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.
Synthesis of betulonic acid derivatives containing amino-acid fragments
Petrenko,Elantseva,Petukhova,Shakirov,Shul'ts,Tolstikov
, p. 331 - 339 (2002)
New derivatives of betulonic acid containing on C-28 fragments of amino acids or their methyl esters were prepared as potential biologically active agents.
Cytotoxic conjugates of betulinic acid and substituted triazoles prepared by Huisgen Cycloaddition from 30-azidoderivatives
Sidova, Veronika,Zoufaly, Pavel,Pokorny, Jan,Dzubak, Petr,Hajduch, Marian,Popa, Igor,Urban, Milan
, (2017)
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.
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.
Semisynthesis, cytotoxicity, antimalarial evaluation and structure-activity relationship of two series of triterpene derivatives
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
, p. 265 - 272 (2018)
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.
Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors
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
, p. 2235 - 2243 (2018)
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.
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 cytotoxic activity of 3-O-acyl/3-hydrazine/2-bromo/20,29- dibromo betulinic acid derivatives
Mukherjee, Rama,Jaggi, Manu,Siddiqui, Mohammad J. A.,Srivastava, Sanjay K.,Rajendran, Praveen,Vardhan, Anand,Burman, Anand C.
, p. 4087 - 4091 (2004)
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.
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.
Pentacyclic triterpene acid conjugated with mitochondria-targeting cation F16: Synthesis and evaluation of cytotoxic activities
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.
, p. 940 - 951 (2021)
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.]
