Design, synthesis and antitumor evaluation of novel celastrol derivatives

Xu, Manyi; Li, Na; Zhao, Zihao; Shi, Zhixian; Sun, Jianbo

doi:10.1016/j.ejmech.2019.04.050

Cited by 20 publications

(16 citation statements)

References 31 publications

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“…It involves the integration of two active drug groups to obtain a new molecular framework with improved efficiency and lower toxicity than those of the parent compounds. Xu et al 97 used this strategy to synthesize 32 derivatives (Scheme 14A). 97 These derivatives are hybrid molecules composed of celastrol and methyl ferulate connected via different linkers.…”

Section: Chemical Synthesis and Structural Modificationsmentioning

confidence: 99%

“…Xu et al 97 used this strategy to synthesize 32 derivatives (Scheme 14A). 97 These derivatives are hybrid molecules composed of celastrol and methyl ferulate connected via different linkers. The SAR study of their in vitro anticancer activity against A549, MCF‐7, and HepG2 cells showed that Compound 191 exhibited the highest cytotoxicity (IC 50 = 0.15–0.26 μM).…”

Section: Chemical Synthesis and Structural Modificationsmentioning

confidence: 99%

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Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone‐methide triterpenoid celastrol

Lü

Liu

Zhou

et al. 2020

Medicinal Research Reviews

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Celastrol, a quinone‐methide triterpenoid, was extracted from Tripterygium wilfordii Hook. F. in 1936 for the first time. Almost 70 years later, it is considered one of the molecules most likely to be developed into modern drugs, as it exhibits notable bioactivity, including anticancer and anti‐inflammatory activity, and exerts antiobesity effects. In addition, the molecular mechanisms underlying its bioactivity are being widely studied, which offers new avenues for its development as a pharmaceutical reagent. Owing to its potential therapeutic effects and unique chemical structure, celastrol has attracted considerable interest in the fields of organic, biosynthesis, and medicinal chemistry. As several steps in the biosynthesis of celastrol have been revealed, the mechanisms of key enzymes catalyzing the formation and postmodifications of the celastrol scaffold have been gradually elucidated, which lays a good foundation for the future heterogeneous biosynthesis of celastrol. Chemical synthesis is also an effective approach to obtain celastrol. The total synthesis of celastrol was realized for the first time in 2015, which established a new strategy to obtain celastroid natural products. However, owing to the toxic effects and suboptimal pharmacological properties of celastrol, its clinical applications remain limited. To search for drug‐like derivatives, several structurally modified compounds were synthesized and tested. This review focuses primarily on the latest research progress in the biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of celastrol. We anticipate that this paper will facilitate a more comprehensive understanding of this promising compound and provide constructive references for future research in this field.

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Section: Chemical Synthesis and Structural Modificationsmentioning

confidence: 99%

Section: Chemical Synthesis and Structural Modificationsmentioning

confidence: 99%

Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone‐methide triterpenoid celastrol

Lü

Liu

Zhou

et al. 2020

Medicinal Research Reviews

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“…In order to disrupt the key hydrogen bond more efficiently, Xu et al recently reported a series of CEL hybrids incorporated with methyl ferulate and its derivatives (hydrophobic structures) and the antiproliferative activity of these hybrids was higher than that of CEL. The immunoprecipitation experiment showed that compound 29 (Xu’s study) disrupted the Hsp90–Cdc37 interaction more efficiently than CEL . Thus, introduction of a hydrophobic structure to CEL may be a promising strategy in the discovery of CEL derivatives as Hsp90–Cdc37 interaction disruptors.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Novel Celastrol Derivatives as Hsp90–Cdc37 Interaction Disruptors with Antitumor Activity

Wang

et al. 2019

J. Med. Chem.

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To develop novel and efficient heat shock protein 90–cell division cycle 37 (Hsp90–Cdc37) interaction disruptors, several lipophilic fragments were introduced into celastrol (CEL) to synthesize 48 new CEL derivatives. Among all the target compounds, 41 was screened with superior antiproliferative activity on related cancer cells (IC50: 0.41–0.94 μM) and 41 could decrease the level of the Hsp90–Cdc37 complex in A549 cells. The capability to disrupt the Hsp90–Cdc37 interaction was stronger than that of CEL. Furthermore, pull-down assay, UV assay, and molecular docking analysis all showed that 41 might disrupt the interaction of the Hsp90–Cdc37 complex by preferentially binding to Cdc37 in cancer cells. Further studies showed that 41 could significantly regulate the levels of Hsp90–Cdc37 clients, thereby inducing the apoptosis of cancer cells. Together, 41 is a novel Hsp90–Cdc37 disruptor by binding to Cdc37 (hydrogen bond and/or covalent bond). Our results may provide reference for the discovery of effective Hsp90–Cdc37 disruptors.

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“…Celastrol exerts potent antiproliferative effects on several cancer cell lines, such as gliomas, hepatocellular carcinomas, prostate cancer, and breast cancer . Although celastrol has potent cytotoxic effects, its high toxicity results in poor selectivity for tumor cells versus nonmalignant cells, severely restricting its clinical application. , In recent years, efforts have been devoted to the optimization of celastrol through structural modification, leading to the production of several celastrol derivatives with enhanced biological effects; however, their toxicity has not been improved. − Reduced toxicity and enhanced efficacy remain the key targets for celastrol modification.…”

mentioning

confidence: 99%

“…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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Design, synthesis and antitumor evaluation of novel celastrol derivatives

Cited by 20 publications

References 31 publications

Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone‐methide triterpenoid celastrol

Biosynthesis, total synthesis, structural modifications, bioactivity, and mechanism of action of the quinone‐methide triterpenoid celastrol

Discovery of Novel Celastrol Derivatives as Hsp90–Cdc37 Interaction Disruptors with Antitumor Activity

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

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