Hybrids of arenobufagin and benzoisoselenazol reducing the cardiotoxicity of arenobufagin

Hou, Wen; Huang, Zhi-Xing; Xu, Hong‐Gui; Lin, Jing; Zhang, Dongmei; Peng, Qing; Lin, Hui Yi; Chang, Yiqun; Wang, Long-Hai; Yao, Zhe; Sun, Ping‐Hua; Chen, Weimin

doi:10.1016/j.bmcl.2018.08.038

Cited by 5 publications

(5 citation statements)

References 21 publications

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“…Arenobufagin is derived from herbal medicines and has been used as a drug to treat liver cancer. , The present study is the first to demonstrate the ER-mediated activity of arenobufagin and its presence in samples of the STP. Loratadine is an antihistamine and is used to treat allergies .…”

Section: Resultsmentioning

confidence: 60%

Molecular Characterization of Estrogen Receptor Agonists during Sewage Treatment Processes Using Effect-Directed Analysis Combined with High-Resolution Full-Scan Screening

Gwak

Lee

Cha

et al. 2022

Environ. Sci. Technol.

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Endocrine-disrupting potential was evaluated during the sewage treatment process using in vitro bioassays. Aryl hydrocarbon receptor (AhR)-, androgen receptor (AR)-, glucocorticoid receptor (GR)-, and estrogen receptor (ER)-mediated activities were assessed over five steps of the treatment process. Bioassays of organic extracts showed that AhR, AR, and GR potencies tended to decrease through the sewage treatment process, whereas ER potencies did not significantly decrease. Bioassays on reverse-phase high-performance liquid chromatography fractions showed that F5 (log K OW 2.5–3.0) had great ER potencies. Full-scan screening of these fractions detected two novel ER agonists, arenobufagin and loratadine, which are used pharmaceuticals. These compounds accounted for 3.3–25% of the total ER potencies and 4% of the ER potencies in the final effluent. The well-known ER agonists, estrone and 17β-estradiol, accounted for 60 and 17% of the ER potencies in F5 of the influent and primary treatment, respectively. Fourier transform ion cyclotron resonance mass spectrometry analysis showed that various molecules were generated during the treatment process, especially CHO and CHOS (C: carbon, H: hydrogen, O: oxygen, and S: sulfur). This study documented that widely used pharmaceuticals are introduced into the aquatic environments without being removed during the sewage treatment process.

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Section: Resultsmentioning

confidence: 60%

Molecular Characterization of Estrogen Receptor Agonists during Sewage Treatment Processes Using Effect-Directed Analysis Combined with High-Resolution Full-Scan Screening

Gwak

Lee

Cha

et al. 2022

Environ. Sci. Technol.

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“…Induced resibufogenin delayed after depolarization and triggered arrhythmias in cardiac fiber at high concentrations in vitro and in vivo (Xie et al, 2002). Arenobufagin was also reported to induce obvious myocardial damage (Deng et al, 2017;Hou et al, 2018). Steroid saponins in some CMM have also been shown to be cardiotoxic.…”

Section: Terpenoidsmentioning

confidence: 99%

Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica–Induced Cardiotoxicity

Zhou

Cao

et al. 2021

Front. Pharmacol.

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Chinese materia medica (CMM) has been applied for the prevention and treatment of diseases for thousands of years. However, arrhythmia, myocardial ischemia, heart failure, and other cardiac adverse reactions during CMM application were gradually reported. CMM-induced cardiotoxicity has aroused widespread attention. Our review aimed to summarize the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity. All relevant articles published on the PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases for the latest twenty years were searched and manually extracted. The risk substances of CMM-induced cardiotoxicity are relatively complex. A single CMM usually contains various risk compounds, and the same risk substance may exist in various CMM. The active and risk substances in CMM may be transformed into each other under different conditions, such as drug dosage, medication methods, and body status. Generally, the risk compounds of CMM-induced cardiotoxicity can be classified into alkaloids, terpenoids, steroids, heavy metals, organic acids, toxic proteins, and peptides. Traditional evaluation methods of chemical drug-induced cardiotoxicity primarily include cardiac function monitoring, endomyocardial biopsy, myocardial zymogram, and biomarker determination. In the preclinical stage, CMM-induced cardiotoxicity should be systematically evaluated at the overall, tissue, cellular, and molecular levels, including cardiac function, histopathology, cytology, myocardial zymogram, and biomarkers. Thanks to the development of systematic biology, the higher specificity and sensitivity of biomarkers, such as genes, proteins, and metabolic small molecules, are gradually applied for evaluating CMM-induced cardiotoxicity. Previous studies on the mechanisms of CMM-induced cardiotoxicity focused on a single drug, monomer or components of CMM. The interaction among ion homeostasis (sodium, potassium, and calcium ions), oxidative damage, mitochondrial injury, apoptosis and autophagy, and metabolic disturbance is involved in CMM-induced cardiotoxicity. Clarification on the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity must be beneficial to guide new CMM development and post-marketed CMM reevaluation.

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“…[18] To reduce the cardiac toxicity which caused by the oxidative damage, novel hybrids of arenobufagin and reactive oxygen species (ROS) scavenger benzoisoselenazols were designed and compound 3 was discovered indicated potent in vitro cytotoxicity against HepG2 and HepG2/ADM cells. [19] Furthermore, compound 3 also showed weaker cytotoxicity against human myocardial AC16 cell than that of arenobufagin.…”

Section: Introductionmentioning

confidence: 99%

“…However, apparent cardiac toxicity limited further antitumor drug development of arenobufagin [15–16] . Motivated by reducing cardiac toxicity and increasing solution, great efforts have been performed and a serial of new molecules have been found with potent antitumor activity and low cardiotoxicity [17–19] . To investigate the structure‐activity relationships (SAR) of arenobufagin, four 3‐ester derivatives had been synthesized by a semi‐synthetic route and their cytotoxic activities were evaluated.…”

Section: Introductionmentioning

confidence: 99%

“… [17] Further investigation on reducing the cardiac toxicity of natural arenobufagin was performed and a tumor‐specific fibroblast activation protein α (FAPα) activated prodrug strategy led to the discovery of compound 2 which exhibited significant antitumor activity with lower cardiotoxicity compared to arenobufagin [18] . To reduce the cardiac toxicity which caused by the oxidative damage, novel hybrids of arenobufagin and reactive oxygen species (ROS) scavenger benzoisoselenazols were designed and compound 3 was discovered indicated potent in vitro cytotoxicity against HepG2 and HepG2/ADM cells [19] . Furthermore, compound 3 also showed weaker cytotoxicity against human myocardial AC16 cell than that of arenobufagin.…”

Section: Introductionmentioning

confidence: 99%

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Discovery of Novel 3,11‐Bispeptide Ester Arenobufagin Derivatives with Potential in Vivo Antitumor Activity and Reduced Cardiotoxicity

Tang

Zhang

Yang

et al. 2023

Chemistry & Biodiversity

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Arenobufagin, one of the bufadienolides isolated from traditional Chinese medicine Chan'su, exhibits potent antitumor activity. However, serious toxicity and small therapeutic window limits its drug development. In the present study, to our knowledge, novel 3,11‐bispeptide ester arenobufagin derivatives have been firstly designed and synthesized on the base of our previous discovery of active 3‐monopeptide ester derivative. The in vitro antiproliferative activity evaluation revealed that the moiety at C3 and C11 hydroxy had an important influence on cytotoxic activity and selectivity. Compound ZM350 notably inhibited tumor growth by 58.8 % at a dose 10 mg/kg in an A549 nude mice xenograft model. Therefore, compound ZM350 also presented a concentration‐dependent apoptosis induction and low inhibitory effect against both hERG potassium channel and Cav1.2 calcium channel. Our study suggests that novel 3,11‐bispeptide ester derivatives will be a potential benefit to further antitumor agent development of arenobufagin.

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Hybrids of arenobufagin and benzoisoselenazol reducing the cardiotoxicity of arenobufagin

Cited by 5 publications

References 21 publications

Molecular Characterization of Estrogen Receptor Agonists during Sewage Treatment Processes Using Effect-Directed Analysis Combined with High-Resolution Full-Scan Screening

Molecular Characterization of Estrogen Receptor Agonists during Sewage Treatment Processes Using Effect-Directed Analysis Combined with High-Resolution Full-Scan Screening

Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica–Induced Cardiotoxicity

Discovery of Novel 3,11‐Bispeptide Ester Arenobufagin Derivatives with Potential in Vivo Antitumor Activity and Reduced Cardiotoxicity

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