作者: Hong, Yue ; Ji, Hong ; Liang, Jiajie ; Zhang, Zhiling ; Lv, Qianqian ; Zhang, Tianwan ; Guo, Peiting ; Pan, Lingxue ; Cai, Jianghong ; Chen, Ruiyao ; Zhang, Jing ; Lin, Jiahui ; Chen, Lexian

In this study, twenty-nine coumarin-3-sulfonamide derivatives, twenty-seven of which are original were designed and synthesized. Cytotoxicity assay indicated that most of these derivatives exhibited moderated to good potency against A549 cells. Among them, compound 8q showed potent inhibition against the four tested cancer cell lines, especially A549 cells with IC₅₀ value of 6.01 ± 0.81 μM, and much lower cytotoxicity on the normal cells was observed compared to the reference compounds. Bioinformatics analysis revealed human carbonic anhydrase IX (CAIX) was highly expressed in lung adenocarcinoma (LUAD) and associated with poor prognosis. The inhibitory activity of compound 8q against CAIX was assessed by using molecular docking and molecular dynamics simulations, which revealed prominent interactions of both compound 8q and CAIX at the active site and their high affinity. The results of ELISA assays verified that compound 8q possessed strong inhibitory activity against CAIX and high subtype selectivity, and could also down-regulate the expression of CAIX in A549 cells. Furthermore, the significant inhibitory effects of compound 8q on the migration and invasion of A549 cells were also found. After treatment with compound 8q, intracellular reactive oxygen species (ROS) levels increased and mitochondrial membrane potential (MMP) decreased. Mechanistic investigation using western blotting revealed compound 8q exerted the anti-migrative and anti-invasive effects probably through mitochondria-mediated PI3K/AKT pathway by targeting CAIX. In summary, coumarin-3-sulfonamide derivatives were developed as potential and effective CAIX inhibitors, which were worthy of further investigation.

2024-03-14·Journal of medicinal chemistry1区 · 医学

Discovery and Structure–Activity Relationships of Novel ssDAF-12 Receptor Modulators

1区 · 医学

Article

作者: Cruciani, Gabriele ; Cipolloni, Marco ; Carotti, Andrea ; Di Bona, Stefano ; Goracci, Laura ; Pellicciari, Roberto ; Gioiello, Antimo ; Paccoia, Federico ; Passeri, Daniela ; Ceccarelli, Giada

The nuclear receptor ssDAF-12 has been recognized as the key molecular player regulating the life cycle of the nematode parasite Strongyloides stercoralis. ssDAF-12 ligands permit the receptor to function as an on/off switch modulating infection, making it vulnerable to therapeutic intervention. In this study, we report the design and synthesis of a set of novel dafachronic acid derivatives, which were used to outline the first structure-activity relationship targeting the ssDAF-12 receptor and to unveil hidden properties shared by the molecular shape of steroidal ligands that are relevant to the receptor binding and modulation. Moreover, biological results led to the discovery of sulfonamide 3 as a submicromolar ssDAF-12 agonist endowed with a high receptor selectivity, no toxicity, and improved properties, as well as to the identification of unprecedented ssDAF-12 antagonists that can be exploited in the search for novel chemical tools and alternative therapeutic approaches for treating parasitism such as Strongyloidiasis.

International journal of molecular sciences

Wounds of Companion Animals as a Habitat of Antibiotic-Resistant Bacteria That Are Potentially Harmful to Humans—Phenotypic, Proteomic and Molecular Detection

Article

作者: Bulanda, Klaudia ; Tischner, Marek ; Heliasz, Miłosz ; Czernecka, Natalia ; Stankiewicz, Klaudia ; Siemińska, Izabela ; Ratajewicz, Anna ; Sosińska, Daria ; Lenart-Boroń, Anna ; Ciesielska, Dominika ; Dworak, Kinga

Skin wounds and their infections by antibiotic-resistant bacteria (ARB) are very common in small animals, posing the risk of acquiring ARB by pet owners or antibiotic resistance gene (ARG) transfer to the owners’ microbiota. The aim of this study was to identify the most common pathogens infecting wounds of companion animals, assess their antibiotic resistance, and determine the ARGs using culture-based, molecular, and proteomic methods. A total of 136 bacterial strains were isolated from wound swabs. Their species was identified using chromogenic media, followed by MALDI-TOF spectrometry. Antibiotic resistance was tested using disc diffusion, and twelve ARGs were detected using PCRs. The dominant species included Staphylococcus pseudintermedius (9.56%), E. coli, and E. faecalis (both n = 11, 8.09%). Enterobacterales were mostly resistant to amoxicillin/clavulanic acid (68.3% strains), all Pseudomonas were resistant to ceftazidime, piperacillin/tazobactam, imipenem, and tylosin, Acinetobacter were mostly resistant to tylosin (55.5%), all Enterococcus were resistant to imipenem, and 39.2% of Staphylococci were resistant to clindamycin. Among ARGs, strA (streptomycin resistance), sul3 (sulfonamide resistance), and blaTEM, an extended-spectrum beta-lactamase determinant, were the most frequent. The risk of ARB and ARG transfer between animals and humans causes the need to search for new antimicrobial therapies in future veterinary medicine.

100 项与 ssDAF-12 agonist(University of Perugia) 相关的药物交易

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