Pyroptosis is a gasdermins mediated programmed cell death, which has been widely studied in inflammatory disease models. Recently, there are growing evidences that pyroptosis can be chemically induced in cancer cells without any bacterial or viral infection. Pyroptosis may affect all stages of carcinogenesis and has become a new topic in cancer research. In this review, we first briefly introduced pyroptosis. In the subsequent section, we discussed the induction of pyroptosis in cancer and its potential role as a promising target for cancer therapy. In addition, the biological characteristics of gasdermin D (GSDMD) and gasdermin E (GSDME), two important pyroptosis substrates, and their prognostic role in cancer management were reviewed. These results help us to understand the pathogenesis of cancer and develop new drugs, which based on pyroptosis modulation, for cancer patients.

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Induction of Pyroptosis and Its Implications in Cancer Management.

Chalcone is an aromatic ketone that forms the central core of many important biological compounds, which are known as chalcones. Chalcones are the biogenetic precursors of flavonoids and isoflavonoids, which are abundant in plants. Chalcones are active lead molecules in medicinal chemistry for the discovery of new drugs. Here, we review properties, biosynthesis and structural diversity of natural chalcones. Then, we present the synthesis of chalcones and their biological activities with focus on structure–activity relationships. Pharmaceutically important and patented chalcones are also discussed.

Chalcone synthesis, properties and medicinal applications: a review

Natural product derived privileged scaffolds in drug discovery.

Correction for 'State-of-the-art strategies for targeting protein-protein interactions by small-molecule inhibitors' by Chunquan Sheng et al., Chem. Soc. Rev., 2015, DOI: 10.1039/c5cs00252d.

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State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

The crisis of antibiotic resistance necessitates creative and innovative approaches, from chemical identification and analysis to the assessment of bioactivity. Plant natural products (NPs) represent a promising source of antibacterial lead compounds that could help fill the drug discovery pipeline in response to the growing antibiotic resistance crisis. The major strength of plant NPs lies in their rich and unique chemodiversity, their worldwide distribution and ease of access, their various antibacterial modes of action, and the proven clinical effectiveness of plant extracts from which they are isolated. While many studies have tried to summarize NPs with antibacterial activities, a comprehensive review with rigorous selection criteria has never been performed. In this work, the literature from 2012 to 2019 was systematically reviewed to highlight plant-derived compounds with antibacterial activity by focusing on their growth inhibitory activity. A total of 459 compounds are included in this Review, of which 50.8% are phenolic derivatives, 26.6% are terpenoids, 5.7% are alkaloids, and 17% are classified as other metabolites. A selection of 183 compounds is further discussed regarding their antibacterial activity, biosynthesis, structure-activity relationship, mechanism of action, and potential as antibiotics. Emerging trends in the field of antibacterial drug discovery from plants are also discussed. This Review brings to the forefront key findings on the antibacterial potential of plant NPs for consideration in future antibiotic discovery and development efforts.

Ethnobotany and the Role of Plant Natural Products in Antibiotic Drug Discovery.

Privileged structures have been widely used as an effective template in medicinal chemistry for drug discovery. Chalcone is a common simple scaffold found in many naturally occurring compounds. Many chalcone derivatives have also been prepared due to their convenient synthesis. These natural products and synthetic compounds have shown numerous interesting biological activities with clinical potentials against various diseases. This review aims to highlight the recent evidence of chalcone as a privileged scaffold in medicinal chemistry. Multiple aspects of chalcone will be summarized herein, including the isolation of novel chalcone derivatives, the development of new synthetic methodologies, the evaluation of their biological properties, and the exploration of the mechanisms of action as well as target identification. This review is expected to be a comprehensive, authoritative, and critical review of the chalcone template to the chemistry community.

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Chalcone: A Privileged Structure in Medicinal Chemistry.

Resistance of hepatocellular carcinoma (HCC) to existing chemotherapeutic agents largely contributes to the poor prognosis of patients, and discovery of novel anti-HCC drug is in an urgent need. Herein we report ψ-Bufarenogin, a novel active compound that we isolated from the extract of toad skin, exhibited potent therapeutic effect in xenografted human hepatoma without notable side effects. In vitro, ψ-Bufarenogin suppressed HCC cells proliferation through impeding cell cycle progression, and it facilitated cell apoptosis by downregulating Mcl-1 expression. Moreover, ψ-Bufarenogin decreased the number of hepatoma stem cells through Sox2 depression and exhibited synergistic effect with conventional chemotherapeutics. Mechanistic study revealed that ψ-Bufarenogin impaired the activation of MEK/ERK pathway, which is essential in the proliferation of hepatoma cells. ψ-Bufarenogin notably suppressed PI3-K/Akt cascade, which was required in ψ-Bufarenogin-mediated reduction of Mcl-1 and Sox2. ψ-Bufarenogin inhibited the auto-phosphorylation and activation of epithelial growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met), thereafter suppressed their primary downstream cascades Raf/MEK/ERK and PI3-K/Akt signaling. Taken together, ψ-Bufarenogin suppressed HCC growth via inhibiting, at least partially, receptor tyrosine kinases-regulated signaling, suggesting that ψ-Bufarenogin could be a novel lead compound for anti-HCC drug.

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ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling

The p53 and nuclear factor κB (NF-κB) pathways play crucial roles in human cancer development. Simultaneous targeting of both pathways is an attractive therapeutic strategy against cancer. In this study, we report an antitumor molecule that bears a pyrrolo[3,4-c]pyrazole scaffold and functions as an enantiomeric inhibitor against both the p53-MDM2 interaction and the NF-κB activation. It is a first-in-class enantiomeric inhibitor with dual efficacy for cancer therapy. Synergistic effect was observed in vitro and in vivo. Docking and molecular dynamics simulation studies further provided insights into the nature of stereoselectivity.

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Wen Zhang

Papers

Chalcone: A Privileged Structure in Medicinal Chemistry.

ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling

A novel drug discovery strategy: mechanistic investigation of an enantiomeric antitumor agent targeting dual p53 and NF-κB pathways.

A novel drug discovery strategy