<i>ent</i>-Jungermannenone C Triggers Reactive Oxygen Species-Dependent Cell Differentiation in Leukemia Cells

Yue, Zhihui; Xiao, Xinhua; Wu, Ji‐Wei; Zhou, Anne X-Z; Liu, Weilong; Liu, Yaxi; Li, Houhua; Chen, Guoqiang; Wu, Yingli; Lei, Xiaoguang

doi:10.1021/acs.jnatprod.7b00722

Cited by 7 publications

(4 citation statements)

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“…As a readout, we performed a flow cytometry assay of the drugs using the myeloid surface marker CD11b, whose expression correlates with morphological and functional differentiation in NB4 cells 15,40,41 . According to literature 40,41,42,43,44,45,46 , many investigational drugs do not significantly induce differentiation in NB4 cells unless combined with ATRA. We thus hypothesised that PML-RARα could be a critical target, and a core component which inhibits differentiation-inducing pathways or mechanisms.…”

Section: Experimental Validation Of Cmap-predicted Drugsmentioning

confidence: 99%

Identification of drugs for leukaemia differentiation therapy by network pharmacology

et al. 2019

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Acute leukaemias differ from their normal haematopoietic counterparts in their inability to differentiate. This phenomenon is thought to be the result of aberrant cellular reprogramming involving transcription factors (TFs). Here we leveraged on Mogrify, a network-based algorithm, to identify TFs and their gene regulatory networks that drive differentiation of the acute promyelocytic leukaemia (APL) cell line NB4 in response to ATRA (all-trans retinoic acid). We further integrated the detected TF regulatory networks with the Connectivity Map (CMAP) repository and recovered small molecule drugs which induce similar transcriptional changes. Our method outperformed standard approaches, retrieving ATRA as the top hit. Of the other drug hits, dimaprit and mebendazole enhanced ATRA-mediated differentiation in both parental NB4 and ATRA-resistant NB4-MR2 cells. Thus, we provide proof-of-principle of our network-based computational platform for drug discovery and repositioning in leukaemia differentiation therapy, which can be extended to other dysregulated disease states.

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Section: Experimental Validation Of Cmap-predicted Drugsmentioning

confidence: 99%

Identification of drugs for leukaemia differentiation therapy by network pharmacology

et al. 2019

Preprint

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“…Interestingly, in addition to HSP70, Fabrizio et al also identified peroxiredoxin‐1 (PRDX1) as a cellular target of oridonin 47 . PRDX1 is overexpressed in AML 115 and is a thiol reductase that plays a critical role in oxidative stress by neutralizing ROS 116 . Therefore, the increase in ROS by oridonin may be associated with its binding to GSH, TrxR, and Trx, as well as PRDX1.…”

Section: Direct Cellular Targets Of Oridonin and Its Derivative Compo...mentioning

confidence: 99%

Direct cellular targets and anticancer mechanisms of the natural product oridonin

Yao

Liu

Sun

et al. 2023

MedComm – Future Medicine

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Cancer is one of the leading causes of death worldwide. The proliferation, survival, and metastasis of cancer cells are governed by a complex series of intracellular and extracellular signaling pathways. Therefore, efficient cancer therapy often requires the modulation of multiple targets. Besides, the modulation of several biological targets with a single drug can lead to synergistic therapeutic effects and avoid side effects associated with combination therapy. Oridonin, an ent-kaurane type diterpenoid isolated from Rabdosia rubescens, has been reported to possess potent antiinflammatory, antioxidant, anticancer, and neuroprotective activities. Among its many benefits, the anticancer effects have attracted the most attention because of its effectiveness in many tumor cells and its potential to overcome therapeutic resistance. Recently, several proteins involved in oncogenic signaling, including CRM1, PHGDH, HSP70, AML1-ETO, and STAT3, were identified as functional targets of oridonin and its analogs. The binding mechanism and the consequence of oridonin binding to these oncogenic proteins are summarized and discussed. These advances suggest that oridonin exhibits broad spectrum anticancer effects by targeting multiple oncogenic proteins mainly via Michael addition between its unsaturated ketone and the cysteines in the target proteins. Therefore, oridonin and its derivatives hold the potential to be developed as multitargeting anticancer drugs.

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“…Our group focuses on the use of bioactive small molecules to probe fundamental biological systems through a forward chemical genetic approach (Figure ). With the aim of discovering novel Nrf2 (nuclear factor erythroid 2-related factor 2) activators as lead compounds for the development of chemoprotective agents, ent -kaurane diterpenoid-pterisolic acid B was discovered from over 3000 compounds, and total synthesis is required as a kick-off course for understanding the MOA of ent -kauranes. Ultimately, we have demonstrated that pterisolic acid B shows a significant cytoprotective effect against cisplatin-induced cytotoxicity by covalently modifying cysteine-171 of keap1 (Kelch-like ECH-associated protein 1) .…”

Section: Total Syntheses Of Ent-kaurane Diterpenoids Through Radical ...mentioning

confidence: 99%

New Strategies in the Efficient Total Syntheses of Polycyclic Natural Products

et al. 2020

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Metrics & MoreArticle Recommendations CONSPECTUS: Polycyclic natural products are an inexhaustible source of medicinal agents, and their complex molecular architecture renders challenging synthetic targets where innovative and effective approaches for their rapid construction are urgently required. The total synthesis of polycyclic natural products has witnessed exponential progression along with the emergence of new synthetic strategies and concepts, such as sequential C−H functionalizations, radical-based transformations, and functional group pairing strategies. Our group exerts continued interest in the construction of bioactive and structurally complex natural products as well as evaluation of the mode of action of these molecules. In this Account, we will showcase how these new synthetic strategies are employed and guide our total synthesis endeavors.During the last two decades, a series of remarkable advances in C−H functionalization have led to the emergence of many new approaches to directly functionalize C−H bonds into useful functional groups. These selective transformations have provided a great opportunity for the step-and atom-economical construction of key fragments in complex molecule synthesis. We recently furnished the total syntheses for polycyclic natural products: incarviatone A, chrysomycin A, polycarcin V, and gilvocarcin V by employing a multiple C−H bond functionalization strategy. The polysubstituted benzene or naphthalene skeleton was constructed through sequential and site-selective C−H functionalizations from readily available simple starting materials, which reduced the number of steps and streamlined synthesis.Recently, we have also completed the total syntheses for a number of skeletally diverse tetracyclic Isodon diterpenoids inspired by their biogenesis and radical-based retrosynthetic disconnections. Radical transformations are strategically and tactically utilized in our syntheses, and radical-based reactions, including organo-SOMO catalysis, Birch reduction, regioselective 1,6-dienyne reductive cyclization, visible-light-mediated Schenck ene reaction, and photoradical-mediated late-stage skeletal rearrangement, play significant roles in our synthetic endeavors. Protecting-group-free and scalable syntheses are also built into our work to achieve the "ideal" synthesis. Furthermore, our synthetic work reveals that late-stage skeletal rearrangement through a photo radical process is possible in a biological setting in complement with nature's carbocation chemistry in complex natural product biosynthesis.Lycopodium alkaloids are a large family of structurally unique polycyclic natural products with impressive biological activities. Owing to their fascinating polycyclic architectures and diverse biological activities, these alkaloids have continued to serve as targets as well as inspirations for the synthetic community for decades. To access these bioactive natural products or natural product-like molecules for biological exploration and drug discovery, we applied a novel functional ...

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ent-Jungermannenone C Triggers Reactive Oxygen Species-Dependent Cell Differentiation in Leukemia Cells

Cited by 7 publications

References 31 publications

Identification of drugs for leukaemia differentiation therapy by network pharmacology

Identification of drugs for leukaemia differentiation therapy by network pharmacology

Direct cellular targets and anticancer mechanisms of the natural product oridonin

New Strategies in the Efficient Total Syntheses of Polycyclic Natural Products

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