Discovery of novel NO-releasing celastrol derivatives with Hsp90 inhibition and cytotoxic activities

Li, Na; Xu, Manyi; Bao, Na; Shi, Wei; Li, Qixing; Zhang, Xiaowei; Sun, Jianbo

doi:10.1016/j.ejmech.2018.10.013

Cited by 9 publications

(3 citation statements)

References 31 publications

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“…In particular, compound (24) had the ability to disturb the Hsp90-CDC37 complex stronger than celastrol, and its antitumor capacity was about 5 times that of celastrol. (Li N. et al, 2018) used esterification and imitization at position C-20 to introduce furoxy NO donors into celastrol to synthesize celastrol/furoxy hybrids. Their antiproliferative to A549, HOS, MCF-7 and HepG2 were evaluated.…”

Section: Other Structural Modifications To Enhance Biological Activitymentioning

confidence: 99%

Celastrol: A Review of Useful Strategies Overcoming its Limitation in Anticancer Application

Shi

et al. 2020

Front. Pharmacol.

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Celastrol, a natural bioactive ingredient derived from Tripterygium wilfordii Hook F, exhibits significant broad-spectrum anticancer activities for the treatment of a variety of cancers including liver cancer, breast cancer, prostate tumor, multiple myeloma, glioma, etc. However, the poor water stability, low bioavailability, narrow therapeutic window, and undesired side effects greatly limit its clinical application. To address this issue, some strategies were employed to improve the anticancer efficacy and reduce the side-effects of celastrol. The present review comprehensively focuses on the various challenges associated with the anticancer efficiency and drug delivery of celastrol, and the useful approaches including combination therapy, structural derivatives and nano/micro-systems development. The specific advantages for the use of celastrol mediated by these strategies are presented. Moreover, the challenges and future research directions are also discussed. Based on this review, it would provide a reference to develop a natural anticancer compound for cancer treatment.

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Section: Other Structural Modifications To Enhance Biological Activitymentioning

confidence: 99%

Celastrol: A Review of Useful Strategies Overcoming its Limitation in Anticancer Application

Shi

et al. 2020

Front. Pharmacol.

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“…To address these concerns, we developed a suitable NO donor by chemical synthesis and molecular dynamics (MD) simulations, namely phenylsulfonylfuroxan (FZ), and the prodrug dimer of FZ (FZ-SS-FZ) which meets the requirements well. FZ is a promising NO donor that can release high levels of NO in the presence of thiol-containing compounds, such as glutathione (GSH), and inhibit tumor growth in vivo , and its potential in anticancer drug design has been well documented. − Specifically, we first synthesized the prodrug dimer (FZ-SS-FZ) of the selected NO donor, which is linked by disulfide and ester bonds. Then, NPs of the prodrug dimer were prepared by the self-assembly of FZ-SS-FZ in water.…”

Section: Introductionmentioning

confidence: 99%

Self-Assembly Dual-Responsive NO Donor Nanoparticles for Effective Cancer Therapy

Chen

Zhang

et al. 2021

ACS Appl. Mater. Interfaces

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Drug resistance and the serious side effects caused by classical chemotherapy drugs necessitate the development of novel targeted drug delivery systems. The high lipophilicity and short half-life of nitric oxide (NO), a gas with strong antitumor activity, make it difficult to reach the tumor site and result in a poor therapeutic effect in vivo. In order to overcome the deficiencies of the existing NO donors and NO delivery vehicles, a novel strategy was proposed to deliver NO for cancer chemotherapy by the prodrug dimer self-assembly nanoparticles of NO donors. Specifically, phenylsulfonylfuroxan (FZ) was chosen as the NO donor to synthesize the prodrug dimer precursor (FZ-SS-FZ) by disulfide linkages and ester bonds. The insertion of disulfide linkages promotes the self-assembly of FZ-SS-FZ in water. After this, the dual-responsive and tumor-targeting NO delivery system (FZ-SS-FZ@FA NPs) will finally be fabricated by further introducing folic acid on the surface of nanoparticles. FZ-SS-FZ can self-assemble to form uniform nanoparticles in water, which can effectively deliver NO to the tumor site and be uptaken by tumor cells, thus resulting in specific NO release in tumor cells and inducing tumor cell apoptosis. FZ-SS-FZ@FA NPs significantly improve the drug loading and delivery efficiencies of NO for chemotherapy, while enhancing its efficacy, providing a novel strategy for the tumortargeted delivery of NO and at the same time laying a theoretical basis for the clinical translation of NO-based gas chemotherapy, opening up a new approach for cancer chemotherapy.

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“…However, unlike its relative triptolide, lots of total synthesis and structural modifications have conducted in the past two decades (Chen, Zhou, & Li, 2012; Hou, Liu, & Xu, 2019b; Kaloun et al., 2016; Liu et al., 2018; Ning et al., 2018; Patil et al., 2015; Wang et al., 2017; Xu, Chen, Tang, Feng, & Li, 2014; Xu et al., 2017; Xu & Liu, 2019; Xu, Tang, Feng, & Li, 2014a, 2014b; Xu, Tang, Yang, Feng, & Li, 2014; Zhang, Xiao, & Xu, 2019; Zhou, Yang, Ding, Li, & Miao, 2012), and some triptolide derivatives have already entered clinic for the treatment of challenging cancer and/or rheumatoid arthritis (RA) (Carter et al., 2012; Pao et al., 2019; Patil et al., 2012; Wang, Xu, Fu, Li, & Lou, 2012; Zhou et al., 2005). So far, there is only one total synthesis (Camelio, Johnson, & Siegel, 2015) and several chemical modifications of celastrol have been reported (Figueiredo, Salvador, Cortés, & Cascante, 2017a; Jiang et al., 2016; Kyriakou et al., 2018; Li et al., 2015, 2018; Pang, Luo, Liu, Wu, & Wang, 2018; Shan et al., 2017; Tang, Huang, Pan, Zhang, & Lu, 2015; Zhang, Zhang, Piao, & Quan, 2018; Zhu et al., 2017), which are largely focused on its anti‐cancer activity. In order to further explore the promising multiple biological activities of celastrol and with the aim to find new anti‐HBV agents with novel chemical structure and mechanism of action, herein we reported the synthesis and anti‐HBV activity evaluation of a series of p QM moiety and C‐20‐modified celastrol derivatives (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of celastrol derivatives as potential non‐nucleoside hepatitis B virus inhibitors

Zhang¹,

Lu²

2020

Chem Biol Drug Des

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A series of para-quinone methide (pQM) moiety and C-20-modified derivatives of celastrol were synthesized and evaluated for their inhibitory effect on the secretion of HBsAg and HBeAg as well as the inhibitory effect against HBV DNA replication. The results suggested that amidation of C-20 carboxylic group could generate derivatives with good anti-HBV profile, among them compound 14 showed the best inhibitory activity on the secretion of HBsAg (IC 50 = 11.9 µμ) and HBeAg (IC 50 = 13.1 µμ) with SI of 3.3 and 3.0, respectively. In addition, 14 also showed potent inhibitory effect against HBV DNA replication (48.5 ± 15.1%, 25 µM). This is, to our knowledge, the first report of celastrol derivatives as potential non-nucleoside HBV inhibitors.

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Discovery of novel NO-releasing celastrol derivatives with Hsp90 inhibition and cytotoxic activities

Cited by 9 publications

References 31 publications

Celastrol: A Review of Useful Strategies Overcoming its Limitation in Anticancer Application

Celastrol: A Review of Useful Strategies Overcoming its Limitation in Anticancer Application

Self-Assembly Dual-Responsive NO Donor Nanoparticles for Effective Cancer Therapy

Synthesis of celastrol derivatives as potential non‐nucleoside hepatitis B virus inhibitors

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