Dual roles of inflammatory programmed cell death in cancer: insights into pyroptosis and necroptosis.

Programmed cell death (PCD) is essential for cellular homeostasis and defense against infections, with inflammatory forms like pyroptosis and necroptosis playing significant roles in cancer. Pyroptosis, mediated by caspases and gasdermin proteins, leads to cell lysis and inflammatory cytokine release. It has been implicated in various diseases, including cancer, where it can either suppress tumor growth or promote tumor progression through chronic inflammation.

Novel Pyrazole-4-Carboxamide Derivatives Containing Oxime Ether Group as Potential SDHIs to Control .

In the search for novel succinate dehydrogenase inhibitor (SDHI) fungicides to control , thirty-five novel pyrazole-4-carboxamides bearing either an oxime ether or an oxime ester group were designed and prepared based on the strategy of molecular hybridization, and their antifungal activities against five plant pathogenic fungi were also investigated. The results indicated that the majority of the compounds containing oxime ether demonstrated outstanding antifungal activity against and some compounds also displayed pronounced antifungal activities against and . Particularly, compound exhibited the most promising antifungal activity against with an EC value of 0.

Stereoselective Synthesis of β, γ-Fused Bicyclic γ-Ureasultams via an Intramolecular Mannich and aza-Michael Addition Cascade.

A novel approach has been developed for the synthesis of bicyclic β, γ-fused bicyclic γ-ureasultams containing two consecutive chiral centers through an intramolecular Mannich and aza-Michael addition cascade of alkenyl sulfamides. The straightforward practical procedure and readily available starting materials enable the synthesis of variously substituted ureasultams. In addition, bicyclic γ-ureasultams is a class of potential biotin analogues.

Design, Synthesis, and Antifungal Activities of Novel Carboxamides Derivatives Bearing a Chalcone Scaffold as Potential SDHIs.

In search for SDHIs fungicides, twenty-five novel carboxamides containing a chalcone scaffold were designed, synthesized, and evaluated for antifungal activities against five pathogenic fungi. The results showed that compound 5 k exhibited outstanding antifungal activity against R. solani with an EC value of 0.

Design, Synthesis, and Antifungal Activities of Novel Pyrazole-4-carboxamide Derivatives Containing an Ether Group as Potential Succinate Dehydrogenase Inhibitors.

A series of novel pyrazole-4-carboxamides bearing an ether group were designed and synthesized on the basis of the structure of commercial succinate dehydrogenase inhibitor (SDHI) fungicide flubeneteram via scaffold hopping and evaluated for their antifungal activities against five fungi. The bioassay results showed that most of the target compounds exhibited excellent antifungal activity against and some compounds exerted remarkable antifungal activities against , , , and . Particularly, compounds and displayed outstanding antifungal activity against , with an EC value of 0.

Histone Deacetylase and Enhancer of Zeste Homologue 2 Dual Inhibitors Presenting a Synergistic Effect for the Treatment of Hematological Malignancies.

Aberrance of epigenetic modification is one of the important factors leading to hematological malignancies. Histone deacetylase (HDAC) inhibitors and enhancers of zeste homologue 2 (EZH2) inhibitors are demonstrated to be significant epigenic modulators. Cocktail therapy of HDAC inhibitors and EZH2 inhibitors was demonstrated to be a promising strategy in hematological malignancies.

Discovery of precision targeting EZH2 degraders for triple-negative breast cancer.

EZH2 is usually overexpressed in TNBC and other tumors, which has a great influence on the occurrence, development and prognosis of tumors. However, current EZH2 inhibitors, including Tazemetostat and GSK126, affect the methyl catalytic capacity of EZH2 and have little effect on the tumorigenic activity of EZH2 itself, resulting in poor efficacy against most solid tumors. Herein, we designed and optimized proteolytic targeting chimeras (PROTACs) precision targeting EZH2.

Harmine-based dual inhibitors targeting histone deacetylase (HDAC) and DNA as a promising strategy for cancer therapy.

Overexpression of histone deacetylases (HDACs) are observed in different types of cancers, but histone deacetylase inhibitors (HDACIs) have not shown significant efficacy as monotherapy against solid tumors. Recently, studies demonstrated that it is promising to combine HDACIs with DNA damage agents to improve DNA damage level to gain better effect on treating solid tumor. Harmine has been demonstrated to cause DNA damage by intercalating DNA.

Parthenolide Derivatives as PKM2 Activators Showing Potential in Colorectal Cancer.

As a vital kinase in the glycolysis system, PKM2 is extensively expressed in colorectal cancer (CRC) to support the energy and biosynthetic needs. In this study, we designed a series of parthenolide (PTL) derivatives through a stepwise structure optimization, and an excellent derivate showed good activity on PKM2 (AC = 86.29 nM) and displayed significant antiproliferative activity against HT29 (IC = 0.

Discovery of PT-65 as a highly potent and selective Proteolysis-targeting chimera degrader of GSK3 for treating Alzheimer's disease.

GSK3 is a promising target for the treatment of Alzheimer's disease. Here, we describe the design and synthesize of a series of GSK3 degraders based on a click chemistry platform. A series of highly potent GSK3 degraders were obtained.

Novel insights into RIPK1 as a promising target for future Alzheimer's disease treatment.

Alzheimer's disease (AD) is an intractable neurodegenerative disease showing a clinical manifestation with memory loss, cognitive impairment and behavioral dysfunction. The predominant pathological characteristics of AD include neuronal loss, β-amyloid (Aβ) deposition and hyperphosphorylated Tau induced neurofibrillary tangles (NFTs), while considerable studies proved these could be triggered by neuronal death and neuroinflammation. Receptor-interacting protein kinase 1 (RIPK1) is a serine/threonine kinase existed at the cross-point of cell death and inflammatory signaling pathways.

Discovery of First-in-Class Dual PARP and EZH2 Inhibitors for Triple-Negative Breast Cancer with Wild-Type BRCA.

PARP inhibitors have highly significant effects on BRCA mutant cells, allowing targeted therapy of triple-negative breast cancer (TNBC). However, some TBNC patients lack BRCA mutations. Recent studies have shown that EZH2 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors.

Synthesis and evaluation of multi-target-directed ligands with BACE-1 inhibitory and Nrf2 agonist activities as potential agents against Alzheimer's disease.

Cumulative evidence suggests that β-amyloid and oxidative stress are closely related with each other and play key roles in the process of Alzheimer's disease (AD). Multitarget regulation of both pathways might represent a promising therapeutic strategy. Here, a series of selenium-containing compounds based on ebselen and verubecestat were designed and synthesized.

Rhodium(iii) catalyzed olefination and deuteration of tetrahydrocarbazole.

The rhodium-catalyzed olefination and deuteration of tetrahydrocarbazoles in water with the aid of an ,-dimethylcarbamoyl-protected group is presented. This olefination method features a broad substrate scope, good functional-group tolerance, and high efficiency in water. Practical applications of the protocol are illustrated by the synthesis of various evodiamine derivatives.

Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer.

NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed.

Identification and optimization of piperlongumine analogues as potential antioxidant and anti-inflammatory agents via activation of Nrf2.

Oxidative stress and inflammation are significant risk factors for neurodegenerative disease. The Keap1-Nrf2-ARE pathway is one of the most promising defensive systems against oxidative stress. Here, dozens of piperlongumine analogues were designed, synthesized, and tested on PC12 cells to examine neuroprotective effects against HO and 6-OHDA induced damage.

Usnic acid derivatives as tau-aggregation and neuroinflammation inhibitors.

Accumulation of tau protein aggregation plays a crucial role in neurodegenerative diseases, such as Alzheimer's disease (AD). Uncontrollable neuroinflammation and tau pathology form a vicious circle that further aggravates AD progression. Herein, we reported the synthesis of usnic acid derivatives and evaluation of their inhibitory activities against tau-aggregation and neuroinflammation.

A hemicyanine derivative for near-infrared imaging of β-amyloid plaques in Alzheimer's disease.

The formation of amyloid-β (Aβ) plaques in the brain is one of the main pathological features of Alzheimer's disease (AD). The imaging probes, capable of detecting Aβ deposition, are important tools for early diagnosis of AD. In this article, we designed, synthesized and evaluated a cyanine-based near-infrared fluorescence (NIRF) probe ZT-1 for the detection of Aβ deposits in the brain.

Application of Sustainable Natural Bioresources in Agriculture: Iodine-Mediated Oxidative Cyclization for Metal-Free One-Pot Synthesis of -Phenylpyrazole Sarisan Analogues as Insecticidal Agents.

In view of potential agricultural activity of sarisan (isolated from many plants or easily synthesized from sesamol, another biorenewable natural product) analogues, many research studies on the application of these biorenewable and abundant natural resources have been proceeded. A series of novel sarisan analogues containing -phenylpyrazole were synthesized and evaluated for their insecticidal activity against a crop-threatening insect pest, Walker. Meanwhile, an iodine-mediated oxidative intramolecular C-N bond formation methodology has been established for the one-pot synthesis of these -phenylpyrazole-containing sarisan analogues.

Design, synthesis, and antibacterial activity of novel 8-methoxyquinoline-2-carboxamide compounds containing 1,3,4-thiadiazole moiety.

A series of novel 8-methoxyquinoline-2-carboxamide compounds containing 1,3,4-thiadiazole moiety was designed and synthesized by using an active substructure combination method. Then, the antibacterial activities of all the target compounds were evaluated in vitro against three Gram-positive bacteria and three Gram-negative bacteria. The antibacterial assay showed that some target compounds displayed moderate to good antibacterial efficacy in comparison with the reference drug Chloromycin.