Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid

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

doi:10.1016/j.ejmech.2015.04.057

Cited by 27 publications

(15 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TMP has been used to treat cerebrovascular and cardiovascular diseases, pulmonary diseases, and cancer (Cai et al, ; Lucius et al, ). In addition, various pyrazine derivatives have been evaluated as agents with diverse pharmacological properties such as antimycobacterial (Doležal, Zitko, & Jampílek, ), antibacterial (Foks et al, ), antitumoral (Zhang et al, ), hypoglycemic (Ambrogi, Bloch, Daturi, Logemann, & Parenti, ), anticancer (Kamal et al, ), antiviral (Sebastian et al, ; Singh & Tomassini, ), and analgesic (Xie et al, ). According to expert opinion and the number of compounds and filed patents, the most promising uses are as (1) inhibitors of protein kinases, applicable as antiproliferative, and (2) inhibitors of β‐secretase, applicable for the treatment of Alzheimer's disease (Doležal & Zitko, ).…”

Section: Introductionmentioning

confidence: 99%

Roasting impact on the chemical and physical structure of Criollo cocoa variety (Theobroma cacao L)

Janna

Ciro

et al. 2020

J Food Process Engineering

View full text Add to dashboard Cite

This work analyzed the effect of infrared roasting at 100, 150, and 200 C on the main physical and chemical changes of cocoa. Raw and roasted cocoa were analyzed using Brunauer-Emmett-Teller, Fourier transform infrared spectroscopy, modulated differential scanning calorimetry (MDSC), thermogravimetric analysis (TGA), SPME, and GC-MS. Using MDSC, the fusion of fat at around 35 C, and the desolvation of water and volatile compounds were identified. TGA detected loss of mass of various groups of chemical compounds, including those present pre-roasting and generated during roasting. The unroasted cocoa's total sugar content of 2.71% decreased to 0.64% when roasted at 200 C, whereas roasting at 200 C generated seven (7) pyrazines. Tetramethylpyrazine is the most abundant, reaching the highest concentration when roasted at 150 C, but decreases when roasted at 200 C, due to the high temperature. To obtain the maximum production of favorable pyrazines, the temperature must be controlled based on the quality objectives of the final product. Practical applicationsThe process of roasting cocoa is of great importance to the chocolate and derivatives industry. Knowledge of the chemical and physical changes that occur during roasting can help to optimize the operating conditions to obtain a better-quality product, in particular by conserving and developing the flavor and aroma of fine Criollo cocoa varieties. This will support the industrialization of fine cocoas, presenting an option for improving the economic and social development of marginalized countries and communities.

show abstract

Section: Introductionmentioning

confidence: 99%

Roasting impact on the chemical and physical structure of Criollo cocoa variety (Theobroma cacao L)

Janna

Ciro

et al. 2020

J Food Process Engineering

View full text Add to dashboard Cite

show abstract

“…Therefore, there is a great interest in the synthesis and evaluation of novel He derivatives in order to develop more potential antitumor drugs. Pyrazine is an N -heteroaromatic ring, and the incorporation of N -heteroaromatic rings into organic molecules could improve their antitumor activity and aqueous solubility [ 10 , 22 , 23 ]. Our research group proved that the introduction of ligustrazine to betulinic acid, ursolic acid, glycyrrhetinic acid, and oleanolic acid could significantly improve their antitumor effects in vitro [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

Fang

Zhang

Han

et al. 2018

IJMS

View full text Add to dashboard Cite

Hederagenin (He) is a novel triterpene template for the development of new antitumor compounds. In this study, 26 new He–pyrazine derivatives were synthetized in an attempt to develop potent antitumor agents; they were screened for in vitro cytotoxicity against tumor and non-tumor cell lines. The majority of these derivatives showed much stronger cytotoxic activity than He. Remarkably, the most potent was compound 9 (half maximal inhibitory concentration (IC50) was 3.45 ± 0.59 μM), which exhibited similar antitumor activities against A549 (human non-small-cell lung cancer) as the positive drug cisplatin (DDP; IC50 was 3.85 ± 0.63 μM), while it showed lower cytotoxicity on H9c2 (murine heart myoblast; IC50 was 16.69 ± 0.12 μM) cell lines. Compound 9 could induce the early apoptosis and evoke cell-cycle arrest at the synthesis (S) phase of A549 cells. Impressively, we innovatively introduced the method of cluster analysis modeled as partial least squares discriminant analysis (PLS-DA) into the structure–activity relationship (SAR) evaluation, and SAR confirmed that pyrazine had a profound effect on the antitumor activity of He. The present studies highlight the importance of pyrazine derivatives of He in the discovery and development of novel antitumor agents.

show abstract

“…In vitro studies have shown that BA and its analogue 23-hydroxy betulinic acid (23-HBA) exhibited anti-cancer activity against a wide variety of cancer cells, including melanoma, prostate carcinoma, lung carcinoma, and leukaemia [20–25]. To enhance the benefits and minimize the side effects of this treatment, several novel derivatives have been synthesized.…”

Section: Introductionmentioning

confidence: 99%

“…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

View full text Add to dashboard Cite

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.

show abstract

Design, synthesis and antitumor activity of triterpenoid pyrazine derivatives from 23-hydroxybetulinic acid

Cited by 27 publications

References 18 publications

Roasting impact on the chemical and physical structure of Criollo cocoa variety (Theobroma cacao L)

Roasting impact on the chemical and physical structure of Criollo cocoa variety (Theobroma cacao L)

Design, Synthesis, and Cytotoxic Analysis of Novel Hederagenin–Pyrazine Derivatives Based on Partial Least Squares Discriminant Analysis

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

Contact Info

Product

Resources

About