- Homopiperazine-rhodamine B adducts of triterpenoic acids are strong mitocans
-
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.
- Wolfram, Ratna Kancana,Fischer, Lucie,Kluge, Ralph,Str?hl, Dieter,Al-Harrasi, Ahmed,Csuk, René
-
-
Read Online
- Synthesis of betulonic acid derivatives containing amino-acid fragments
-
New derivatives of betulonic acid containing on C-28 fragments of amino acids or their methyl esters were prepared as potential biologically active agents.
- Petrenko,Elantseva,Petukhova,Shakirov,Shul'ts,Tolstikov
-
-
Read Online
- Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives
-
In this work, we describe synthesis of conjugates of betulinic acid with substituted triazoles prepared via Huisgen 1,3-cycloaddition. All compounds contain free 28-COOH group. Allylic bromination of protected betulinic acid by NBS gave corresponding 30-bromoderivatives, their substitution with sodium azides produced 30-azidoderivatives and these azides were subjected to CuI catalysed Huisgen 1,3-cycloaddition to give the final conjugates. Reactions had moderate to high yields. All new compounds were tested for their in vitro cytotoxic activities on eight cancer and two non-cancer cell lines. The most active compounds were conjugates of 3β-O-acetylbetulinic acid and among them, conjugate with triazole substituted by benzaldehyde 9b was the best with IC50 of 3.3 μM and therapeutic index of 9.1. Five compounds in this study had IC50 below 10 μM and inhibited DNA and RNA synthesis and caused block in G0/G1 cell cycle phase which is highly similar to actinomycin D. It is unusual that here prepared 3β-O-acetates were more active than compounds with the free 3-OH group and this suggests that this set may have common mechanism of action that is different from the mechanism of action of previously known 3β-O-acetoxybetulinic acid derivatives. Benzaldehyde type conjugate 9b is the best candidate for further drug development.
- Sidova, Veronika,Zoufaly, Pavel,Pokorny, Jan,Dzubak, Petr,Hajduch, Marian,Popa, Igor,Urban, Milan
-
-
Read Online
- Synthesis of three triterpene series and their activity against respiratory syncytial virus
-
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.
- 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.
-
-
Read Online
- Semisynthesis, cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives
-
In this report, we describe the semisynthesis of two series of ursolic and betulinic acid derivatives through designed by modifications at the C-3 and C-28 positions and demonstrate their antimalarial activity against chloroquine-resistant P. falciparum (W2 strain). Structural modifications at C-3 were more advantageous to antimalarial activity than simultaneous modifications at C-3 and C-28 positions. The ester derivative, 3β-butanoyl betulinic acid (7b), was the most active compound (IC50 = 3.4 μM) and it did not exhibit cytotoxicity against VERO nor HepG2 cells (CC50 > 400 μM), showing selectivity towards parasites (selectivity index > 117.47). In combination with artemisinin, compound 7b showed an additive effect (CI = 1.14). While docking analysis showed a possible interaction of 7b with the Plasmodium protease PfSUB1, with an optimum binding affinity of ?7.02 kcal/mol, the rather low inhibition displayed on a Bacillus licheniformis subtilisin A protease activity assay (IC50 = 93 μM) and the observed accumulation of ring forms together with a delay of appearance of trophozoites in vitro suggests that the main target of 3β-butanoyl betulinic acid on Plasmodium may be related to other molecules and processes pertaining to the ring stage. Therefore, compound 7b is the most promising compound for further studies on antimalarial chemotherapy. The results obtained in this study provide suitable information about scaffolds to develop novel antimalarials from natural sources.
- Cargnin, Simone Tasca,Staudt, Andressa Finkler,Medeiros, Patrícia,de Medeiros Sol Sol, Daniel,de Azevedo dos Santos, Ana Paula,Zanchi, Fernando Berton,Gosmann, Grace,Puyet, Antonio,Garcia Teles, Carolina Bioni,Gnoatto, Simone Baggio
-
-
Read Online
- Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors
-
Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular end-points with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-κB, STAT3, Nrf2, TGR5) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (5b) was selected for further studies, and evaluation of its effect on HIF-1α expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.
- Minassi, Alberto,Rogati, Federica,Cruz, Cristina,Prados, M. Eugenia,Galera, Nuria,Jinénez, Carla,Appendino, Giovanni,Bellido, M. Luz,Calzado, Marco A,Caprioglio, Diego,Mu?oz, Eduardo
-
-
Read Online
- Tobacco Caterpillar Antifeedent from the Gotti Stem Wood Triterpene Betulinic Acid
-
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
-
-
Read Online
- Synthesis and cytotoxic activity of 3-O-acyl/3-hydrazine/2-bromo/20,29- dibromo betulinic acid derivatives
-
A series of 3-O-acyl, 3-hydrazine, 2-bromo, and 20,29-dibromo betulinic acid derivatives (1-27) have been synthesized and screened for in vitro cytotoxic activity on human cancer cell lines MOLT-4, JurkatE6.1, CEM.CM3, BRISTOL8, U937, DU145, PA-1, A549, and L132. A number of compounds have shown ED501μg/mL against the cancer cell lines tested and have shown better cytotoxicity than betulinic acid. Compounds 13, 19, 20, 23, and 27 were the best derivatives and were selected as lead molecules for further development. The structure-activity relationship has been described.
- Mukherjee, Rama,Jaggi, Manu,Siddiqui, Mohammad J. A.,Srivastava, Sanjay K.,Rajendran, Praveen,Vardhan, Anand,Burman, Anand C.
-
-
Read Online
- Synthesis and biological evaluation of a new derivative of bevirimat that targets the Gag CA-SP1 cleavage site
-
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.
- Coric, Pascale,Turcaud, Serge,Souquet, Florence,Briant, Laurence,Gay, Bernard,Royer, Jacques,Chazal, Nathalie,Bouaziz, Serge
-
-
Read Online
- Pentacyclic triterpene acid conjugated with mitochondria-targeting cation F16: Synthesis and evaluation of cytotoxic activities
-
The first representatives of F16-conjugated pentacyclic triterpenoids, betulin and betulinic, ursolic, oleanolic, and glycyrrhetic acid derivatives, were synthesized. The triterpene core was linked, at the С-3, С-28, or С-30 position, to one or two mitochondria-targeting delocalized lipophilic cations F16 via butane or triethylene glycol spacer. The human cancer cell lines U937 (leukemic monocyte lymphoma), K562 (chronic myeloid leukemia), and Jurkat (T-lymphoblastic leukemia), and a human nonmalignant fibroblast cell line were used to evaluate the cytotoxic activities of the products. Most of the obtained conjugates showed considerable enhancement of the antitumor action in comparison with the parent betulinic acid (≈100?200-fold) and a markedly higher cytotoxic effect against tumor cell lines over healthy fibroblast cells. In the series of test compounds, F16 conjugates with betulin and betulinic acid 6, 8, and 11 were most selective, showing acceptable values of selectivity index (≥10). [Figure not available: see fulltext.]
- Spivak, Anna Yu.,Nedopekina, Darya A.,Gubaidullin, Rinat R.,Davletshin, Eldar V.,Tukhbatullin, Adis A.,D’yakonov, Vladimir A.,Yunusbaeva, Milyausha M.,Dzhemileva, Lilya U.,Dzhemilev, Usein M.
-
-
Read Online
- Ficusanolide A and ficusanolide B, two new cinnamic acid derivative stereoisomers and other constituents of the stem barks of Ficus exasperata Vahl. (Moraceae)
-
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.
- 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
-
-
Read Online
- Anti-AIDS agents. 78. Design, synthesis, metabolic stability assessment, and antiviral evaluation of novel betulinic acid derivatives as potent anti-human immunodeficiency virus (HIV) agents
-
In a continuing study of potent anti-HIV agents, seventeen 28,30-disubstituted betulinic acid (BA, 1) derivatives and seven novel 3,28-disubstituted BA analogues were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, compound 21 showed an improved solubility and equal anti-HIV potency (EC50 = 0.09 μM) when compared to HIV entry inhibitors 3b (IC9564, (3R,4S)-N′-[N-[3β-hydroxylup-20(29)-en- 28-oyl]-8-aminooctanoyl]-4-amino-3-hydroxy-6-methylheptanoic acid) and 4 (A43-D, [[N-[3β-O-(3′,3′-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7- aminoheptyl]carbamoyl]methane). Using a cyclic secondary amine to form the C-28 amide bond increased the metabolic stability of the derivatives significantly in pooled human liver microsomes. The most potent compounds 47 and 48 displayed potent anti-HIV activity with EC50 values of 0.007 and 0.006 μM, respectively. These results are slightly better than that of bevirimat (2, 3′,3′-dimethylsuccinylbetulinic acid), which is currently in phase IIb clinical trials. Compounds 47 and 48 should serve as attractive promising leads to develop next generation, metabolically stable, 3,28-disubstituted bifunctional HIV-1 inhibitors as clinical trials candidates.
- Qian, Keduo,Yu, Donglei,Chen, Chin-Ho,Huang, Li,Morris-Natschke, Susan L.,Nitz, Theodore J.,Salzwedel, Karl,Reddick, Mary,Allaway, Graham P.,Lee, Kuo-Hsiung
-
-
Read Online
- Targeting mitochondria: Esters of rhodamine B with triterpenoids are mitocanic triggers of apoptosis
-
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
-
-
Read Online
- A-type doubly linked proanthocyanidin trimer and other metabolites from Canthium venosum fruits, and their biological activities
-
Phytochemical investigation of Canthium venosum fruits led to the isolation of a new doubly linked A-type proanthocyanidin trimer: epicatechin-(2β→O→7, 4β →8)-catechin-(5→O→2β, 6→4β)-epicatechin [venosumtannin A-1 (1)], along with twenty known compounds 2-21. Allyl (9a) and acetyl (9b) derivatives of 9 were prepared. The structures of compounds were established using comprehensive spectroscopic analysis including 1D NMR, 2D NMR (COSY, HMQC, HMBC, and NOESY) and circular dichroism (CD), and by comparison with the corresponding literature data. The antioxidant, cytotoxic, acetylcholinesterase and antibacterial activities of some of the isolated compounds were investigated. In the acetylcholinesterase inhibitory activity test, compounds 2 and 9 (IC50: 0.03 ± 1.22 × 10?3 and 0.04 ± 1.23 × 10?3 μM) were more active than the references (eserine and tacrine; IC50: 0.77 ± 1.84 × 10?3 and 0.15 ± 1.04 × 10?3 μM respectively).
- Chouna, Jean Rodolphe,Dongmo, Appolinaire Kene,Frese, Marcel,Kaaniche, Fatma,Lenta, Bruno Ndjakou,Mawabo, Isabelle Kamga,Ngnokam, David,Nkenfou, Celine Nguefeu,Nkeng-Efouet-Alango, Pépin,Nono, Raymond Ngansop,Sewald, Norbert
-
-
Read Online
- Design, Synthesis, and Cytotoxicity of Semisynthetic Betulinic Acid-1,2,4-Oxadiazole Amide Derivatives
-
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.
- Krishna,Bhargavi,Krupadanam
-
-
Read Online
- Enhancing effect of cystamine in its amides with betulinic acid as antimicrobial and antitumor agent in vitro
-
Amides of betulinic acid with cystamine were synthesized to investigate their antimicrobial and antitumor activity, and their influence on the cell cycle and cell apoptosis. The former target amide (6) displayed cytotoxicity in CEM cell line after 72 h of treatment (IC50 = 3.0 ± 0.7 μM; TI = 20), and induced apoptosis by caspase-3/7 activation in CEM cells. The latter target amide (9) displayed antimicrobial activity against Streptococcus mutans (MIC 3.125 μM; MBC 3.125 μM) and Bacillus cereus (MIC 25 μM; MBC 25 μM). The achieved results demonstrate enhancing of their biological activity over that of the parent compounds. However, two intermediate compounds (2 and 7) displayed either considerable cytotoxicity (2; 7.5 ± 0.8 μM; TI = 10, against G361) or antimicrobial activity (7; both against Actinomyces odontolycus and Clostridium perfrigens with MIC 12.5 μM and MBC 12.5 μM). The experimental data were compared with the in silico calculated physico-chemical and ADME parameters of the target compounds, including successful intermediates.
- Bildziukevich, Uladzimir,Rárová, Lucie,Janovská, Lucie,?aman, David,Wimmer, Zdeněk
-
-
Read Online
- Triterpene-based carboxamides act as good inhibitors of butyrylcholinesterase
-
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.
- Loesche, Anne,Kahnt, Michael,Serbian, Immo,Brandt, Wolfgang,Csuk, René
-
-
Read Online
- Antiprotozoal activity of Betulinic acid derivatives
-
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
-
-
Read Online
- The presence of a cyclohexyldiamine moiety confers cytotoxicity to pentacyclic triterpenoids
-
Pentacyclic triterpenoids oleanolic acid, ursolic acid, betulinic acid, and platanic acid were acetylated and converted into several amides 9–31; the cytotoxicity of which has been determined in sulforhodamine B assays employing seral human tumor cell lines and nonmalignant fibrob-lasts. Thereby, a betulinic acid/trans-1,4-cyclohexyldiamine amide showed excellent cytotoxicity (for example, EC50 = 0.6 μM for HT29 colon adenocarcinoma cells).
- Al-Harrasi, Ahmed,Brandes, Benjamin,Christoph, Martin A.,Csuk, René,Deigner, Hans-Peter,Friedrich, Sander,Heise, Niels,Hoenke, Sophie
-
-
Read Online
- Development of C-20 modified betulinic acid derivatives as antitumor agents
-
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.
- Kim, Jin Yung,Koo, Han-Mo,Kim, Darrick S.H.L
-
-
Read Online
- Synthesis of glycosides of lupane-type triterpene acids
-
A preparative synthesis of glucosides of the lupane-type triterpene acids betulinic, dihydrobetulinic, betulonic, dihydrobetulonic, and 3,20-dioxo-30-norlupan-28-oic was proposed. Glycosylation of 3-hydroxyacids by α-acetobromoglucose (ABG) with Ag2O was performed in pyridine (Py) to form glycosides at C-28, repeated glycosylation of which by these same reagents but in CH2Cl2 generated a glycoside bond at C-3 to form bisglucosides. 28-Glucosides of ketoacids were formed in high yields in both Py and CH2Cl2.
- Samoshina,Denisenko,Denisenko,Uvarova
-
-
Read Online
- A concise semi-synthetic approach to betulinic acid from betulin
-
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.
- Kim, Darrick S.H.L.,Chen, Zhidong,Van Nguyen, Tuyen,Pezzuto, John M.,Qiu, Shengxiang,Lu, Zhi-Zhen
-
-
Read Online
- Cytotoxic triterpenoid–safirinium conjugates target the endoplasmic reticulum
-
Safirinium P and Q fluorescence labels were synthesized and conjugated with spacered triterpenoic acids to access hybrid structures. While the parent safirinium compounds were not cytotoxic at all, many triterpenoid safirinium P and Q conjugates showed moderate cytotoxicity. An exception, however, was safirinium P derived compound 30 holding low EC50 = 5.4 μM (for A375 cells) to EC50 = 7.5 μM (for FaDu cells) as well as EC50 = 6.6 μM for non-malignant fibroblasts NIH 3T3. Fluorescence imaging showed that the safirinium core structures cannot enter the cells (not even after a prolonged incubation time of 24 h), while the conjugates (as exemplified for 30) are accumulating in the endoplasmic reticulum but not in the mitochondria. The development of safirinium–hybrids targeting the endoplasmic reticulum can be regarded as a promising strategy in the development of cytotoxic agents.
- Kraft, Oliver,Kozubek, Marie,Hoenke, Sophie,Serbian, Immo,Major, Daniel,Csuk, René
-
-
Read Online
- Picolyl amides of betulinic acid as antitumor agents causing tumor cell apoptosis
-
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.
- Bildziukevich, Uladzimir,Rárová, Lucie,?aman, David,Wimmer, Zdeněk
-
-
Read Online
- Design, synthesis, and anti-tumor activity of novel betulinic acid derivatives
-
Seventeen new derivatives of betulinic acid (BA) with potential anti-tumor activity have been synthesized. In order to improve the bioactivity of BA, we connected BA and nitric oxide donors together via different linkers. The results of the biological activity of these derivatives showed that four compounds exhibited obvious cytotoxicity against human hepatocellular carcinoma cells in vitro.
- Liu, Jin-Hong,Tang, Jia,Zhu, Zi-Fei,Chen, Li
-
-
Read Online
- Synthesis and antiplasmodial activity of betulinic acid and ursolic acid analogues
-
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).
- 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.
-
-
Read Online
- Combination of betulinic acid with diazen-1-ium-1,2-diolate nitric oxide moiety donating a novel anticancer candidate
-
Background: Betulinic acid (BA) is a complex lupane triterpenoid with unique antineoplastic activity. However, its antiproliferative activity is far from satisfaction. In order to improve its anticancer efficacy, betulinic acid was conjugated with a nitric oxide (NO)-releasing moiety to get a novel hybrid, BA-78. Methods: The antiproliferative activity of BA-78 against 6 cell lines and the ability of releasing nitric oxide were determined. The pro-apoptosis mechanism of BA-78 was investigated as well. Results: BA-78 exhibited time-dependent release of NO, and it displayed higher antiproliferative potential than BA through increasing apoptosis and inducing cell cycle arrest at G1 phase. Western blotting results showed that BA-78 increased the expression of Bax, Bid, Bad and cytochrome C and reduced the level of anti-apoptosis proteins including Bcl-2 and Bcl-xl. Conclusion: Our study revealed that novel compound BA-78, possessing betulinic acid and nitric oxide (NO)-releasing moiety, could be developed as an antitumor agent.
- Zhang, Laiyin,Hou, Shuangxing,Li, Bo,Pan, Jianjian,Jiang, Liping,Zhou, Guiying,Gu, Hong,Zhao, Caixing,Lu, Huiping,Ma, Fenfen
-
-
Read Online
- Synthesis and anticancer activity of novel betulinic acid and betulin derivatives
-
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
-
-
Read Online
- Ethylenediamine derived carboxamides of betulinic and ursolic acid as potential cytotoxic agents
-
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.
- Kahnt, Michael,Heller, Lucie Fischer Née,Al-Harrasi, Ahmed,Csuk, René
-
-
Read Online
- Absolute configuration of 3-acetylbetulinic acid
-
The absolute configuration of 3-acetoxybetulinic acid is determined by single crystal X-ray diffraction.
- Suleimen,Van Hecke,Van Meervelt,Deborggraeve, Wim,Dehaen, Wim
-
-
Read Online
- Synthesis of isosteric triterpenoid derivatives and antifungal activity
-
Dermatomycoses are among the most widespread and common superficial and cutaneous fungal infections in humans. There is an urgent need to develop efficient and non-toxic antimycotic agents with a specific spectrum of activity. Triterpenes have been demonstrated to exhibit a wide range of biological activities, including antifungal activities. In this study, through hemisynthesis, we aimed to obtain triterpene-isosteric molecules from betulinic and ursolic acids to improve the antifungal activity and spectrum of action of these compounds. Six compounds were resynthesized and tested against eleven mucocutaneous and cutaneous mycotic agents. The results of the susceptibility assays were expressed as the minimal inhibitory concentration (MIC). The MIC values of the piperazinyl derivatives of ursolic and betulinic acids that were active against pathogenic yeasts were in the range of 16-32 μg/mL and 4-16 μg/mL, respectively, whereas fungicidal effects were observed at concentrations ranging from 16 to 128 μg/mL and 8 to 128 μg/mL, respectively. The piperazinyl derivative of betulinic acid exhibited an antifungal profile similar to that of terbinafine and was the most effective derivative against dermatophytes. This strategy led to a promising candidate for the development of a new antifungal agent.
- Innocente, Adrine,Casanova, Bruna B.,Klein, Fernanda,Lana, Aline D.,Pereira, Dariane,Muniz, Mauro N.,Sonnet, Pascal,Gosmann, Grace,Fuentefria, Alexandre M.,Gnoatto, Simone C.B.
-
-
Read Online
- Mitochondria-targeted betulinic and ursolic acid derivatives: Synthesis and anticancer activity
-
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).
- 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.
-
-
Read Online
- Small structural changes of pentacyclic lupane type triterpenoid derivatives lead to significant differences in their anticancer properties
-
In the present investigations five new derivatives of betulinic and betulonic acid were synthesized and the effect of this structural variations on anticancer activity was studied and discussed. The anti-proliferative activity of betulinic and betulonic acid derivatives was studied against eight tumor cell lines of different histogenic origin. The derivatives exerted a dose dependent antiproliferative action at micromolar concentrations toward target tumor cell lines. The apoptotic mode of cell death on colon cancer cell line HT-29 was induced by the most active compounds 5,2-amino-3-hydroxy-2-(hydroxy-methyl) propyl (3-O-acetyl)betulinate,and 9,2-amino-3-hydroxy-2-(hydroxymethyl)propyl betulonate. Treatment of HT-29 cells with 5 and 9 induced apoptosis,as observed by dye exclusion test (trypan blue) and by the appearance of a typical ladder pattern in the DNA fragmentation assay and FITC annexin V assay. Cell cycle perturbations caused by compound 5 are also presented.
- Kommera, Harish,Kaluderovic, Goran N.,Kalbitz, Jutta,Draeger, Birgit,Paschke, Reinhard
-
-
Read Online
- N-methylated diazabicyclo[3.2.2]nonane substituted triterpenoic acids are excellent, hyperbolic and selective inhibitors for butyrylcholinesterase
-
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.
- Heise, Niels,Friedrich, Sander,Temml, Veronika,Schuster, Daniela,Siewert, Bianka,Csuk, René
-
supporting information
(2021/11/08)
-
- MSBA-S – A pentacyclic sulfamate as a new option for radiotherapy of human breast cancer cells
-
Many pentacyclic triterpenoids show anti-cancer and anti-inflammatory properties. Recently, we detected a pronounced cytotoxicity and radiosensitivity of two betulinyl sulfamates in human breast cancer cells. Besides betulinic acid scaffold (BSBA-S), we synthesized several new sulfamate-coupled scaffolds from oleanolic acid (OSBA-S), ursolic acid (USBA-S), platanic acid (PSBA-S) and maslinic acid (MSBA-S). Highest cytotoxicity was monitored in breast cancer cell lines after MSBA-S treatment showing in SRB assays IC50 values between 3.7 μM and 5.8 μM. Other sulfamate/triterpene conjugates, however, were less cytotoxic holding IC50 values between 6.6 μM and >50 μM, respectively. MSBA-S-treated breast cancer cells displayed significantly reduced clonogenic survival and an increased rate of apoptosis as compared to the other conjugates. In addition, MSBA-S in combination with irradiation resulted in effects on radiosensitivity in MDA-MB-231 cells (DMF10 = 1.14). In particular, ROS formation was strongly assessed in MSBA-S-treated breast cancer cells. Our findings suggest that the sulfamate derivative of maslinic acid MSBA-S might be a new option for the radiation therapy in breast cancer cells.
- Bache, Matthias,Eiselt, Yvonne,Funtan, Anne,Kahnt, Michael,Paschke, Reinhard,Petrenko, Marina,Serbian, Immo,Vordermark, Dirk,Csuk, René,Güttler, Antje,Ke?ler, Jacqueline,Pflüger, Elena
-
-
- NOVEL TRITERPENE DERIVATIVES AS HIV INHIBITORS
-
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.
- -
-
Page/Page column 44
(2021/08/20)
-
- Antimicrobial properties of amine- and guanidine-functionalized derivatives of betulinic, ursolic and oleanolic acids: Synthesis and structure/activity evaluation
-
A series of 34 new amine- and guanidine-functionalized derivatives of betulinic, ursolic, and oleanolic acids were synthesized and tested for their antimicrobial activity against the growth of four bacterial strains (Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, and Staphylococcus aureus (MRSA)) and two fungal strains (Candida albicans and Cryptococcus neoformans). The obtained compounds were also tested for the cytotoxic effect against HEK293 human embryonic kidney cell line and hemolytic activity against human red blood cells. Most of the prepared amino and guanidinium derivatives of betulinic, ursolic, and oleanolic acids showed a considerably higher bacteriostatic activity against methicillin-resistant S. aureus than the parent compounds. The most active compounds (MICs ≤ 0.25 μg/ml or 0.4–0.5 μM) were superior over the clinically used antibiotic vancomycin in the antibacterial effect (MIC of 1 μg/ml or 0.7 μM). Apart from antibacterial activity, new triterpene acid derivatives exhibited excellent antifungal activity against Cryptococcus neoformans, with MICs values being as low as 0.25 μg/ml (0.4 μM), and were approximately 65 times as active as fluconazole, a known antifungal agent. Four most promising compounds we identified (7, 13, 24, and 33) showed not only high bacteriostatic effect, but also low cytotoxicity against mammalian HEK293 cells and high hemolytic selectivity.
- Spivak, Anna Yu.,Khalitova, Rezeda R.,Nedopekina, Darya A.,Gubaidullin, Rinat R.
-
-
- 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).
- -
-
Paragraph 00306
(2020/01/24)
-
- Betulinic acid derived amides are highly cytotoxic, apoptotic and selective
-
Betulinic and platanic acid derived amides were prepared and screened for their cytotoxic activity. All of the compounds were shown to be cytotoxic for a panel of human tumor cell lines, and especially apoptotic betulinic acid derived compounds 6, 8 and 19 showed low EC50 values. Of special interest was a 4-isoquinolinyl amide of 3-O-acetyl-betulinic acid (compound 19), being the most cytotoxic compound of this series and holding EC50 values as low as EC50 = 1.48 μM (A375 melanoma cells) while being significantly less cytotoxic for non-malignant fibroblasts NIH 3T3 with a selectivity index of >91.2. This finding parallels previous results obtained for SAA21, a augustic acid derived compound thus making the 4-isoquinolinyl moiety to a privileged scaffold.
- Deigner, Hans-Peter,Heise, Niels V.,Hoenke, Sophie,Kahnt, Michael,Csuk, René
-
-
- NOVEL TRITERPENE DERIVATIVES AS HIV INHIBITORS
-
The present invention relates to novel triterpene derivatives of formula (I); and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, and ring are as defined herein. 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.
- -
-
Page/Page column 23
(2020/08/28)
-
- Spectral and microscopic study of self-assembly of novel cationic spermine amides of betulinic acid
-
Supramolecular characteristics of two spermine amides of betulinic acid (1 and 2) were studied by measuring and evaluating their UV–VIS-NIR spectra in aqueous acetonitrile and DOSY-NMR spectra in tetradeuteromethanol, accompanied by atomic force microscopy (AFM) images, scanning electron microscopy (SEM) micrographs, and transmission electron microscopy (TEM) micrographs. Fibrous supramolecular self-assembly of 1 and 2 was observed by AFM images, as well as by the SEM and TEM micrographs. Bathochromic shifts of the absorbance maximum at 870?nm to 1015–970?nm in the UV–VIS-NIR spectra were observed with increasing water content in the acetonitrile/water systems, indicating formation of fibrous J-type aggregates. Variable temperature DOSY-NMR spectral measurement showed non-linear dependence that also suggests self-assembly behavior of the studied systems. Chiral supramolecular structures were formed by self-assembling due to the chirality of the monomeric molecules. Application of aqueous media during self-assembly procedures is an important factor in the development of targeted drug delivery systems.
- Bildziukevich, Uladzimir,Kaletová, Eva,?aman, David,Siev?nen, Elina,Kolehmainen, Erkki T.,?louf, Miroslav,Wimmer, Zdeněk
-
supporting information
p. 90 - 96
(2016/12/26)
-
- Rhodamine B conjugates of triterpenoic acids are cytotoxic mitocans even at nanomolar concentrations
-
Triterpenoic acids 1–6 exhibited very low or no cytotoxicity at all, but their corresponding 2,3-di-O-acetyl-piperazinyl amides 13–18 showed low EC50values for several human tumor cell lines. Their cytotoxicity, however, was also high for the non-malignant mouse fibroblasts NIH 3T3. A significant improvement was achieved by preparing the rhodamine B derivatives 19–24. While rhodamine B is not cytotoxic (up to a concentration of 30μM – cut-off of the assay), the triterpenoid piperazine-spacered rhodamine B derivatives were cytotoxic in nano-molar concentration. Compound 24 (a diacetylated maslinic acid derivative) was most toxic for several human tumor cell lines but less toxic for mouse fibroblasts NIH 3T3. Staining and double-staining experiments revealed 24 to act as a mitocan.
- Sommerwerk, Sven,Heller, Lucie,Kerzig, Christoph,Kramell, Annemarie E.,Csuk, René
-
-
- Polyamine derivatives of betulinic acid and β-sitosterol: A comparative investigation
-
β-Sitosterol and betulinic acid were used in designing their conjugates with selected polyamines bearing either an amide bond, or an ester and an amide bond simultaneously in the target molecule. The synthesized compounds were subjected to basic cytotoxic and antimicrobial tests. The synthetic protocol is described separately for each of the three series of the target amides, because each series of compounds required a different synthetic approach. The cytotoxicity was tested on cells derived from human T-lymphoblastic leukemia, breast adenocarcinoma and cervical cancer, and compared with the tests on normal human fibroblasts. Most of the target compounds (5a-5c, 11a-11c and 16a-16c) showed medium to high cytotoxicity (0.7-7.8 μM), however, in some cases the compounds showed high cytotoxicity even toward normal human fibroblasts (11a-11c). Two compounds of this series (11c and 16c) also displayed antimicrobial activity with high and selective microbe specificity. The compound 11c was potent against Escherichia coli (minimal inhibition concentration (MIC) 6.25 μg mL-1, i.e. 9.75 nM mL-1) and Staphylococcus aureus (MIC 12.5 μg mL-1, i.e. 19.5 nM mL-1), and showed medium activity against Pseudomonas aeruginosa. The compound 16c was highly active against Enterococcus faecalis and S. aureus (both, MIC 3.125 μg mL-1, i.e. 4.22 nM mL-1), both Gram-positive bacteria, however showed only weak activity against E. coli and no activity against P. aeruginosa, both Gram-negative bacteria, which indicates possible microbe specificity of 16c. Comparing β-sitosterol-based series (5a-5c) and betulinic acid series (11a-11c and 16a-16c) of the target compounds, the latter one gave more promising structures. The compounds 11c and 16c showed effects which may be described as multifarious activity (pleiotropic effects).
- Bildziukevich, Uladzimir,Vida, Norbert,Rárová, Lucie,Kolá?, Milan,?aman, David,Havlí?ek, Libor,Dra?ar, Pavel,Wimmer, Zdeněk
-
supporting information
p. 27 - 35
(2015/05/27)
-
- Betulinic acid derived hydroxamates and betulin derived carbamates are interesting scaffolds for the synthesis of novel cytotoxic compounds
-
The betulinic acid-derived hydroxamates 5-18, the amides 19-24, and betulin-derived bis-carbamates 25-28 as well as the carbamates 31-40 and 44-48 were prepared and evaluated for their antiproliferative activity in a photometric sulforhodamine B (SRB) assay against several human cancer cell lines and nonmalignant mouse fibroblasts (NIH 3T3). While for 3-O-acetyl hydroxamic acid 5 EC50 values as low as EC50 = 1.3 μM were found, N,O-bis-alkyl substituted hydroxamates showed lowered cytotoxicity (EC50 = 16-20 μM). In general, hydroxamic acid derivatives showed only reduced selectivity for tumor cells, except for allyl substituted compound 13 (EC50 = 5.9 μM for A2780 human ovarian carcinoma cells and EC50 > 30 μM for nonmalignant mouse fibroblasts). The cytotoxicity of betulinic acid derived amides 19-24 and of betulin derived bis-carbamates 25-28 was low, except for N-ethyl substituted 25. Hexyl substituted 39 showed EC50 = 5.6 μM (518A2 cells) while for mouse fibroblasts EC50 > 30 was determined.
- Wiemann, Jana,Heller, Lucie,Perl, Vincent,Kluge, Ralph,Str?hl, Dieter,Csuk, René
-
p. 194 - 210
(2015/11/17)
-
- Conjugation of a nonspecific antiviral sapogenin with a specific HIV fusion Inhibitor: A promising strategy for discovering new antiviral therapeutics
-
Triterpene saponins are a major group of active components in natural products with nonspecific antiviral activities, while T20 peptide (enfuvirtide), which contains a helix zone-binding domain (HBD), is a gp41-specific HIV-1 fusion inhibitor. In this paper, we report the design, synthesis, and structure-activity relationship (SAR) of a group of hybrid molecules in which bioactive triterpene sapogenins were covalently attached to the HBD-containing peptides via click chemistry. We found that either the triterpenes or peptide part alone showed weak activity against HIV-1 Env-mediated cell-cell fusion, while the hybrids generated a strong cooperative effect. Among them, P26-BApc exhibited anti-HIV-1 activity against both T20-sensitive and -resistant HIV-1 strains and improved pharmacokinetic properties. These results suggest that this scaffold design is a promising strategy for developing new HIV-1 fusion inhibitors and possibly novel antiviral therapeutics against other viruses with class I fusion proteins.
- Wang, Chao,Lu, Lu,Na, Heya,Li, Xiangpeng,Wang, Qian,Jiang, Xifeng,Xu, Xiaoyu,Yu, Fei,Zhang, Tianhong,Li, Jinglai,Zhang, Zhenqing,Zheng, Baohua,Liang, Guodong,Cai, Lifeng,Jiang, Shibo,Liu, Keliang
-
p. 7342 - 7354
(2015/01/09)
-
- NOVEL BETULINIC ACID DERIVATIVES AS HIV INHIBITORS
-
(I)The invention relates to novel novel betulinic acid derivatives and related compounds, and pharmaceutical compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
- -
-
Paragraph 0127
(2013/11/18)
-
- Derivatives of 3-O-(3',3'-dimethylsuccinyl)-betulinic acid
-
The present invention relates to compounds of the following formula (I): or a pharmaceutically acceptable salt thereof, a stereoisomer or a mixture of stereoisomers in any proportion, in particular a mixture of enantiomers, and particularly a racemate mixture, in which R represents a (C1-C10)alkyl group substituted with one or more, preferably one or two, groups chosen from COOH and NHR1, with R1 representing a hydrogen atom or a -Alk, -C(O)-Alk or -C(O)O-Alk group, Alk representing a (C1-C6)alkyl group, as well as a method for preparing them, and their use as a medicine, notably for treating an infection with a retrovirus such as HIV.
- -
-
Paragraph 0072
(2013/03/26)
-
- LUPEOL-TYPE TRITERPENE DERIVATIVES AS ANTIVIRALS
-
The invention relates to novel lupeol-type triterpene derivatives and related compounds, and pharmaceutical compositions useful for therapeutic treatment of viral diseases and particularly HIV mediated diseases.
- -
-
Page/Page column 35-36
(2011/02/18)
-
- New betulinic acid derivatives as potent proteasome inhibitors
-
In this study, 22 new betulinic acid (BA) derivatives were synthesized and tested for their inhibition of the chymotrypsin-like activity of 20S proteasome. From the SAR study, we concluded that the C-3 and C-30 positions are the pharmacophores for increasing the proteasome inhibition effects, and larger lipophilic or aromatic side chains are favored at these positions. Among the BA derivatives tested, compounds 13, 20, and 21 showed the best proteasome inhibition activity with IC50 values of 1.42, 1.56, and 1.80 μM, respectively, which are three to fourfold more potent than the proteasome inhibition controls LLM-F and lactacystin.
- Qian, Keduo,Kim, Sang-Yong,Hung, Hsin-Yi,Huang, Li,Chen, Chin-Ho,Lee, Kuo-Hsiung
-
scheme or table
p. 5944 - 5947
(2011/10/19)
-
- An amphiphilic conjugate approach toward the design and synthesis of betulinic acid-polyphenol conjugates as inhibitors of the HIV-1 gp41 fusion core formation
-
Exploration of potent inhibitors of the HIV-1 gp41 fusion core formation is a promising strategy to discover small-molecule HIV-1 entry inhibitors for the treatment of HIV-1 infection. In this paper, a series of novel betulinic acid-polyphenol conjugates was designed, guided by molecular modeling of the binding of betulinic acid (BA) and phenolic galloyl/caffeoyl groups in the groove on the gp41 N-terminal heptad repeat (NHR) trimeric coiled coil. These conjugates were synthesized via conjugation of galloyl and caffeoyl groups with BA at the C-28 position. Their inhibitory activities of HIV gp41 six-helix bundle (6-HB) formation between the NHR peptide N36 and the C-terminal heptad repeat (CHR) peptide C34 were evaluated with size-exclusion HPLC. Conjugates bearing a galloyl group were found to exhibit four to sixfold higher inhibitory activities than that of parent compound BA, suggesting that they may be exploitable as HIV-1 fusion/entry inhibitors targeting gp41. The docking study on BA and its derivatives suggests that hydrophobic and hydrogen-bonding pockets exist in the groove of the gp41 NHR trimeric coiled coil and that a potent inhibitor should have amphiphilic structures to cooperatively interact with both pockets. This possibility was explored by incorporating both lipophilic and hydrophilic groups into the conjugates in a well-defined orientation to bind with both pockets in the gp41 NHR-trimer.
- Liu, Yan,Ke, Zhuofeng,Wu, Kwok Yiu,Liu, Shuwen,Chen, Wen-Hua,Jiang, Shibo,Jiang, Zhi-Hong
-
scheme or table
p. 1654 - 1664
(2012/01/06)
-
- 3,28-DISUBSTITUTED BETULINIC ACID DERIVATIVES AS ANTI-HIV AGENTS
-
Compounds according to Formula (I) are described along with compositions containing the same and methods of use thereof for the treatment of viral infections.
- -
-
Page/Page column 41
(2010/12/17)
-
- Spectroscopic data of 3-O-acetyl-betulinic acid: An antitumor reagent
-
In this paper, the spectroscopic data of the 3-O-acetyl betulinic acid is reported. This compound was prepared by enzymatic reaction of betulinic acid and acetic anhydride in the presence of lipase from Candida antarctica (Novozem 435) at 54oC for 20 h in 79.3 % yield.
- Ahmad,Ghaffari,Basri,Abdul Rahman
-
experimental part
p. 3186 - 3192
(2010/11/17)
-
- Anticancer activity of 3-O-acylated betulinic acid derivatives obtained by enzymatic synthesis
-
An easy and efficient strategy to prepare betulinic acid esters with various anhydrides was used by the enzymatic synthesis method. It involves lipase-catalyzed acylation of betulinic acid with anhydrides as acylating agents in organic solvent. Lipase from Candida antarctica immobilized on an acrylic resin (Novozym 435) was employed as a biocatalyst. Several 3-O-acyl-betulinic acid derivatives were successfully obtained by this procedure. The anticancer activity of betulinic acid and its 3-O-acylated derivatives were then evaluated in vitro against human lung carcinoma (A549) and human ovarian (CAOV3) cancer cell lines. 3-O-glutarylbetulinic acid, 3-O-acetyl-betulinic acid, and 3-O-succinyl-betulinic acid showed IC50 10 μg/ml against A549 cancer cell line tested and showed better cytotoxicity than betulinic acid. In an ovarian cancer cell line, all betulinic acid derivatives prepared showed weaker cytotoxicity than betulinic acid.
- Ahmad, Faujan Bin H.,Moghaddam, Mansour Ghaffari,Basri, Mahiran,Abdul Rahman, Mohd Basyaruddin
-
experimental part
p. 1025 - 1029
(2011/04/24)
-
- NOVEL 17? LUPANE DERIVATIVES
-
The invention relates to 17? lupane derivatives of formula (I): wherein R1 and X are as defined herein, and pharmaceutically acceptable salts and solvates thereof. These compounds exhibit significant anti-HIV activity. Thus, the invention also
- -
-
Page/Page column 65
(2009/10/09)
-
- TRITERPENES DERIVATIVES AND USES THEREOF AS ANTITUMOR AGENTS OR ANTI-INFLAMMATORY AGENTS
-
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.
- -
-
Page/Page column 9
(2008/12/06)
-
- COMPOUNDS FOR TREATING VIRAL INFECTIONS
-
The invention relates to compounds, pharmaceutical compositions and methods useful for treating viral infection.
- -
-
Page/Page column 34; 36; 76; 79
(2008/12/08)
-