Synthesis and Biological Evaluation of Oxygen‐containing Heterocyclic Ring‐fused 23‐Hydroxybetulinic Acid Derivatives as Antitumor Agents

Zhang, Hengyuan; Li, Fangzheng; Zhu, Peiqing; Liu, Jie; Yao, Hequan; Jiang, Jieyun; Ye, Wen‐Cai; Wu, Xiaoming; Xu, Jinyi

doi:10.1111/cbdd.12543

Cited by 19 publications

(10 citation statements)

References 21 publications

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“…Thus, exploring the mechanisms of ROS production and the relationship between mitochondrial dysfunction and ROS production would provide an in-depth understanding of the antitumour mechanisms of BA, 23-HBA and their derivatives. Recently, several in vivo antitumour experiments assessing 23-HBA derivatives against H22 liver cancer and B16 melanoma have been reported [25, 31–33], but these derivatives showed weak antitumour activity. Therefore, the development of novel 23-HBA derivatives with excellent in vivo antitumour activity is urgently needed.…”

Section: Introductionmentioning

confidence: 99%

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Yao

Lei

et al. 2016

J Exp Clin Cancer Res

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BackgroundElevated production of reactive oxygen species (ROS) and an altered redox state have frequently been observed in hepatocellular carcinoma (HCC); therefore, selective killing of HCC cells by chemotherapeutic agents that stimulate ROS generation or impair antioxidant systems may be a feasible approach in HCC chemotherapy. Recently, betulinic acid and its derivatives have attracted attention because they showed anti-cancer effects via a ROS- and mitochondria-related mechanism. However, the source of ROS overproduction and the role of mitochondria were poorly identified, and the weak in vivo antitumour activity of these compounds limits their development as drugs.MethodsCytotoxicity was detected using MTT assays. In vivo anti-HCC effects were assessed using nude mice bearing HepG2 tumour xenografts. Cell cycle analysis, apoptosis rate and mitochondrial membrane potential were measured by flow cytometry. ROS production was detected using a microplate reader or a fluorescence microscope. Changes in gene and protein levels were measured by RT-PCR and western blotting, respectively. Other assays were performed using related detection kits.ResultsB5G9, a piperazidine derivative of 23-hydroxy betulinic acid (23-HBA), showed excellent in vivo anti-HCC effects, with a tumour growth inhibitory rate of greater than 80%, and no significant side effects. B5G9 stimulated the production of ROS, which were derived from the mitochondria, but it had no effect on various other antioxidant systems. Moreover, B5G9 induced mitochondrial dysfunction, which was characterized by morphological changes, membrane potential collapse, membrane permeabilization, and decreases in the O2 consumption rate and ATP production. Furthermore, mtDNA-depleted ρ0 HepG2 cells were less sensitive to B5G9 treatment than wt HepG2 cells, indicating the importance of mitochondria in B5G9-induced cell death.ConclusionWe discovered a piperazidine derivative of 23-HBA, B5G9, with excellent anti-HCC effects both in vivo and in vitro and no obvious toxic effects. The underlying mechanism was associated with mitochondria-derived ROS overproduction, and mitochondria played essential roles in B5G9-induced cell death. This study identified a potential agent for anti-HCC therapy and elucidated the mitochondria-related mechanism of BA and its derivatives.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0457-1) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

Yao

Lei

et al. 2016

J Exp Clin Cancer Res

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“…Since then, Zhang and co-workers have been using similar approaches, to the previously described, to synthesize heterocycle-fused HBA derivatives, starting from the protected form of 3-oxo-HBA 123 (Scheme 32) [80,81,82]. They prepared pyrazine-, pyrazole-, and isoxazole-fused HBA derivatives 135 – 137 , which were assessed for their antitumor activity against cancer cell lines.…”

Section: Synthesis Of Heterocycle-fused Ba/hba Derivativesmentioning

confidence: 99%

“…Moreover, compound 136e (IC 50 = 5.58 and 6.13 µM against B16 and SF763 cancer cell lines, respectively) displayed the most potent activity among the pyrazole-fused HBA series [81]. In addition, compounds 137a and 137e (IC 50 = 6.08–10.04 µM and 6.94–9.74 µM, respectively, against cell lines HL-60, BEL-7402, SF-763, Hela, and B16) were the most potent derivatives among the isoxazole-fused HBA series [82]. Regarding the synthesis of these heterocycle-fused HBA derivatives, the pyrazine-fused HBA derivative 132 was obtained in 68% yield through the reaction of 123 with ethylenediamine and sulfur in refluxing morpholine.…”

Section: Synthesis Of Heterocycle-fused Ba/hba Derivativesmentioning

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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“…Anemoside A3 also showed substantial content in the herb and exerted cognitive enhancing, neuroprotective and vasorelaxing effects (Gao et al, ; Ip et al, ; Zhang et al, ). Moreover, 23‐hydroxybetulinic acid, the aglycone of anemoside B4 and anemoside A3, exhibited anti‐inflammatory and strong cytotoxicity in several cancer cell lines, such as human leukemia HL‐60 cells, hepatocellular carcinoma, cervical adenocarcinoma and melanoma cells (Liu et al, ; Suh et al, ; Zhang et al, ). It was demonstrated that 23‐hydroxybetulinic acid induced apoptosis in HL‐60 cells via the downregulation of pro‐apoptotic gene bcl‐2 expression and telomerase activity as well as the upregulation of the apoptotic gene beclin‐1 expression (Ye & Ji, ).…”

Section: Introductionmentioning

confidence: 99%

A sensitive HPLC–MS/MS method for the simultaneous determination of anemoside B4, anemoside A3 and 23‐hydroxybetulinic acid: Application to the pharmacokinetics and liver distribution of Pulsatilla chinensis saponins

Xie

Lian

et al. 2017

Biomedical Chromatography

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Pulsatilla chinensis saponins, the major active components in the herb, have drawn great attention as potential hepatitis B virus infection and hepatoma treatments. Here, a sensitive and accurate HPLC-MS/MS method was established for simultaneous determination of three saponins - anemoside B4, anemoside A3 and 23-hydroxybetulinic acid - in rat plasma and liver, and fully validated. The method was successfully applied to a pharmacokinetics and liver distribution study of P. chinensis saponins. Consequently, 23-hydroxybetulinic acid, with an extremely low content in the P. chinensis saponins, exhibited the highest exposure in the liver and in sites before and after hepatic disposition, namely, in the portal vein plasma and systemic plasma, followed by anemoside B4, which showed the highest content in the herb, whereas anemoside A3 displayed quite limited exposure. The hepatic first-pass effects were 71% for 23-hydroxybetulinic acid, 27% for anemoside B4 and 37% for anemoside A3, corresponding to their different extents of liver distribution. To our knowledge, this is the first investigation on the liver first-pass effect and distribution of P. chinensis saponins to date. These results also provide valuable information for the understanding of the pharmacological effect of P. chinensis saponins on liver diseases.

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Synthesis and Biological Evaluation of Oxygen‐containing Heterocyclic Ring‐fused 23‐Hydroxybetulinic Acid Derivatives as Antitumor Agents

Cited by 19 publications

References 21 publications

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

A piperazidine derivative of 23-hydroxy betulinic acid induces a mitochondria-derived ROS burst to trigger apoptotic cell death in hepatocellular carcinoma cells

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

A sensitive HPLC–MS/MS method for the simultaneous determination of anemoside B4, anemoside A3 and 23‐hydroxybetulinic acid: Application to the pharmacokinetics and liver distribution of Pulsatilla chinensis saponins

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