10376-50-8Relevant articles and documents
Homopiperazine-rhodamine B adducts of triterpenoic acids are strong mitocans
Wolfram, Ratna Kancana,Fischer, Lucie,Kluge, Ralph,Str?hl, Dieter,Al-Harrasi, Ahmed,Csuk, René
, p. 869 - 879 (2018)
Parent pentacyclic triterpenoic acids such as ursolic-, oleanolic, glycyrrhetinic, betulinic and boswellic acid were converted into their acetylated piperazinyl amides that were coupled with rhodamine B. SRB assays to evaluate their cytotoxicity showed all of these triterpene-homopiperazinyl-rhodamine adducts 16–20 being highly cytotoxic for a panel of human tumor cell lines even in nanomolar concentrations while being significantly less cytotoxic for non-malignant cells. Interestingly enough, these compounds were even more cytotoxic than previously prepared piperazinyl analogs, thus making the homopiperazinyl spacer a very interesting scaffold for the development of biologically active compounds. Extra staining experiments showed that the cytostatic effect of compounds 18 and 20 onto A2780 cancer cells is due to their ability to act as a mitocan.
Pakrashi et al.
, p. 461,466 (1968)
Synthesis of three triterpene series and their activity against respiratory syncytial virus
Santos da Silva, Gloria N.,Monti Atik, Diana,Antunes Fernandes, Jheini L.,de Freitas do Nascimento, Deise,Fazolo, Tiago,Duarte de Souza, Ana Paula,Baggio Gnoatto, Simone C.
, (2018)
The human respiratory syncytial virus (hRSV) is a leading cause of hospitalization due to acute lower respiratory infection especially in infants and young children, sometimes causing fatal cases. The monoclonal antibody palivizumab is one of the available options for preventing this virus, and at the moment there are several hRSV vaccine trials underway. Unfortunately, the only drug option to treat hRSV infection is ribavirin, which can be used in severe high-risk cases. For this reason, new medicines are needed and, in this context, the triterpenes and their derivatives are promising alternatives, since many of them have shown important antiviral activity, such as bevirimat. Therefore, we report three series of triterpene (betulin (BE), betulinic acid (BA), and ursolic acid (UA)) derivatives tested against hRSV. The derivatives were synthesized by using commercial anhydrides in an easy and inexpensive step reaction. For the antiviral assay, A549 cells were infected by hRSV and after 96 h of compound or ribavirin (positive control) treatment, the cell viability was tested by MTT assay. DMSO, non-infected cells and infected cells without treatment were used as negative control. The triterpene esterification at the hydroxyl group resulted in 17 derivatives. The 3,28-di-O-acetylbetulin derivative (1a) showed the best results for cell viability, and real-time PCR amplification was performed for 1a treatment. Remarkably, one new anti-hRSV prototype was obtained through an easy synthesis of BE, which shall represent an alternative for a new lead compound for anti-hRSV therapy.
Hargreaves et al.
, p. 331 (1968)
Tobacco Caterpillar Antifeedent from the Gotti Stem Wood Triterpene Betulinic Acid
Jagadeesh,Krupadanam, G. L. David,Srimannarayana,Murthy, S. Samba,Kaur, Amarjit,Raja
, p. 2797 - 2799 (1998)
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.
Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site
Coric, Pascale,Turcaud, Serge,Souquet, Florence,Briant, Laurence,Gay, Bernard,Royer, Jacques,Chazal, Nathalie,Bouaziz, Serge
, p. 453 - 465 (2013)
Bevirimat (2), the first-in-class HIV-1 maturation inhibitor, shows a low efficacy due essentially to the natural polymorphism of its target, the CA-SP1 junction. Moreover, its low hydrosolubility makes it difficult to study its interaction with the CA-SP1 junction. We have synthesized new derivatives of bevirimat by adding different hydrophilic substituents at the C-28 position to improve their hydrosolubility and perform the structural study of a complex by NMR. Synthesis of the new derivatives, the effect of substituents at the C-28 position and their hydrosolubility are discussed. The ability of these molecules to inhibit viral infection and their cytotoxicity is assessed. Compared to the well-known bevirimat (2), one of our compounds (16) shows a higher hydrosolubility associated with a 2.5 fold increase in activity, a higher selectivity index and a better antiviral profile. Moreover, for the first time a direct interaction between a derivative of bevirimat (16) and the domain CA-SP1-NC is shown by NMR. Information from this study should allow us to decipher the mechanism by which bevirimat inhibits HIV-1 maturation and how the natural polymorphism of the spacer peptide SP1 triggers resistance to inhibitors.
Ficusanolide A and ficusanolide B, two new cinnamic acid derivative stereoisomers and other constituents of the stem barks of Ficus exasperata Vahl. (Moraceae)
Popwo Tameye, Stevine Claudiale,Djamen Mbeunkeu, Ahri Bernie,Fouokeng, Yannick,Jouwa Tameye, Nathalie Samantha,Tabekoueng, Georges Bellier,Wansi, Jean Duplex,Sewald, Norbert,Ndom, Jean Claude,Azebaze, Anatole Guy Blaise
, p. 150 - 153 (2021)
Phytochemical investigation of the stem barks of Ficus exasperata Vahl. (Moraceae) led to the isolation of two new cinnamic acid derivatives stereoisomers, named ficusanolide A (1) and ficusanolide B (2) along with twelve known compounds: ficusanol (3), umbelliferone-6-carboxylic acid (4), oxypeucedanin hydrate (5), marmesin (6), decursinol (7), β-amyrin acetate (8), lupeol (9), betulinic acid (10), ursolic acid (11), a mixture of stigmasterol (12) and β-sitosterol (13), sitosteryl-3-O-β-D-glucopyranoside (14); and one hemisynthetic derivative: per acetylated betulinic acid (15). Their structures were established by the means of their physical data (melting point, rotatory power), their spectroscopic data, particularly IR, NMR (1H, 13C, DEPT, COSY, HSQC and HMBC) data, and HR-ESIMS data. Crude extract, compounds 1, 2, 3, 5, 6, 7, 9, 10, 11, as well as the semisynthetic derivative 15 were evaluated for their cytotoxic activity on the human cervix carcinoma cell line KB-3?1 and the human colon cancer cell line HT-29. Ursolic acid 11 showed a moderate activity on both cancer cells tested with IC50s of 50.9 μM and 34.4 μM respectively.
Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis
Wolfram, Ratna Kancana,Heller, Lucie,Csuk, René
, p. 21 - 30 (2018)
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.
Design, Synthesis, and Cytotoxicity of Semisynthetic Betulinic Acid-1,2,4-Oxadiazole Amide Derivatives
Krishna,Bhargavi,Krupadanam
, p. 312 - 318 (2018)
Biological activity of betulinic acid derivatives containing a 1,2,4-oxadiazole ring prompted us to synthesize betulinic acid-1,2,4-oxadiazole amide derivatives 14–25 starting with the amide coupling reaction of betulinic acid 1 and (3-aryl-1,2,4-oxadiazol-5-yl)methanamines 2–13. The products were tested for cytotoxicity on three human cancer cell lines in vitro. All tested compounds demonstrated high activity. The structures of the synthesized compounds were elucidated from IR, NMR and mass spectra.
Triterpene-based carboxamides act as good inhibitors of butyrylcholinesterase
Loesche, Anne,Kahnt, Michael,Serbian, Immo,Brandt, Wolfgang,Csuk, René
, (2019)
A set of overall 40 carboxamides was prepared from five different natural occurring triterpenoids including oleanolic, ursolic, maslinic, betulinic, and platanic acid. All of which were derived from ethylene diamine holding an additional substituent connected to the ethylene diamine group. These derivatives were evaluated regarding their inhibitory activity of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) employing Ellman’s assay. We further determined the type of inhibition and inhibition constants. Carboxamides derived from platanic acid have been shown to be potent and selective BChE inhibitors. Especially the mixed-type inhibitor (3β)-N-(2-pyrrolidin-1-ylethyl)-3-acetyloxy-20-oxo-30-norlupan-28-amide (35) showed a remarkably low Ki of 0.07 ± 0.01 μM (Ki0 = 2.38 ± 0.48 μM) for the inhibition of BChE.
Antiprotozoal activity of Betulinic acid derivatives
Domínguez-Carmona,Escalante-Erosa,García-Sosa,Ruiz-Pinell,Gutierrez-Yapu,Chan-Bacab,Giménez-Turba,Pe?a-Rodríguez
, p. 379 - 382 (2010)
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.
Development of C-20 modified betulinic acid derivatives as antitumor agents
Kim, Jin Yung,Koo, Han-Mo,Kim, Darrick S.H.L
, p. 2405 - 2408 (2001)
Chemical modifications were performed on C-20 position of betulinic acid for a structure-activity relationship study. The evaluation of the compounds using human colon carcinoma HCT-116, human prostate adenocarcinoma PC3, and human melanoma cell lines M14-MEL, SK-MEL-2, and UACC-257 did not show any selective cytotoxicity towards melanoma cells. The results from both MTT reduction assay and SRB staining assay were comparable that no remarkable differences in cytotoxicity profile of the compounds were noticed. The C-20 position was found to be sensitive to the size and the electron density of the substituents in retaining the cytotoxicity of betulinic acid and was found to be undesirable position to derivatize.
A concise semi-synthetic approach to betulinic acid from betulin
Kim, Darrick S.H.L.,Chen, Zhidong,Van Nguyen, Tuyen,Pezzuto, John M.,Qiu, Shengxiang,Lu, Zhi-Zhen
, p. 1607 - 1612 (1997)
Betulin was convert to betulinic acid using two different synthetic routes. The first approach involved an oxidation of betulin using Jones' reagent to betulinic acid and subsequent NaBH4 reduction to betulinic acid. The second approach involved steps utilizing different protecting groups on the alcohol functional groups of betulin and Jones' oxidation to circumvent the isomerization of the secondary alcohol of betulinic acid.
Picolyl amides of betulinic acid as antitumor agents causing tumor cell apoptosis
Bildziukevich, Uladzimir,Rárová, Lucie,?aman, David,Wimmer, Zdeněk
, p. 41 - 50 (2018)
A series of picolyl amides of betulinic acid (3a–3c and 6a–6c) was prepared and subjected to the cytotoxicity screening tests. Structure-activity relationships studies resulted in finding differences in biological activity in dependence on o-, m- and p-substitution of the pyridine ring in the target amides, when cytotoxicity data of 3a–3c and 6a–6c were obtained and compared. The amides 3b and 3a displayed cytotoxicity (given in the IC50 values) in G-361 (0.5 ± 0.1 μM and 2.4 ± 0.0 μM, respectively), MCF7 (1.4 ± 0.1 μM and 2.2 ± 0.2 μM, respectively), HeLa (2.4 ± 0.4 μM and 2.3 ± 0.5 μM, respectively) and CEM (6.5 ± 1.5 μM and 6.9 ± 0.4 μM, respectively) tumor cell lines, and showed weak effect in the normal human fibroblasts (BJ). Selectivity against all tested cancer cells was determined and compared to normal cells with therapeutic index (TI) between 7 and 100 for compounds 3a and 3b. The therapeutic index (TI = 100) was calculated for human malignant melanoma cell line (G-361) versus normal human fibroblasts (BJ). The cytotoxicity of other target amides (3c and 6a–6c) revealed lower effects than 3a and 3b in the tested cancer cell lines.
Synthesis and antiplasmodial activity of betulinic acid and ursolic acid analogues
Innocente, Adrine M.,Silva, Gloria N.S.,Cruz, Laura Nogueira,Moraes, Miriam S.,Nakabashi, Myna,Sonnet, Pascal,Gosmann, Grace,Garcia, Celia R.S.,Gnoatto, Simone C.B.
, p. 12003 - 12014 (2012)
More than 40% of the World population is at risk of contracting malaria, which affects primarily poor populations in tropical and subtropical areas. Antimalarial pharmacotherapy has utilised plant-derived products such as quinine and artemisinin as well as their derivatives. However, worldwide use of these antimalarials has caused the spread of resistant parasites, resulting in increased malaria morbidity and mortality. Considering that the literature has demonstrated the antimalarial potential of triterpenes, specially betulinic acid (1) and ursolic acid (2), this study investigated the antimalarial activity against P. falciparum chloroquine-sensitive 3D7 strain of some new derivatives of 1 and 2 with modifications at C-3 and C-28. The antiplasmodial study employed flow cytometry and spectrofluorimetric analyses using YOYO-1, dihydroethidium and Fluo4/AM for staining. Among the six analogues obtained, compounds 1c and 2c showed excellent activity (IC50 = 220 and 175 nM, respectively) while 1a and b demonstrated good activity (IC50 = 4 and 5 μM, respectively). After cytotoxicity evaluation against HEK293T cells, 1a was not toxic, while 1c and 2c showed IC50 of 4 μM and a selectivity index (SI) value of 18 and 23, respectively. Moreover, compound 2c, which presents the best antiplasmodial activity, is involved in the calcium-regulated pathway(s).
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Mauerer,Meier,Reiff
, p. 1870 (1939)
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Ethylenediamine derived carboxamides of betulinic and ursolic acid as potential cytotoxic agents
Kahnt, Michael,Heller, Lucie Fischer Née,Al-Harrasi, Ahmed,Csuk, René
, (2018)
Two easily accessible, natural occurring triterpenoids, betulinic and ursolic acid, were used as starting materials for the synthesis of novel cytotoxic agents. A set of 28 ethylenediamine-spacered carboxamides was prepared holding an additional substituent connected to the ethylenediamine group. The compounds were screened in SRB assays to evaluate their cytotoxic activity employing several human tumor cell lines. Betulinic acid-derived carboxamides 17-30 showed significantly higher cytotoxicity than their ursolic acid analogs 3-16. In particular, compounds 25 and 26 were highly cytotoxic, as indicated by EC50 values lower than 1 μM.
Absolute configuration of 3-acetylbetulinic acid
Suleimen,Van Hecke,Van Meervelt,Deborggraeve, Wim,Dehaen, Wim
, p. 189 - 191 (2013)
The absolute configuration of 3-acetoxybetulinic acid is determined by single crystal X-ray diffraction.
Mitochondria-targeted betulinic and ursolic acid derivatives: Synthesis and anticancer activity
Nedopekina, Darya A.,Gubaidullin, Rinat R.,Odinokov, Victor N.,Maximchik, Polina V.,Zhivotovsky, Boris,Bel'Skii, Yuriy P.,Khazanov, Veniamin A.,Manuylova, Arina V.,Gogvadze, Vladimir,Spivak, Anna Yu.
, p. 1934 - 1945 (2017)
A series of new betulinic and ursolic acid conjugates with a lipophilic triphenylphosphonium cation, meant to enhance the bioavailability and mitochondriotropic action of natural triterpenes, have been synthesized. The in vitro experiments on three human cancer cell lines (MCF-7, HCT-116 and TET21N) revealed that all the obtained triphenylphosphonium triterpene acid derivatives not only showed higher cytotoxicity as compared to betulinic acid but were also markedly superior in triggering mitochondria-dependent apoptosis, as assessed using a range of apoptosis markers such as cytochrome c release, stimulation of caspase-3 activity, and cleavage of poly(ADP-ribose) polymerase, which is one of the targets of caspase 3. The IC50 was much lower for all triphenylphosphonium derivatives when compared to betulinic acid. Out of the tested group of conjugates, the most potent toxicity was exhibited by the betulinic acid conjugate 9 (for 9, the IC50 values against MCF-7 and TET21N cells were 0.70 μM and 0.74 μM; for betulinic acid (BA), IC50 > 25 μM against MCF-7 cells).
N-methylated diazabicyclo[3.2.2]nonane substituted triterpenoic acids are excellent, hyperbolic and selective inhibitors for butyrylcholinesterase
Heise, Niels,Friedrich, Sander,Temml, Veronika,Schuster, Daniela,Siewert, Bianka,Csuk, René
supporting information, (2021/11/08)
Triterpenoic acids (oleanolic, ursolic, betulinic, platanic and glycyrrhetinic acid) were acetylated and coupled with 1,3- or 1,4-diazabicyclo[3.2.2]nonanes to yield amides. Reaction of these amides with methyl iodide at the distal nitrogen of the bicyclic system gave the corresponding quaternary ammonium salts. These compounds were shown to act as excellent inhibitors of the enzyme butyrylcholinesterase (BChE) while being only weak inhibitors for acetylcholinesterase (AChE). Evaluation of the enzyme kinetics revealed these compounds to act as hyperbolic inhibitors for BChE while the results from molecular modeling gave an explanation for their selectivity between AChE and BChE.
NOVEL TRITERPENE DERIVATIVES AS HIV INHIBITORS
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Page/Page column 44, (2021/08/20)
The present invention relates to novel triterpene derivatives of formula (I); and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, n, and ring (II) are as defined in formula (I). The invention also relates to novel triterpene derivatives, related compounds, and pharmaceutical compositions useful for the therapeutic treatment of viral diseases and particularly HIV mediated diseases.
