Optimization of 3-aminotetrahydrothiophene 1,1-dioxides with improved potency and efficacy as non-electrophilic antioxidant response element (ARE) activators.

Activating NRF2-driven transcription with non-electrophilic small molecules represents an attractive strategy to therapeutically target disease states associated with oxidative stress and inflammation. In this study, we describe a campaign to optimize the potency and efficacy of a previously identified bis-sulfone based non-electrophilic ARE activator 2. This work identifies the efficacious analog 17, a compound with a non-cytotoxic profile in IMR32 cells, as well as ARE activators 18 and 22, analogs with improved cellular potency. In silico drug-likeness prediction suggested the optimized bis-sulfones 17, 18, and 22 will likely be of pharmacological utility.

Amelioration of Astrocyte-Mediated Neuroinflammation by EI-16004 Confers Neuroprotection in an MPTP-induced Parkinson's Disease Model.

Parkinson's disease (PD) is a neurodegenerative disorder that results in motor impairment due to dopaminergic neuronal loss. The pathology of PD is closely associated with neuroinflammation, which can be characterized by astrocyte activation. Thus, targeting the inflammatory response in astrocytes might provide a novel therapeutic approach. We conducted a luciferase assay on an in-house chemical library to identify compounds with anti-inflammatory effects capable of reducing MPP+-induced NF-κB activity in astrocytes. Among the compounds identified, EI-16004, a novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides, exhibited a significant anti-inflammatory effect by significantly reducing MPP+-induced astrocyte activation. Biochemical analysis and docking simulation indicated that EI-16004 inhibited the MPP+-induced phosphorylation of p65 by attenuating ERK phosphorylation, and EI-16004 reduced pro-inflammatory cytokine and chemokine levels in astrocytes. In vivo studies on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in male C57BL/6 mice showed that EI-16004 ameliorated motor impairment and protected against dopaminergic neuronal loss, and EI-16004 effectively mitigated the MPTP-induced astrocyte activation in striatum (STR) and substantia nigra (SN). These results indicate EI-16004 is a potential neuroprotective agent for the prevention and treatment of astrocyte-mediated neuroinflammatory conditions in PD.

Regulatory role of Echinochrome A in cancer-associated fibroblast-mediated lung cancer cell migration.

Echinochrome A (Ech A), a marine biosubstance isolated from sea urchins, is a strong antioxidant, and its clinical form, histochrome, is being used to treat several diseases, such as ophthalmic, cardiovascular, and metabolic diseases. Cancer-associated fibroblasts (CAFs) are a component of the tumor stroma and induce phenotypes related to tumor malignancy, including epithelial-mesenchymal transition (EMT) and cancer stemness, through reciprocal interactions with cancer cells. Here, we investigated whether Ech A modulates the properties of CAFs and alleviates CAF-induced lung cancer cell migration. First, we observed that the expression levels of CAF markers, Vimentin and fibroblast-activating protein (FAP), were decreased in Ech A-treated CAF-like MRC5 cells. The mRNA transcriptome analysis revealed that in MRC5 cells, the expression of genes associated with cell migration was largely modulated after Ech A treatment. In particular, the expression and secretion of cytokine and chemokine, such as IL6 and CCL2, stimulating cancer cell metastasis was reduced through the inactivation of STAT3 and Akt in MRC5 cells treated with Ech A compared to untreated MRC5 cells. Moreover, while conditioned medium from MRC5 cells enhanced the migration of non-small cell lung cancer cells, conditioned medium from MRC5 cells treated with Ech A suppressed cancer cell migration. In conclusion, we suggest that Ech A might be a potent adjuvant that increases the efficacy of cancer treatments to mitigate lung cancer progression.

A molecular design towards sulfonyl aza-BODIPY based NIR fluorescent and colorimetric probe for selective cysteine detection.

Cysteine (Cys), homocysteine (Hcy) and glutathione (GSH) are essential biothiols for cellular growth, metabolism, and maintenance of a biological system. Thus, the detection of biothiols is highly important for early diagnosis and evaluation of disease progression. In this article, a series of sulfonyl aza-BODIPYs was synthesized, characterized, and examined by 1H-NMR, 13C-NMR, crystallization, photophysical properties and DFT calculation. Among these structures, a fluorescent probe, BDP-1, exhibited selective detection of Cys among various biothiols via nucleophilic aromatic substitution and typical size of Cys molecules. BDP-1 showed color change and near-infrared (NIR) fluorescence enhancement after reaction with Cys to generate BDP-OH, confirmed by HRMS. The red shift of absorption wavelength showed a similar tendency resulting in time-dependent density functional theory (TD-DFT). Furthermore, the calculated detection limit of BDP-1 toward Cys was 5.23 µM. This probe facilitates the colorimetric and fluorescent detection of Cys over other biothiols.