Mitochondria-targeted betulinic and ursolic acid derivatives: synthesis and anticancer activity

Nedopekina, Darya A.; Gubaidullin, Rinat R.; Odinokov, V. N.; Maximchik, Polina V.; Zhivotovsky, Boris; Bel'skii, Yuriy P.; Хазанов, В. А.; Manuylova, Arina V.; Gogvadze, Vladimir; Spivak, A. Yu.

doi:10.1039/c7md00248c

Cited by 64 publications

(32 citation statements)

References 40 publications

(35 reference statements)

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“…Spivak et al reported the synthesis of BN- and BA-based triphenylphosphonium derivatives [89,90,91,92]. For instance, BA-based triphenylphosphonium salt 175 was synthesized from 2β-allyl-BA methyl ester 172 (this compound was synthesized through a similar procedure to the one described in Scheme 17 [57]) as follows (Scheme 40): compound 172 underwent hydroboration with BH 3 ·THF, in THF to obtain diol 173 in 55% yield.…”

Section: Miscellaneous Methodologiesmentioning

confidence: 99%

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

et al. 2019

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Betulinic acid (BA) and its natural analogues betulin (BN), betulonic (BoA), and 23-hydroxybetulinic (HBA) acids are lupane-type pentacyclic triterpenoids. They are present in many plants and display important biological activities. This review focuses on the chemical transformations used to functionalize BA/BN/BoA/HBA in order to obtain new derivatives with improved biological activity, covering the period since 2013 to 2018. It is divided by the main chemical transformations reported in the literature, including amination, esterification, alkylation, sulfonation, copper(I)-catalyzed alkyne-azide cycloaddition, palladium-catalyzed cross-coupling, hydroxylation, and aldol condensation reactions. In addition, the synthesis of heterocycle-fused BA/HBA derivatives and polymer‒BA conjugates are also addressed. The new derivatives are mainly used as antitumor agents, but there are other biological applications such as antimalarial activity, drug delivery, bioimaging, among others.

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Section: Miscellaneous Methodologiesmentioning

confidence: 99%

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

et al. 2019

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“…Two of the conjugates derived from ursolic acid and betulinic acid indicated a good range of IC 50 values. Compound 17 ( Table 4 ) derived from UA was obtained by the alkylation of the carboxyl group, C-28 of UA, with triethylene glycol dibromide in dimethylformamide (DMF) using K 2 CO 3 at 50 °C for 3 h [ 159 ]. Jiang et al synthesized a series of UA derivatives as inhibitors of Nuclear factor kappa B (NF-κB) by introducing long-chain amide moieties at the C-28 position, and the β-hydroxy group C-3 was protected by an acetyl group.…”

Section: Chemistry Of Uamentioning

confidence: 99%

Ursolic Acid-Based Derivatives as Potential Anti-Cancer Agents: An Update

Khwaza

Oyedeji

Aderibigbe

2020

IJMS

115

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Ursolic acid is a pharmacologically active pentacyclic triterpenoid derived from medicinal plants, fruit, and vegetables. The pharmacological activities of ursolic acid have been extensively studied over the past few years and various reports have revealed that ursolic acid has multiple biological activities, which include anti-inflammatory, antioxidant, anti-cancer, etc. In terms of cancer treatment, ursolic acid interacts with a number of molecular targets that play an essential role in many cell signaling pathways. It suppresses transformation, inhibits proliferation, and induces apoptosis of tumor cells. Although ursolic acid has many benefits, its therapeutic applications in clinical medicine are limited by its poor bioavailability and absorption. To overcome such disadvantages, researchers around the globe have designed and developed synthetic ursolic acid derivatives with enhanced therapeutic effects by structurally modifying the parent skeleton of ursolic acid. These structurally modified compounds display enhanced therapeutic effects when compared to ursolic acid. This present review summarizes various synthesized derivatives of ursolic acid with anti-cancer activity which were reported from 2015 to date.

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“…This property of triterpenes is widely used in the synthesis of new therapeutic agents that, among other things, have a targeted effect. In particular, a popular trend is the creation of synthetic hybrids based on triterpenes and mitochondria-targeted delocalized cations, which can be used to modulate the activity of membrane proteins and enzymes of these organelles [ 2 , 3 , 4 , 5 , 6 ]. It is well known that mitochondria not only support the functioning of healthy cells, but are also involved in neoplasia and differentiation of cancer cells [ 7 , 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, the poor water solubility of these triterpenes requires the use of high concentrations to accumulate in mitochondria and achieve the desired therapeutic effect, and this may cause numerous side effects that limit their use in clinical medicine. At the same time, triphenylphosphonium (or Rhodamine B)-linked triterpenoid derivatives show a much higher antitumor activity, inducing mitochondria-mediated apoptosis of tumor cells [ 2 , 3 , 4 , 5 , 6 ]. One of the promising penetrating cations showing mitochondrial targeting is the lipophilic delocalized F16 cation exhibiting anticancer activity in the free form [ 22 ], which, however, is manifoldly enhanced upon hybridization with triterpenes.…”

Section: Introductionmentioning

confidence: 99%

Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation

et al. 2021

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This work demonstrates the effects of a newly synthesized conjugate of the plant triterpenoid betulin and the penetrating cation F16 used for mitochondrial targeting. The resulting F16-betulin conjugate revealed a mitochondria-targeted effect, decreasing the mitochondrial potential and inducing superoxide overproduction in rat thymocytes in vitro. It has been suggested that this may cause the cytotoxic effect of the conjugate, which significantly exceeds the effectiveness of its precursors, betulin and F16. Using isolated rat liver mitochondria, we found that the F16-betulin conjugate has a surface-active effect on mitochondrial membranes, causing organelle aggregation. This effect of the derivative resulted in a dose-dependent decrease in mitochondrial transmembrane potential, as well as suppression of respiration and oxidative phosphorylation, especially in the case of nicotinamide adenine dinucleotide (NAD)-fueled organelles. In addition, the F16-betulin conjugate caused an increase in H2O2 generation by mitochondria fueled with glutamate and malate. These effects of the derivative can presumably be due to the powerful suppression of the redox activity of complex I of the mitochondrial electron transport chain. The paper discusses how the mitochondria-targeted effects of the F16-betulin conjugate may be related to its cytotoxic effects.

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Mitochondria-targeted betulinic and ursolic acid derivatives: synthesis and anticancer activity

Abstract: Conjugation of native triterpenoids, namely, betulinic and ursolic acids, with a lypophilic triphenylphosphonium cation led to the dramatic enhancement, as compared to betulinic acid, of their ability to trigger the mitochondrial apoptosis pathway in various types of cancer cells.

Cited by 64 publications

References 40 publications

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

Recent Developments in the Functionalization of Betulinic Acid and Its Natural Analogues: A Route to New Bioactive Compounds

Ursolic Acid-Based Derivatives as Potential Anti-Cancer Agents: An Update

Effect of F16-Betulin Conjugate on Mitochondrial Membranes and Its Role in Cell Death Initiation

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