Synthesis of Isosteviol analogues as potential protective agents against Doxorubicin-induced cardiomyopathy in zebrafish embryos

Jayachandra, R.; Zhao, Huan; Cheng, Zuchun; Li, Luo; Sun, Tingwei; Tan, Wen

doi:10.1016/j.bmcl.2019.05.033

Cited by 9 publications

(12 citation statements)

References 22 publications

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“…HRMS (ESI+): m/z calcd. for 24.7 (CH 3 ), 28.9 (CH 3 ), 33.0 (CH 2 ), 34.8 (CH 2 ), 37.9 (CH 2 ), 38.0 (C q ), 39.5 (CH 2 ), 41.4 (C q ), 42.9 (C q ), 43.6 (C q ), 43.7 (CH), 48.7 (CH 2 ), 49.9 (CH 2 ), 51.3 (CH 3 ), 53.4 (CH 2 ), 55.2 (CH 3 ), 56.9 (CH), 57.8 (CH), 84.9 (CH), 114.4 (2xCH), 122.3 (C q ), 131.8 (2xCH), 160.2 (C q ), 177.6 (C=O). 25.0 (CH 3 ), 28.9 (CH 3 ), 33.0 (CH 2 ), 35.0 (CH 2 ), 38.0 (CH 2 ), 38.1 (C q ), 39.6 (CH 2 ), 40.7 (C q ), 42.3 (C q ), 43.8 (C q ), 48.4 (CH), 51.1 (CH 3 ), 51.7 (CH 2 ), 53.4 (CH 2 ), 54.3 (CH 2 ), 57.2 (CH), 57.8 (CH), 88.6 (CH), 115.0 (CH), 115.2 (CH), 129.5 (CH), 129.6 (CH), 136.3 (C q-F ), 136.4 (C q-F ) 161.0 (C q-F ), 162.9 (C q-F ), 177.8 (C=O); 19 General procedure for the preparation of amino ketones: To a solution of isosteviol methyl ester 13 (1.80 mmol, 0.60 g) in glacial acetic acid (4 mL), paraformaldehyde (3.60 mmol, 0.10 g) and then secondary amine hydrochlorides (1.80 mmol) was added, and the mixture was treated under reflux conditions for 1.5 h. The solvent was evaporated, and the residue was dissolved in DCM (100 mL).…”

Section: -((((S)-1-phenylethyl) Amino)methyl)tetradecahydro-6a9-methanocyclohepta[a]naphthalene-4-carboxylate (9)mentioning

confidence: 99%

“…Li and co-workers reported compounds with an α-methylenecyclopentanone moiety in the D-ring of isosteviol displaying remarkable anticancer activity against MDA-MB-231 cell line with an IC 50 value of 1.58 µM [23]. Jayachandra and co-workers synthesised isosteviol analogues showing a potential protective effect against DOX-induced cardiotoxicity in zebrafish embryos in vivo [24]. Tao and co-workers reported that Esophageal carcinoma cells were more sensitive to 1,3-aminoalcohols, exhibiting anticancer activities superior to Cisplatin with an IC 50 value 4.01 µM [25].…”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Application of Isosteviol-Based 1,3-Aminoalcohols

Nagy

Zupkó

Szakonyi

2021

IJMS

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Starting from isosteviol, a series of diterpenoid 1,3-aminoalcohol derivatives were stereoselectively synthesised. The acid-catalysed hydrolysis and rearrangement of natural stevioside gave isosteviol, which was transformed to the key intermediate methyl ester. In the next step, Mannich condensation of diterpenoid ketone, paraformaldehyde, and secondary amines resulted in the formation of 1,3-aminoketones with different stereoselectivities. During the Mannich condensation with dibenzylamine, an interesting N-benzyl → N-methyl substituent exchange was observed. Reduction of 1,3-aminoketones produced diastereoisomeric 1,3-aminoalcohols. Alternatively, aminoalcohols were obtained via stereoselective hydroxy-formylation, followed by oxime preparation, reduction, and finally, reductive alkylation of the obtained primary aminoalcohols. An alternative 1,3-aminoalcohol library was prepared by reductive amination of the intermediate 3-hydroxyaldehyde obtained from isosteviol in two-step synthesis. Cytotoxic activity of compounds against human tumour cell lines (A2780, SiHa, HeLa, MCF-7 and MDA-MB-231) was investigated. In our preliminary study, the 1,3-aminoalcohol function and N-benzyl substitution seemed to be essential for the reliable antiproliferative activity. To extend their application, a diterpenoid condensed with 2-phenylimino-1,3-thiazine and -1,3-oxazine was also attempted to prepare, but only formation of thioether intermediate was observed.

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Section: -((((S)-1-phenylethyl) Amino)methyl)tetradecahydro-6a9-methanocyclohepta[a]naphthalene-4-carboxylate (9)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Application of Isosteviol-Based 1,3-Aminoalcohols

Nagy

Zupkó

Szakonyi

2021

IJMS

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“…We have demonstrated that one of those analogues (compound 9), named JC105, protects zebrafish embryos against doxorubicin‐induced cardiotoxicity in vivo. This particular finding suggests that this compound could have cardioprotective properties 3 …”

Section: Introductionmentioning

confidence: 78%

Cardioprotection by isosteviol derivate JC105: A unique drug property to activate ERK1/2 only when cells are exposed to hypoxia‐reoxygenation

Abdul

Rayadurgam

Faiz

et al. 2020

J Cellular Molecular Medi

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In the present study, we have investigated potential cardioprotective properties of Isosteviol analogue we recently synthesized and named JC105. Treatment of heart embryonic H9c2 cells with JC105 (10 μM) significantly increased survival of cells exposed to hypoxia‐reoxygenation. JC105 (10 μM) activated ERK1/2, DRP1 and increased levels of cardioprotective SUR2A in hypoxia‐reoxygenation, but did not have any effects on ERK1/2, DRP1 and/or SUR2A in normoxia. U0126 (10 μM) inhibited JC105‐mediated phosphorylation of ERK1/2 and DRP1 without affecting AKT or AMPK, which were also not regulated by JC105. Seahorse bioenergetic analysis demonstrated that JC105 (10 μM) did not affect mitochondria at rest, but it counteracted all mitochondrial effects of hypoxia‐reoxygenation. Cytoprotection afforded by JC105 was inhibited by U0126 (10 μM). Taken all together, these demonstrate that (a) JC105 protects H9c2 cells against hypoxia‐reoxygenation and that (b) this effect is mediated via ERK1/2. The unique property of JC105 is that selectively activates ERK1/2 in cells exposed to stress, but not in cells under non‐stress conditions.

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“…A single intraperitoneal injection of DOX (10 mg/kg or 20 mg/kg or 25 mg/kg) or a single tail vein DOX (20 mg/ kg) can be used to construct acute cardiotoxicity models in rats and mice [28][29][30][31][32], which showed symptoms such as reduced dietary intake, weight loss, diarrhea, reduced activity, decreased left ventricular ejection fraction, decreased left ventricular pressure change rate (± DP/DTmax), decreased -dP/dtmax, increased left ventricular end-diastolic pressure (LVEDP), myocardial fiber distortion and rupture, increased myocardial cell necrosis, increased type B (BNP), increased lactate dehydrogenase (LDH), and increased calponin T (cTnT); zebrafish embryos were placed in DOX at 30 μM/ 100 μM, and intraperitoneal injection of DOX (20 mg/kg) can replicate the zebrafish embryo and adult zebrafish models of acute cardiotoxicity of doxorubicin, which showed that doxorubicin can cause partial myocardial fiber arrangement disorder, cardiomyocyte sequestration, decreased left ventricular minor axis decoration rate (LVFS) and heart rate (HR), and increased serum BNP [33,34].…”

Section: Animal Model Of Acute Cardiotoxicity Of Doxorubicinmentioning

confidence: 99%

Preparation and Evaluation of Animal Models of Cardiotoxicity in Antineoplastic Therapy

Meng

Fan

Wang

et al. 2022

Oxidative Medicine and Cellular Longevity

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The continuous development of antineoplastic therapy has significantly reduced the mortality of patients with malignant tumors, but its induced cardiotoxicity has become the primary cause of long-term death in patients with malignant tumors. However, the pathogenesis of cardiotoxicity of antineoplastic therapy is currently unknown, and practical means of prevention and treatment are lacking in clinical practice. Therefore, how to effectively prevent and treat cardiotoxicity while treating tumors is a major challenge. Animal models are important tools for studying cardiotoxicity in antitumor therapy and are of great importance in elucidating pathophysiological mechanisms and developing and evaluating modality drugs. In this paper, we summarize the existing animal models in antitumor therapeutic cardiotoxicity studies and evaluate the models by observing the macroscopic signs, echocardiography, and pathological morphology of the animals, aiming to provide a reference for subsequent experimental development and clinical application.

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Synthesis of Isosteviol analogues as potential protective agents against Doxorubicin-induced cardiomyopathy in zebrafish embryos

Cited by 9 publications

References 22 publications

Synthesis and Biological Application of Isosteviol-Based 1,3-Aminoalcohols

Synthesis and Biological Application of Isosteviol-Based 1,3-Aminoalcohols

Cardioprotection by isosteviol derivate JC105: A unique drug property to activate ERK1/2 only when cells are exposed to hypoxia‐reoxygenation

Preparation and Evaluation of Animal Models of Cardiotoxicity in Antineoplastic Therapy

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