Synthesis and Biological Evaluation of Celastrol Derivatives as Potential Immunosuppressive Agents

He, Qi-Wei; Feng, Jiahao; Hu, Xiaolong; Liu, Huan; Huang, Xuefeng; Jiang, Zhenzhou; Zhang, Xiaoqi; Ye, Wen‐Cai; Wang, Hao

doi:10.1021/acs.jnatprod.0c00067

Cited by 18 publications

(14 citation statements)

References 23 publications

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“…As previously reported for other methylene quinones and phenolic nor-triterpenes compounds, replacement of the carboxylic group present in celastrol on C-29 by a methyl ester group reduces the antibacterial activity [14,43]. Celastrol has shown interesting pharmacological activities, although inconveniences related to poor water solubility, high toxicity, or poor stability have also been described [29,44]. Structural modifications in the triterpene quinones scaffolds could be of interest to obtain derivatives with improved antimicrobial activities and to overcome the pharmacokinetic limitations of these compounds.…”

Section: Antimicrobial Activitymentioning

confidence: 87%

Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources

Padilla-Montaño

Guerra

Moujir

2021

Foods

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Species of the Celastraceae family are traditionally consumed in different world regions for their stimulating properties. Celastrol, a triterpene methylene quinone isolated from plants of celastraceas, specifically activates satiety centers in the brain that play an important role in controlling body weight. In this work, the antimicrobial activity and mechanism of action of celastrol and a natural derivative, pristimerin, were investigated in Bacillus subtilis. Celastrol showed a higher antimicrobial activity compared with pristimerin, being active against Gram-positive bacteria with minimum inhibitory concentrations (MICs) that ranged between 0.16 and 2.5 µg/mL. Killing curves displayed a bactericidal effect that was dependent on the inoculum size. Monitoring of macromolecular synthesis in bacterial populations treated with these compounds revealed inhibition in the incorporation of all radiolabeled precursors, but not simultaneously. Celastrol at 3 µg/mL and pristimerin at 10 µg/mL affected DNA and RNA synthesis first, followed by protein synthesis, although the inhibitory action on the uptake of radiolabeled precursors was more dramatic with celastrol. This compound also caused cytoplasmic membrane disruption observed by potassium leakage and formation of mesosome-like structures. The inhibition of oxygen consumption of whole and disrupted cells after treatments with both quinones indicates damage in the cellular structure, suggesting the cytoplasmic membrane as a potential target. These findings indicate that celastrol could be considered as an interesting alternative to control outbreaks caused by spore-forming bacteria.

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Section: Antimicrobial Activitymentioning

confidence: 87%

Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources

Padilla-Montaño

Guerra

Moujir

2021

Foods

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“…1-Hydroxybenzotriazole is a widely-used coupling reagent along with carbodiimides used mostly in amide and ester synthesis [ 11 , 12 ]. While this reagent is mainly used to form intermediate active esters of various natural compounds that further react to form final amides or esters, several studies reported the biological assessment of various 1-hydroxybenzotriazole-triterpene esters, some of which exhibited higher biological effects as opposed to unmodified triterpenes [ 13 , 14 , 15 , 16 , 17 ]. Therefore, 1-hydroxybenzotriazole is a reagent that can be easily used to obtain triazole-containing triterpene esters, with potential increased biological potential.…”

Section: Introductionmentioning

confidence: 99%

Novel Triterpenic Acid—Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents

Mioc

Prodea

et al. 2022

IJMS

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Pentacyclic triterpenes, such as betulinic, ursolic, and oleanolic acids are efficient and selective anticancer agents whose underlying mechanisms of action have been widely investigated. The introduction of N-bearing heterocycles (e.g., triazoles) into the structures of natural compounds (particularly pentacyclic triterpenes) has yielded semisynthetic derivatives with increased antiproliferative potential as opposed to unmodified starting compounds. In this work, we report the synthesis and biological assessment of benzotriazole esters of betulinic acid (BA), oleanolic acid (OA), and ursolic acid (UA) (compounds 1–3). The esters were obtained in moderate yields (28–42%). All three compounds showed dose-dependent reductions in cell viability against A375 melanoma cells and no cytotoxic effects against healthy human keratinocytes. The morphology analysis of treated cells showed characteristic apoptotic changes consisting of nuclear shrinkage, condensation, fragmentation, and cellular membrane disruption. rtPCR analysis reinforced the proapoptotic evidence, showing a reduction in anti-apoptotic Bcl-2 expression and upregulation of the pro-apoptotic Bax. High-resolution respirometry studies showed that all three compounds were able to significantly inhibit mitochondrial function. Molecular docking showed that compounds 1–3 showed an increase in binding affinity against Bcl-2 as opposed to BA, OA, and UA and similar binding patterns compared to known Bcl-2 inhibitors.

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“…The celastrol derivatives 1a – 1o (Table ) were synthesized through nucleophilic reactions between celastrol and organic halides in N , N -dimethylformamide at room temperature. NaHCO 3 was used as the base (see previously published work for details). Then, the C-3 ester derivatives 2a – 2d were synthesized through the reaction of compound 1i with the corresponding anhydride or acyl chloride (Scheme ).…”

Section: Resultsmentioning

confidence: 97%

“…Celastrol derivatives incorporated with hydrophobic structures at the C-29 position can promote disruptions to Hsp90–Cdc37 interactions (Figure ). , Recently, our group has developed three types of celastrol derivatives, namely, C-6-indole-substituted, C-29-esterified, and C-29-amidated celastrol derivatives, and demonstrated their immunosuppressive effects in vitro . Among these compounds, 1a – 1o , in which the C-29 position is substituted by hydrophobic units (Table ), may have more potent Hsp90–Cdc37 disruption activities and antiproliferative activities than celastrol.…”

mentioning

confidence: 99%

Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities

Liu

et al. 2021

J. Nat. Prod.

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Cdc37 associates kinase clients to Hsp90 and promotes the development of cancers. Celastrol, a natural friedelane triterpenoid, can disrupt the Hsp90–Cdc37 interaction to provide antitumor effects. In this study, 31 new celastrol derivatives, 2a–2d, 3a–3g, and 4a–4t, were designed and synthesized, and their Hsp90–Cdc37 disruption activities and antiproliferative activities against cancer cells were evaluated. Among these compounds, 4f, with the highest tumor cell selectivity (15.4-fold), potent Hsp90–Cdc37 disruption activity (IC50 = 1.9 μM), and antiproliferative activity against MDA-MB-231 cells (IC50 = 0.2 μM), was selected as the lead compound. Further studies demonstrated 4f has strong antitumor activities both in vitro and in vivo through disrupting the Hsp90–Cdc37 interaction and inhibiting angiogenesis. In addition, 4f exhibited less toxicity than celastrol and showed a good pharmacokinetics profile in vivo. These findings suggest that 4f may be a promising candidate for development of new cancer therapies.

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Synthesis and Biological Evaluation of Celastrol Derivatives as Potential Immunosuppressive Agents

Cited by 18 publications

References 23 publications

Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources

Antimicrobial Activity and Mode of Action of Celastrol, a Nortriterpen Quinone Isolated from Natural Sources

Novel Triterpenic Acid—Benzotriazole Esters Act as Pro-Apoptotic Antimelanoma Agents

Synthesis and Biological Evaluation of Celastrol Derivatives with Improved Cytotoxic Selectivity and Antitumor Activities

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