- New Class of Betulinic Acid-Based Nanoassemblies of Cabazitaxel, Podophyllotoxin, and Thiocolchicine
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Betulinic acid is validated as a new self-assembly inducer for the formation of nanoparticles (NPs) in combination with different drugs. The target compounds are characterized by the presence of anticancer drugs acting on tubulin dynamics and of a linker that could be a carbon chain or a triazole-based one. Nanoparticles formed are characterized and their biological activity is evaluated.
- Colombo, Eleonora,Polito, Laura,Biocotino, Michele,Marzullo, Paola,Hyeraci, Mariafrancesca,Via, Lisa Dalla,Passarella, Daniele
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- The potential of Cyathus africanus for transformation of terpene substrates
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The insecticidal sesquiterpenes cadina-4,10(15)-dien-3-one and aromadendr-1(10)-en-9-one were administered to the fungus Cyathus africanus ATCC 35853. Biotransformation of the former produced (4R)-9α-hydroxycadin- 10(15)-en-3-one, while the latter gave 2β-hydroxyaromadendr-1(10)-en-9-one, 2α-hydroxyaromadendr-1(10)-en-9-one and 10α-hydroxy-1β, 2β-epoxyaromadendran-9-one. The bioconversion of santonin led to the production of two analogues, 11,13-dihydroxysantonin and the hitherto unreported 8α,13-dihydroxysantonin, while cedrol yielded 3β,8β- dihydroxycedrane and 3α,8β-dihydroxycedrane. Stemod-12-ene, a diterpene, was transformed to 2-oxostemar-13-ene, a hitherto unknown analogue with a rearranged carbon framework. When methyl betulonate, a triterpenoid belonging to the lupane family, was supplied to the fungus 18α-ursane and 18α-oleanane derivatives, namely 19β-hydroxy-3-oxo-18α-oleanan- 28-oic acid and 19α-hydroxy-3-oxo-18α-ursan-28-oic acids, were generated. There are no previous reports of fungal transformation of a triterpene in which a skeletal rearrangement occurred. All substrate administration experiments were done in the presence of the terpene cyclase inhibitor chlorocholine chloride (CCC), using the single phase - pulse feed method.
- McCook, Kayanne P.,Chen, Avril R.M.,Reynolds, William F.,Reese, Paul B.
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- Synthesis of 30-amino derivatives of lupane triterpenoids
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New derivatives of betulin and betulinic acid containing various amines on C-30 that are of interest as potentially biologically active agents were prepared. 2005 Springer Science+Business Media, Inc.
- Uzenkova,Petrenko,Shakirov,Shul ts,Tolstikov
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- Novel semisynthetic derivatives of betulin and betulinic acid with cytotoxic activity
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A series of new imidazole carboxylic esters (carbamates) and N-acylimidazole derivatives of betulin and betulinic acid (14-29) have been synthesized. The new compounds were screened for in vitro cytotoxicity activity against human cancer cell lines HepG2, Jurkat and HeLa. A number of compounds have shown IC50 values lower than 2 μM against the cancer cell lines tested and the vast majority has shown a better cytotoxicity profile than betulinic acid, including the betulin derivatives. N-Acylimidazole derivatives 26 and 27 (IC50 0.8 and 1.7 μM in HepG2 cells) and the C-3 carbamate derivative 16 (IC50 2.0 μM in HepG2 cells) were the most promising compounds. Based on the observed cytotoxicity, structure-activity relationships have been established.
- Santos, Rita C.,Salvador, Jorge A.R.,Marin, Silvia,Cascante, Marta
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- Investigation of the importance of the C-2 oxygen function in the transformation of stemodin analogues by Rhizopus oryzae ATCC 11145
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A new stemodinoside, stemodin-α-L-arabinofuranoside (5), was isolated from the plant Stemodia maritima. Incubation of stemodin (2) with Rhizopus oryzae ATCC 11145 gave 2α,7β,13(S)-trihydroxystemodane (17) and 2α,3β,13(S),16α-tetrahydroxystemodane (18) whilst stemodinone (8) afforded 6α,13(S)-dihydroxystemodan-2-one (19). The bioconversion of 2β,13(S)-dihydroxystemodane (10) by the fungus yielded 2β,7β,13(S)-trihydroxystemodane (20) whereas stemod-12-en-2-one (9) provided 7β,17-dihydroxystemod-12-en-2-one (21). The results provide useful information about the relationship between the functional groups of the substrates and their potential for bioconversion.
- Martin, Glenroy D.A.,Reynolds, William F.,Reese, Paul B.
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- Influence of esterification and modification of A-ring in a group of lupane acids on their cytotoxicity
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The aim of this work was to find an optimal ester group for preparation of lupane derivatives connecting high cytotoxicity with good chemical and pharmacological properties. Activities of methyl-, pivaloyloxymethyl- (Pom-), and acetoxymethyl- (Acm-) esters were compared with the activity of free acids. Although the methyl- and Pom-esters were generally less active than free acids, some Acm-esters had cytotoxicity similar to or even better than the starting compounds. Cytotoxic activity was measured in five cancer cell lines.
- Urban, Milan,Sarek, Jan,Tislerova, Iva,Dzubak, Petr,Hajduch, Marian
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- Triterpenoids from the stem bark of Vitellaria paradoxa (Sapotaceae) and derived esters exhibit cytotoxicity against a breast cancer cell line
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A study of the chemical constituents of the stem bark of Vitellaria paradoxa (Sapotaceae) has resulted in the isolation and characterization of a new ursane-type triterpenoid, 2β,3β,19α-trihydroxyurs-12-en-28-oic acid (1), together with seven known compounds: betulinic acid (2), 1α,2β,3β,19α-tretrahydroxyurs-12-en-28-oic acid (3), β-sitosterol (7), sigmasterol (8), (-)-epicatechin (9), (+)-catechin (10) and quercetin (11). The structure of the novel, ursane-type acid 1 was elucidated on the basis of detailed spectroscopic analysis including IR, HRMS (ESI), 1D and 2D NMR and a comparison to previously described, related natural products. Preliminary cytotoxicity assays against the MDA-MB-231 breast cancer cell line indicated that betulinic acid 2 and its corresponding methyl ester 5 were the most active compounds tested with IC50 values of 19.9 μM (17.2–23.1 μM, 95% CI) and 32.9 μM (24.9–43.4 μM, 95% CI), respectively. Esterification of acids 1–3 afforded the corresponding methyl esters 4–6 for additional structure-activity relationship (SAR) analysis. In general, the activity against the MDA-MB-231 breast cancer cell line increased upon esterification of the triterpenoids screened.
- Eyong, Kenneth O.,Bairy, Guerisson,Eno, Anna A.,Taube, Joseph,Hull, Kenneth G.,Folefoc, Gabriel N.,Foyet, Harquin S.,Romo, Daniel
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- Synthesis of betulinic acid gelator and preparation method of supramolecular gel
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The invention discloses synthesis of a betulinic acid gelator and a preparation method of supramolecular gel. The betulinic acid gelator is obtained by taking a natural penta-cyclic triterpene compound betulinic acid as a raw material and introducing pyridinium groups through simple chemical modification. The invention further discloses a supramolecular gel, which is obtained by self-assembling the gelator in a mixed solvent of chloroform and benzene solvents or cyclohexane, and the microstructure of the supramolecular gel is a regular nano fiber and nano rod structure. The gelator and supramolecular gel preparation method is simple, direct, mild in conditions and easy to operate, a new thought is provided for construction of the supramolecular gel, and a new reference is provided for application of natural triterpene compounds in the field of supramolecules.
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Paragraph 0035-0038
(2020/05/05)
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- Synthesis of oxadiazole derivative of pentacyclic triterpenoid and its biological activity
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Triterpenoid betunilic acid is extracted from outer bark of Biscofia javanica blume from Darjeeling hilly region and carried out transformative reaction to introduce oxadiazole moiety to ring A of the triterpenoid which was identified as 28-carbomethoxy lupan (2,3-c)-1′,2′,5′-oxadiazole. The derivative obtained has been selected for its antibacterial and fungicidal activity at different concentrations with respect to the parent compound. The structures of these compounds were established based on spectroscopic (UV, IR, NMR) analysis.
- Rasul, Mohammed Golam
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p. 1143 - 1147
(2019/07/12)
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- Nanolipid-trehalose conjugates and nano-assemblies as putative autophagy inducers
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The disaccharide trehalose is an autophagy inducer, but its pharmacological application is severely limited by its poor pharmacokinetics properties. Thus, trehalose was coupled via suitable spacers with squalene (in 1:2 and 1:1 stoichiometry) and with betulinic acid (1:2 stoichiometry), in order to yield the corresponding nanolipid-trehalose conjugates 1-Sq-mono, 2-Sq-bis and 3-Be-mono. The conjugates were assembled to produce the corresponding nano-assemblies (NAs) Sq-NA1, Sq-NA2 and Be-NA3. The synthetic and assembly protocols are described in detail. The resulting NAs were characterized in terms of loading and structure, and tested in vitro for their capability to induce autophagy. Our results are presented and thoroughly commented upon.
- Colombo, Eleonora,Biocotino, Michele,Frapporti, Giulia,Randazzo, Pietro,Christodoulou, Michael S.,Piccoli, Giovanni,Polito, Laura,Seneci, Pierfausto,Passarella, Daniele
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- Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis
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Triterpenoic acids, ursolic acid (1), oleanolic acid (2), glycyrrhetinic acid (3) and betulinic acid (4) were converted into their corresponding methyl 5–8 and benzyl esters 9–12 or benzyl amides 21–24. These derivatives served as starting materials for the synthesis of pink colored rhodamine B derivatives 25–36 which were screened for cytotoxicity in colorimetric SRB assays. All of the compounds were cytotoxic for a variety of human tumor cell lines. The activity of the benzyl ester derivatives 29–32 was lower than the cytotoxicity of the methyl esters 25–28. The benzyl amides 33–36 were the most cytotoxic compounds of this series. The most potential compound was a glycyrrhetinic acid rhodamine B benzyl amide 35. This compound showed activity against the different cancer cell lines in a two-digit to low three-digit nano-molar range. Staining experiments combined with fluorescence microscopy showed that this compound triggered apoptosis in A2780 ovarian carcinoma cells and acted as a mitocan.
- Wolfram, Ratna Kancana,Heller, Lucie,Csuk, René
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supporting information
p. 21 - 30
(2018/04/26)
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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 and cytotoxic activity of triterpenoid thiazoles derived from allobetulin, methyl betulonate, methyl oleanonate, and oleanonic acid
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A total of 41 new triterpenoids were prepared from allobetulone, methyl betulonate, methyl oleanonate, and oleanonic acid to study their influence on cancer cells. Each 3-oxotriterpene was brominated at C2 and substituted with thiocyanate; subsequent cyclization with the appropriate ammonium salts gave N-substituted thiazoles. All compounds were tested for their in vitro cytotoxic activity on eight cancer cell lines and two non-cancer fibroblasts. 2-Bromoallobetulone (2b) methyl 2-bromobetulonate (3b), 2-bromooleanonic acid (5b), and 2- thiocyanooleanonic acid (5c) were best, with IC50 values less than 10 mm against CCRF-CEM cells (e.g., 3b: IC50=2.9 μm) as well as 2'-(diethylamino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5 f, IC50=9.7 μm) and 2'-(N-methylpiperazino)olean-12(13)-eno[2,3-d]thiazole-28-oic acid (5k, IC50=11.4 μm). Compound 5c leads to the accumulation of cells in the G2 phase of the cell cycle and inhibits RNA and DNA synthesis significantly at 1xIC50. The G2/M cell-cycle arrest probably corresponds to the inhibition of DNA/RNA synthesis, similar to the mechanism of action of actinomycin D. Compound 5c is new, active, and nontoxic; it is therefore the most promising compound in this series for future drug development. Methyl 2-bromobetulonate (3b) and methyl 2-thiocyanometulonate (3c) were found to inhibit nucleic acid synthesis only at 5xIC50. We assume that in 3b and 3c (unlike in 5c), DNA/RNA inhibition is a nonspecific event, and an unknown primary cytotoxic target is activated at 1xIC50 or lower concentration.
- Borkova, Lucie,Adamek, Richard,Kalina, Petr,Dra?ar, Pavel,Dzubak, Petr,Gurska, Sona,Rehulka, Jiri,Hajduch, Marian,Urban, Milan,Sarek, Jan
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supporting information
p. 390 - 398
(2017/12/07)
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- Saponin of which monosaccharide units are D-mannose, as well as preparation method and application of saponin in pharmacy
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The invention belongs to the technical field of medicines, provides saponin of which monosaccharide units are D-mannose, as well as a preparation method and application of the saponin in pharmacy, and particularly relates to oleanolic acid saponin and betulinic acid saponin, of which the monosaccharide units are the D-mannose, a preparation method of the oleanolic acid saponin and the betulinic acid saponin, and the application of the oleanolic acid saponin and the betulinic acid saponin in preparation of anti-influenza medicines. According to the saponin disclosed by the invention, natural products including oleanolic acid and betulinic acid are used as raw materials, firstly ester groups are introduced at a C-28 position through structural modification, and then D-mannose in alpha-configuration is introduced at a C-3 position so that the saponin of which the monosaccharide units are the D-mannose and which can restrain highly pathogenic influenza virus H5N1 from infecting host cells is obtained. According to the saponin disclosed by the invention, pharmacological experiments are performed, results indicate that saponin compounds have an obvious effect of restraining the process that the highly pathogenic influenza virus H5N1 invades the host cells, and can be further used for preparing medicines for preventing or treating influenza viruses, and preparing medicines in united use with other antivirus medicines and medical compositions comprising the saponin.
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Paragraph 0034; 0035; 0036
(2016/11/17)
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- Sulfamates of methyl triterpenoates are effective and competitive inhibitors of carbonic anhydrase II
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Carbonic anhydrase II, belonging to one of the most important enzyme groups of the human body, is a well-studied isozyme from the family of the carbonic anhydrases. Since it is involved in several physiological processes, it has been a pharmaceutical target for many years. In this study we synthesized a number of sulfamates derived from pentacyclic methyl triterpenoates, and we demonstrate their potential as carbonic anhydrase II inhibitors using the well-established photometric 4-nitrophenyl acetate assay. Inhibition constants, as an indicator of their inhibition strength, were in the micromolar range; one compound (10, methyl (3β) 3-(aminosulfonyloxy)-oleanoate) showed a Ki value as low as 0.3 μM. This Ki value is comparable to that of acetazolamide which is a potent carbonic anhydrase inhibitor and a drug for the treatment of glaucoma.
- Schwarz, Stefan,Sommerwerk, Sven,Lucas, Susana D.,Heller, Lucie,Csuk, René
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- Preparation of betulinic acid derivatives by chemical and biotransformation methods and determination of cytotoxicity against selected cancer cell lines
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Several novel 2,4-dinitrophenylhydrazone betulinic acid derivatives have been prepared by chemical and biotransformation methods using fungi and carrot cells. Some compounds showed significant cytotoxicity and selectivity against some tumor cell lines. The most active, 3-[(2,4-dinitrophenyl)hydrazono]lup- (20R)-29-oxolupan-28-oic acid, showed IC50 values between 1.76 and 2.51 μM against five human cancer cell lines. The most selective, 3-hydroxy-20-[(2,4-dinitrophenyl)hydrazono]-29-norlupan-28-oic acid, was five to seven times more selective for cancer cells when compared to fibroblasts. Cell cycle analysis and apoptosis induction were studied for the most active derivatives.
- Baratto, Leopoldo C.,Porsani, Mariana V.,Pimentel, Ida C.,Pereira Netto, Adaucto B.,Paschke, Reinhard,Oliveira, Brás H.
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p. 121 - 131
(2013/10/01)
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- Synthesis of bioactive 28-hydroxy-3-oxolup-20(29)-en-30-al with antileukemic activity
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An easy and efficient route to partial synthesis of bioactive 28-hydroxy-3-oxolup-20(29)-en-30-al (1), starting from betulinic acid (2), has been developed (eight steps, 44% overall yield). Structures of all the compounds were determined by spectral studies (IR, 1H, 13C NMR, MS, NOESY, COSY, etc.). Compound 1 and the precursors (2, 3, 5, and 7) showed antiproliferative activities against human K562 leukemia, murine WEHI3 leukemia, and murine MEL erythroid progenitor.
- Ghosh, Pranab,Mandal, Amitava,Ghosh, Joydip,Pal, Chiranjib,Nanda, Ashis Kumar
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experimental part
p. 141 - 153
(2012/05/05)
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- MODIFIED C-3 BETULINIC ACID DERIVATIVES AS HIV MATURATION INHIBITORS
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Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, modified C-3 betulinic acid and other structurally related natural products derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors. These compounds are useful for the treatment of HIV and AIDS.
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Page/Page column 53; 54
(2011/12/14)
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- Carbamate derivatives of betulinic acid and betulin with selective cytotoxic activity
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Synthesis and antiproliferative activity of eight new derivatives of betulinic acid (1) and betulin (2) are described. The compounds were tested against fifteen tumor cell lines. The toxicity against normal human fibroblasts and the mode of cell death on lung cancer cell line induced by the most active compounds 9 (bis(ethylcarbamate)betulin) and 11 (3-O-ethylcarbamate of 28-O-acetylbetulin) was investigated. Caspase 3 activity on lung cancer cell line (A549) was determined for 1, 5 (3-O-ethylcarbamate of betulinic acid), 9 and 11. All derivatives exerted a dose dependent antiproliferative action at micromolar concentrations toward target tumor cell lines. Treatment of lung cancer cells for 24 h with 9 and 11 induced apoptosis, as observed by the appearance of a typical ladder pattern in the DNA fragmentation assay.
- Kommera, Harish,Kaluderovi?, Goran N.,Dittrich, Sebastian,Kalbitz, Jutta,Dr?ger, Birgit,Mueller, Thomas,Paschke, Reinhard
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scheme or table
p. 3409 - 3412
(2010/08/20)
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- Synthesis and anticancer activity of novel betulinic acid and betulin derivatives
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A series of novel betulinic acid derivatives 3-11 and betulin derivatives 12-17 were synthesized. The compounds were characterized by the means of 1H- and 13C-NMR spectroscopy as well as mass spectrometry. The compounds have been tested on ten tumor cell lines of different histogenic origin. The most active derivatives, containing a chloroacetyl group on C-3 in betulinic acid 9 and C-28 in betulin 15, were up to ten times more cytotoxic and many fold more selective towards tumor cells in comparison to normal cells (fibroblasts) than betulinic acid. Furthermore, compound 15 was found to possess cell growth inhibition even when treated for a short time on anaplastic thyroid cancer cells (SW1736).
- Kommera, Harish,Kaluderovic, Goran N.,Kalbitz, Jutta,Paschke, Reinhard
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scheme or table
p. 449 - 457
(2011/04/16)
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- Antiprotozoal activity of Betulinic acid derivatives
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Betulinic acid (1), isolated from the crude extract of the leaves of Pentalinon andrieuxii (Apocynaceae), together with betulinic acid acetate (2), betulonic acid (3), betulinic acid methyl ester (4), and betulin (5) were evaluated for their antiprotozoal activity. The results showed that modifying the C-3 position increases leishmanicidal activity while modification of the C-3 and C-28 positions decreases trypanocidal activity.
- Domínguez-Carmona,Escalante-Erosa,García-Sosa,Ruiz-Pinell,Gutierrez-Yapu,Chan-Bacab,Giménez-Turba,Pe?a-Rodríguez
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experimental part
p. 379 - 382
(2011/06/10)
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- Synthesis and structure-activity relationship study of novel cytotoxic carbamate and N-acylheterocyclic bearing derivatives of betulin and betulinic acid
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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).
- Santos, Rita C.,Salvador, Jorge A.R.,Marin, Silvia,Cascante, Marta,Moreira, Joao N.,Dinis, Teresa C.P.
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scheme or table
p. 4385 - 4396
(2010/09/12)
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- Structure - Activity relationship study of betulinic acid, a novel and selective TGR5 agonist, and its synthetic derivatives: Potential impact in diabetes
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We describe here the biological screening of a collection of natural occurring triterpenoids against the G protein-coupled receptor TGR5, known to be activated by bile acids and which mediates some important cell functions. This work revealed that betulinic (1), oleanolic (2), and ursolic acid (3) exhibited TGR5 agonist activity in a selective manner compared to bile acids, which also activated FXR, the nuclear bile acid receptor. The most potent natural triterpenoid betulinic acid was chosen as a reference compound for an SAR study. Hemisyntheses were performed on the betulinic acid scaffold, and we focused on structural modifications of the C-3 alcohol, the C-17 carboxylic acid, and the C-20 alkene. In particular, structural variations around the C-3 position gave rise to major improvements of potency exemplified with derivatives 18 dia 2 (RG-239) and 19 dia 2. The best derivative was tested in vitro and in vivo, and its biological profile is discussed.
- Genet, Cédric,Strehle, Axelle,Schmidt, Céline,Boudjelal, Geoffrey,Lobstein, Annelise,Schoonjans, Kristina,Souchet, Michel,Auwerx, Johan,Saladin, Régis,Wagner, Alain
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supporting information; experimental part
p. 178 - 190
(2010/04/30)
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- TRITERPENOID DERIVATIVES USEFUL AS ANTIPROLIFERATIVE AGENTS
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Formula (I) and (II). The present invention relates to the use of a new lupane derivative of general formula (I) or (II), or a pharmaceutically acceptable salt, crystal form, complex, hydrate, or hydrolysable ester thereof, for preventing and/or inhibiting tumor growth and for treating cancer and other proliferative diseases, more particularly for treating leukemia, liver, cervical, colon and prostate cancer. The present invention also relates to the synthesis of these compounds and to pharmaceutical compositions which contain them.
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Page/Page column 30
(2010/12/18)
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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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- TRITERPENES DERIVATIVES AND USES THEREOF AS ANTITUMOR AGENTS OR ANTI-INFLAMMATORY AGENTS
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A compound of formula (1): wherein R1 is selected from the group consisting of H, α-L-Rhamnopyranose, α-D-Mannopyranose, β-D-Xylopyranose, β-D-Glucopyranose, and α-D-Arabinopyranose; R2 is selected from CH3, COOH, CH2OH, COOCH3 and CH2O-α-D-Arabinopyranose; with the proviso that the compound of formula (I) is not a compound of formula (I) wherein R1 is β-D-Glucopyranose and R2 is COOH; wherein R1 is α-L-Rhamnopyranose and R2 is CH3; wherein R1 is β-D-Glucopyranose and R2 is CH2OH; wherein R1 is β-D-Xylopyranose and R2 is CH2OH; wherein R1 is α-L-Rhamnopyranose and R2 is COOCH3, wherein R1 is H and R2 is CH3; wherein R1 is H and R2 is CH2OH; wherein R1 is H and R2 is COOH; or wherein R1 is H and R2 is COOCH3, or a pharmaceutically acceptable salt thereof.
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Page/Page column 5-6
(2008/12/06)
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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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- Chemical phenotypes of the hmg1 and hmg2 mutants of Arabidopsis demonstrate the in-planta role of HMG-CoA reductase in triterpene biosynthesis
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Plants produce a wide variety of cyclic triterpenes, such as sterols and triterpenoids, which are the major products of the mevalonate (MVA) pathway. It is important to understand the physiological functions of HMG-CoA reductase (HMGR) because HMGR is the rate-limiting enzyme in the MVA pathway. We have previously isolated Arabidopsis mutants in HMG1 and HMG2. Although the biochemical function of HMGR2 has been thought to be almost equal to that of HMGR1, based on similarities in their sequences, the phenotypes of mutants in these genes are quite different. Whereas hmg2 shows no abnormal phenotype under normal growth conditions, hmg1 shows pleiotropic phenotypes, including dwarfing, early senescence, and male sterility. We previously postulated that the 50% decrease in the sterol content of hmg1, as compared to that in the wild type, was a cause of these phenotypes,1) but comprehensive triterpene profiles of these mutants had not yet been determined. Here, we present the triterpene profiles of hmg1 and hmg2. In contrast to hmg1, hmg2 showed a sterol content 15% lower than that of the wild type. A precise triterpenoid quantification using synthesized deuterated compounds of β-amyrin (1), α-amyrin (2), and lupeol (3) showed that the levels of triterpenoids in hmg1 and hmg2 were 65% and 25% lower than in the wild type (WT), respectively. These results demonstrate that HMGR2 as well as HMGR1 is responsible for the biosynthesis of triterpenes in spite of the lack of visible phenotypes in hmg2.
- Ohyama, Kiyoshi,Suzuki, Masashi,Masuda, Kazuo,Yoshida, Shigeo,Muranaka, Toshiya
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p. 1518 - 1521
(2008/12/23)
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- Design, synthesis, and anti-inflammatory activity both in vitro and in vivo of new betulinic acid analogues having an enone functionality in ring A
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Fifteen new betulinic acid analogues were designed, synthesized, and tested for anti-inflammatory activity. Many of these analogues effectively suppress nitric oxide (NO) production in RAW cells stimulated with interferon-γ. Analogue 10 is highly and orally active in vivo for induction of the anti-inflammatory and cytoprotective enzyme, heme oxygenase-1.
- Honda, Tadashi,Liby, Karen T.,Su, Xiaobo,Sundararajan, Chitra,Honda, Yukiko,Suh, Nanjoo,Risingsong, Renee,Williams, Charlotte R.,Royce, Darlene B.,Sporn, Michael B.,Gribble, Gordon W.
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p. 6306 - 6309
(2007/10/03)
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- Glycosidation of lupane-type triterpenoids as potent in vitro cytotoxic agents
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The weak hydrosolubility of betulinic acid (3) hampers the clinical development of this natural anticancer agent. In order to circumvent this problem and to enhance the pharmacological properties of betulinic acid (3) and the lupane-type triterpenes lupeol (1), betulin (2), and methyl betulinate (7), glycosides (β-d-glucosides, α-l-rhamnosides, and α-d-arabinosides) were synthesized and in vitro tested for cytotoxicity against three cancerous (A-549, DLD-1, and B16-F1) and one healthy (WS1) cell lines. The addition of a sugar moiety at the C-3 or C-28 position of betulin (2) resulted in a loss of cytotoxicity. In contrast, the 3-O-β-d-glucosidation of lupeol (1) improved the activity by 7- to 12-fold (IC50 14-15.0 μM). Moreover, the results showed that cancer cell lines are 8- to 12-fold more sensitive to the 3-O-α-l-rhamnopyranoside derivative of betulinic acid (IC50 2.6-3.9 μM, 22) than the healthy cells (IC50 31 μM). Thus, this study indicates that 3-O-glycosides of lupane-type triterpenoids represent an interesting class of potent in vitro cytotoxic agents.
- Gauthier, Charles,Legault, Jean,Lebrun, Maxime,Dufour, Philippe,Pichette, Andre
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p. 6713 - 6725
(2007/10/03)
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- Synthesis of A-seco derivatives of betulinic acid with cytotoxic activity
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In this study, the relationships between the chemical structure and cytotoxic activity of betulinic acid (1) derivatives were investigated. Eight lupane derivatives (1-8), one of them new (6), five diosphenols (9-13), four of them new (10-13), two new norderivatives (14 and 15), five seco derivatives (16-20), four of them new (16, 17, 19, and 20), and three new seco-anhydrides (21-23) were synthesized from 1, and their activities were compared with the activities of known compounds. The effects of substitution on the A-ring and esterification of the carboxyl group in position 28 on cytotoxicity were of special interest. Significant cytotoxic activity against the T-lymphoblastic leukemia cell line CEM was found in diosphenols 9 and 13 (TCS50 4 and 5 μmol/L) and seco-anhydrides 22 and 23 (TCS50 7 and 6 μmol/L). All compounds were also tested on cancer cell lines HT 29, K562, K562 Tax, and PC-3, and these confirmed activity of diosphenols 9, 10, and 11 and anhydride 22. Diosphenols, as the most promising group of derivatives, were further tested on four more lines (A 549, DU 145, MCF 7, SK-Mel2).
- Urban, Milan,Sarek, Jan,Klinot, Jiri,Korinkova, Gabriela,Hajduch, Marian
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p. 1100 - 1105
(2007/10/03)
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- Erythrocyte membrane modifying agents and the inhibition of Plasmodium falciparum growth: Structure-activity relationships for betulinic acid analogues
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The natural triterpene betulinic acid and its analogues (betulinic aldehyde, lupeol, betulin, methyl betulinate and betulinic acid amide) caused concentration-dependent alterations of erythrocyte membrane shape towards stomatocytes or echinocytes according to their hydrogen bonding properties. Thus, the analogues with a functional group having a capacity of donating a hydrogen bond (COOH, CH2OH, CONH2) caused formation of echinocytes, whereas those lacking this ability (CH3, CHO, COOCH 3) induced formation of stomatocytes. Both kinds of erythrocyte alterations were prohibitive with respect to Plasmodium falciparum invasion and growth; all compounds were inhibitory with IC50 values in the range 7-28 μM, and the growth inhibition correlated well with the extent of membrane curvature changes assessed by transmission electron microscopy. Erythrocytes pre-loaded with betulinic acid or its analogues and extensively washed in order to remove excess of the chemicals could not serve as hosts for P. falciparum parasites. Betulinic acid and congeners can be responsible for in vitro antiplasmodial activity of plant extracts, as shown for Zataria multiflora Boiss. (Labiatae) and Zizyphus vulgaris Lam. (Rhamnaceae). The activity is evidently due to the incorporation of the compounds into the lipid bilayer of erythrocytes, and may be caused by modifications of cholesterol-rich membrane rafts, recently shown to play an important role in parasite vacuolization. The established link between erythrocyte membrane modifications and antiplasmodial activity may provide a novel target for potential antimalarial drugs.
- Ziegler, Hanne L.,Franzyk, Henrik,Sairafianpour, Majid,Tabatabai, Mehrnoush,Tehrani, Mahboubeh D.,Bagherzadeh, Karim,Haegerstrand, Henry,Staerk, Dan,Jaroszewski, Jerzy W.
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p. 119 - 127
(2007/10/03)
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- Terpenoid constituents from some indigenous plants
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Isolation of lupeol acetate, stigmasterol, β-sitosterol, betulin, β-amyrin, lupeol, oleanolic acid from aerial parts and stigmasterol, β-sitosterol, β-amyrin, oleanolic acid from flowers of Pyrostegia venusta; β-sitosterol, friedelin, friedel-1-en-3-one, lupeol from heartwood of Salmalia malabarica; β-sitosterol, β-amyrin, epifriedelinol, oleanolic acid from heartwood of Vitex negundo and stigmasterol β-sitosterol, friedelin, betulinic acid from heartwood of Punica granatum have been reported.
- Krishna, Vivek,Sharma, Sneh,Pareek,Singh, Pahup
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p. 550 - 552
(2007/10/03)
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- Triterpenoids and other compounds from Salvia roborowskii Maxim
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Two new triterpenoids, 2α-hydroxy-3β-methoxyurs-12-en-28-oic acid and 3α-hydroxy-2α-methoxyurs-12-en-28-oic acid as well as 25 known compounds were isolated from the whole plant of Salvia roborowskii Maxim. Their structures were elucidated by means of spectral data and chemical transformation. This is the first report on the chemical constituents of this plant. The presence of eugenyl β-D-glucopyranoside 22 in a plant of the genus Salvia is also reported for the first time.
- Wang,Li,Li,Li
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p. 420 - 422
(2007/10/03)
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- Inhibitory effects of constituents from Cynomorium songaricum and related triterpene derivatives on HIV-1 protease
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From CH2Cl2 and MeOH extracts of the stems of Cynomorium songaricum RUPR. (Cynomoriaceae), ursolic acid and its hydrogen malonate were isolated as inhibitors of human immunodeficiency virus type 1 (HIV-1) protease, with 50% inhibitory concentrations (IC50) of 8 and 6 μM, respectively. Amongst various synthesized dicarboxylic acid hemiesters of related triterpenes, inhibitory activity tended to increase in the order of oxalyl, malonyl, succinyl and glutaryl hemiesters, for triterpenes such as ursolic acid, oleanolic acid and betulinic acid. The most potent inhibition was observed for the glutaryl hemiesters, with an IC50 of 4 μM. From the water extract of the stems of C. songaricum, flavan-3-ol polymers, consisting of epicatechin as their extender flavan units, were also found to be potent inhibitory principles against HIV-1 protease.
- Ma, Chaomei,Nakamura, Norio,Miyashiro, Hirotsugu,Hattori, Masao,Shimotohno, Kunitada
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p. 141 - 145
(2007/10/03)
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- Tobacco Caterpillar Antifeedent from the Gotti Stem Wood Triterpene Betulinic Acid
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Betulinic acid (I), a pentacyclic triterpene, on derivatization gives six compounds: 3β-hydroxylup-20(29)-en-28 oic acid methyl ester (II), 3β-acetoxylup-20(29)-en-28-oic acid (III), 3β-allyloxylup-20(29)-en-28-oic acid (IV), 3β-p-methylcinnamatoxylup-20(29)-en-28-oic acid (V), 3β-p-methoxycinnamatoxylup-20(29)-en-28-oic acid (VI), and 3β-tri-O-methylgallotoxylup-20(29)-en-28-oic acid (VII). Their antifeedent activity against the agricultural pest tobacco caterpillar larvae (Spodoptera litura F) in a no-choice laboratory study showed the active compounds are V, VI, and VII.
- Jagadeesh,Krupadanam, G. L. David,Srimannarayana,Murthy, S. Samba,Kaur, Amarjit,Raja
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p. 2797 - 2799
(2007/10/03)
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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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- Reactions on naturally occurring triterpene: Part 1
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From Diospyros peregrina G. stem bark betulinic acid, betulin, lupeol and β-sitosterol have been isolated.The major constituent betulinic acid has been subjected to hydroboration with diborane and the resultant alkyl borane oxidized successively with alkaline hydrogen peroxide, pyridinium dichromate and Jones'reagent.Other oxidative reactions of betulinic acid with selenium dioxide, lead tetraacetate and m-chloroperbenzoic acid have also been studied.All the reaction products have been characterized by spectroscopic studies.
- Dinda, B.,Hajra, A. K.,Das, S. K.,Chel, G.,Chakraborty, R.,Ranu, B. C.
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p. 624 - 628
(2007/10/03)
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- ORGANIC PHOTOCHEMISTRY- PART II, PHOTOCHEMICAL SYNTHESIS OF THE NATURALLY OCCURING TRITERPENE LACTONE, 3β-HYDROXY LUPAN-28,13β-OLIDE
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The photochemical synthesis of the title lactone was achieved by irradiation in the presence of Pb(IV) acetate alone or Pb(IV) acetate + calcium carbonate + iodine or mercuric oxide + iodine.Chiroptical measurements (CD) of this and other related lactones provided convincing evidence in support of the lactone ring structure.
- Nag, Swapan K.,Bose, Samarendra N.
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p. 2855 - 2856
(2007/10/02)
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- BIARYLHEPTANOIDS AND OTHER CONSTITUENTS FROM WOOD OF ALNUS JAPONICA
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The wood of Alnus japonica has been shown to contain a number of biarylheptanoids as well as other phenolics, including secoisolariciresinol diferulate.The co-occurence of cyclized biarylheptanoids with their corresponding acyclic biarylheptanoids has been demonstrated and this fact may have biosynthetic significance.The possible chemotaxonomic importance of biarylheptanoids in members of the Betulaceae is discussed.The isolation and identification of several steroids and triterpenoids are also described.Key Word Index- Alnus japonica; Betulaceae; new biarylheptanoids; biosynthesis; chemotaxonomy; secoisolariciresinol diferulate; steroids; oleanan triterpenoids.
- Nomura, Masayasu,Tokoroyama, Takashi,Kubota, Takashi
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p. 1097 - 1104
(2007/10/02)
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- PAVOPHYLLINE, A NEW SAPONIN FROM THE STEM OF PAVONIA ZEYLANICA
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Key Word Index - Pavona zeylanica; Malvaceae; pavophylline; lup-20(29)-en-28-oic-3-O-β-D-glucopyranosyl(4-->1)-O-α-L-rhamnopyranosyl(2-->1)-O-α-L-arabino furanoside.
- Tiwari, K. P.,Minocha, P. K.
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p. 701 - 704
(2007/10/02)
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