Novel Triazole Hybrids of Betulin: Synthesis and Biological Activity Profile

Bębenek, Ewa; Jastrzębska, Maria; Kadela-Tomanek, Monika; Chrobak, Elwira; Orzechowska, Beata; Zwolińska, Katarzyna; Latocha, Małgorzata; Mertas, Anna; Czuba, Zenon; Boryczka, Stanisław

doi:10.3390/molecules22111876

Cited by 54 publications

(47 citation statements)

References 34 publications

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“…These compounds, as well as their derivatives, have a broad spectrum of biological activity, including anticancer, antiviral, antimalarial, antibacterial, anti-inflammatory and hepatoprotective effects [2,3,4]. However, betulin derivatives inhibiting the HIV-1 replication were described for the first time in 1994 and included betulinic acid (half maximal effective concentration (EC 50 ) = 1.6 μM, therapeutic index (TI) = 9.3) and dihydrobetulin (EC 50 = 0.9 µM, TI = 14) [5].…”

Section: Introductionmentioning

confidence: 99%

New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

Chrobak

Marciniec

Dąbrowska

et al. 2019

IJMS

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Since the beginning of the human immunodeficiency virus (HIV) epidemic, many groups of drugs characterized by diverse mechanisms of action have been developed, which can suppress HIV viremia. 3-O-(3′,3′-Dimethylsuccinyl) betulinic acid, known as bevirimat (BVM), was the first compound in the class of HIV maturation inhibitors. In the present work, phosphate and phosphonate derivatives of 3-carboxyacylbetulinic acid were synthesized and evaluated for anti-HIV-1 activity. In vitro studies showed that 30-diethylphosphonate analog of BVM (compound 14a) has comparable effects to BVM (half maximal inhibitory concentrations (IC50) equal to 0.02 μM and 0.03 μM, respectively) and is also more selective (selectivity indices: 3450 and 967, respectively). To investigate the possible mechanism of antiviral effect of 14a, molecular docking was carried out on the C-terminal domain (CTD) of HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1, which was described as a molecular target for maturation inhibitors. Compared with interactions between BVM and the protein, an increased number of strong interactions between ligand 14a and protein, generated by the phosphonate group, was observed.

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Section: Introductionmentioning

confidence: 99%

New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

Chrobak

Marciniec

Dąbrowska

et al. 2019

IJMS

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“…Our studies suggest, that the introduction of acetyl or carbonyl group at the C-3 position of triazole derivatives of triterpenes afforded compounds having a higher anticancer activity against amelanotic melanoma C-32 cell line. Additionally, the compounds 5f and 6f containing the 1-deoxy-β-D-glucopyranosyl substituted triazole ring had a better activity than their parent 3-hydroxyl substituted analogs against C-32, T47D, and SNB-19 cell lines (Bębenek et al 2017 ).…”

Section: Resultsmentioning

confidence: 99%

“…Based on the previously reported method, the acetylenic esters 3 – 4 were converted into triazoles 5a-i and 6a-j by reactions with organic azides in toluene in the presence of copper(I) iodide (Bębenek et al 2017 ). The copper(I) iodide (0.1 eqv, 0.004 g, 0.02 mmol) and the organic azide (1.05 eqv, 0.21 mmol) were added to a solution of propynoylated derivatives 3 or 4 (0.20 mmol) in toluene (4 mL).…”

Section: Methodsmentioning

confidence: 99%

Novel triazoles of 3-acetylbetulin and betulone as anticancer agents

et al. 2018

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The CuAAC reaction of azides and acetylenic triterpenes was used for synthesis of new triazoles of 3-acetylbetulin and betulone. The triazole derivatives were evaluated for their anticancer activity in vitro against amelanotic melanoma C-32, ductal carcinoma T47D and glioblastoma SNB-19 cell lines. 28-[1-(3’-Deoxythymidine-5’-yl)-1H-1,2,3-triazol-4-yl]carbonylbetulone 6e exhibited a significant IC50 value (0.17 µM) against the human glioblastoma SNB-19 cell line, an almost 5-fold higher potency while compared with reference cisplatin.

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“…It consists in the fact that cancer cells produce their Scheme 1. Functionalization of betulin at the C3, C28, and C30 position via CuAAC [33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Glycoconjugation of Betulin Derivatives Using Copper-Catalyzed 1,3-Dipolar Azido-Alkyne Cycloaddition Reaction and a Preliminary Assay of Cytotoxicity of the Obtained Compounds

et al. 2020

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Pentacyclic lupane-type triterpenoids, such as betulin and its synthetic derivatives, display a broad spectrum of biological activity. However, one of the major drawbacks of these compounds as potential therapeutic agents is their high hydrophobicity and low bioavailability. On the other hand, the presence of easily transformable functional groups in the parent structure makes betulin have a high synthetic potential and the ability to form different derivatives. In this context, research on the synthesis of new betulin derivatives as conjugates of naturally occurring triterpenoid with a monosaccharide via a linker containing a heteroaromatic 1,2,3-triazole ring was presented. It has been shown that copper-catalyzed 1,3-dipolar azide-alkyne cycloaddition reaction (CuAAC) provides an easy and effective way to synthesize new molecular hybrids based on natural products. The chemical structures of the obtained betulin glycoconjugates were confirmed by spectroscopic analysis. Cytotoxicity of the obtained compounds was evaluated on a human breast adenocarcinoma cell line (MCF-7) and colorectal carcinoma cell line (HCT 116). The obtained results show that despite the fact that the obtained betulin glycoconjugates do not show interesting antitumor activity, the idea of adding a sugar unit to the betulin backbone may, after some modifications, turn out to be correct and allow for the targeted transport of betulin glycoconjugates into the tumor cells.

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Novel Triazole Hybrids of Betulin: Synthesis and Biological Activity Profile

Cited by 54 publications

References 34 publications

New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

New Phosphorus Analogs of Bevirimat: Synthesis, Evaluation of Anti-HIV-1 Activity and Molecular Docking Study

Novel triazoles of 3-acetylbetulin and betulone as anticancer agents

Glycoconjugation of Betulin Derivatives Using Copper-Catalyzed 1,3-Dipolar Azido-Alkyne Cycloaddition Reaction and a Preliminary Assay of Cytotoxicity of the Obtained Compounds

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