mediated apoptosis pathway by losing MMP level, which was related with the upregulation of Bax, P53 and cytochrome c expression; the downregulation of Bcl-2 expression; activation of the expression levels of caspase-3, caspase-9, cleaved caspase-3 and cleaved caspase-9; and an increase in the amounts of intracellular reactive oxygen species. These results indicated that compound 8f may be used as a valuable skeleton structure for developing novel antitumor agents.

Electrosynthesis of Stable Betulin-Derived Nitrile Oxides and their Application in Synthesis of Cytostatic Lupane-Type Triterpenoid-Isoxazole Conjugates

Novel lupane-type triterpenoid-isoxazole conjugates were designed by direct placing of isoxazole linker at C(17) of triterpenoid. The suggested synthetic sequence demonstrates successful combination of electro-organic synthesis and conventional approaches. TEMPO-mediated electrooxidation of betulin to betulinal was developed and optimized at boron-doped diamond anodes with potassium acetate as inexpensive supporting electrolyte. Betulinal-derived oxime was further selectively electro-oxidized at a graphite anode to nitrile oxide, which proved to be stable and isolable species. The same reaction sequence was performed with 3β-lupane-3,28-diol. Nitrile oxides were characterized by 15N NMR and X-ray crystallography. The isolable nitrile oxides allowed creation of isoxazole library by 1,3-dipolar cycloaddition reactions with various alkynes. Some of the title conjugates exhibit cytostatic properties against breast cancer cell line MCF7, glioblastoma multiform cell line U-87 MG and lung carcinoma cell line A549 with growth inhibition (GI50) concentrations up to 11 μm, while being harmless to immortalized human fibroblasts hTERT (GI50 >100 μm).

TRITERPENE AMINE DERIVATIVES

The present invention concerns novel pharmaceutically active triterpene amine derivatives, pharmaceutical compositions containing the same, their use as medicaments, and the use of the compounds for the manufacture of specific medicaments. The present invention also concerns a method of treatment involving administration of the triterpene amine compounds. Specifically, the compounds are derivatives of betulinic acid having substitutions at one or more of the C-3, C-28 and C-19 positions as further described herein. The novel compounds are useful as antiretroviral agents. In particular, the novel compounds are useful for the treatment of Human Immunodeficiency Virus-1 (HIV-1).

Oxidation of a wood extractive betulin to biologically active oxo-derivatives using supported gold catalysts

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.

Preparation of Betulone Via Betulin Oxidation Over Ru Nanoparticles Deposited on Graphitic Carbon Nitride

Derivatives of betulin obtained by oxidation have broad pharmacological applications, demonstrating anti-inflammatory, antioxidant, hepatoprotective, and anticancer activity. Ru supported catalysts based on graphitic carbon nitride or N-doped carbon were prepared via a mild reduction of the initial Ru precursor with hydrazine. These catalysts along with Ru supported on carbon nanofibers and a mesoporous carbon support Sibunit were studied in catalytic oxidation of betulin. Ru/carbon nitride demonstrated catalytic activity in betulin oxidation higher than Ru/N-doped carbon (conversion of betulin up to ca. 70% and 30%, respectively). Selectivity to different oxidation products was dependent on the properties of the carbon supports.

Alkyl amine bevirimat derivatives are potent and broadly active HIV-1 maturation inhibitors

Concomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM-treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1.

Development of an azanoradamantane-type nitroxyl radical catalyst for class-selective oxidation of alcohols

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.

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

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.

Synthesis and biological activity of new homolupanes and homolupane saponins

A concise synthesis of 28a-homolupane triterpenes and the corresponding saponins containing d-mannose, d-idose, d-arabinose, and l-rhamnose moieties was elaborated. The overall synthesis of the new triterpenes involved three linear steps starting from readily available 3-O-acetyl-betulinal: elongation of the carbon chain by Wittig reaction followed by enol ether hydrolysis and reduction (or oxidation) of the elongated aldehyde. Saponins were obtained by glycosylation of triterpenes with classical Schmidt donors. Cytotoxic activities of new lupane and homolupane compounds were evaluated in vitro. Several triterpenes and the corresponding saponins exhibited an interesting cytotoxic activity profile against human cancer cell lines. Influence of the side-chain structure and substituents on the cytotoxicity of betulin and homobetulin derivatives was investigated. These results open the way to the synthesis of various lupane-type triterpene and saponin derivatives as potential anticancer compounds.

METHOD FOR PREPARATION OF BETULINIC ACID

The present invention relates to a method for preparation of betulinic acid from betulin. The method comprises oxidizing betulin to betulinic acid with a catalyst of formula (5), e.g. 2,2,6,6-tetramethylpiperidine 1 - oxyl (TEMPO), in the presence of a hypervalent iodine reagent as oxidant.