| Autor: |
Kciuk M; Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland.; Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha Street 12/16, 90-237 Lodz, Poland., Marciniak B; Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland., Celik I; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Erciyes University, Kayseri 38280, Turkey., Zerroug E; Group of Computational and Pharmaceutical Chemistry, LMCE Laboratory, University of Biskra, BP 145, Biskra 07000, Algeria., Dubey A; Computational Chemistry and Drug Discovery Division, Quanta Calculus, Greater Noida 274203, Uttar Prades, India.; Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences, Chennai 602105, Tamil Nadu, India., Sundaraj R; Centre for Drug Discovery, Department of Biochemistry, Karpagam Academy of Higher Education, Coimbatore 641021, Tamil Nadu, India., Mujwar S; Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, India., Bukowski K; Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland., Mojzych M; Department of Chemistry, Siedlce University of Natural Sciences and Humanities, 3 Maja 54, 08-110 Siedlce, Poland., Kontek R; Department of Molecular Biotechnology and Genetics, University of Lodz, Banacha 12/16, 90-237 Lodz, Poland. |
| Abstrakt: |
Pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine sulfonamides ( MM -compounds) are a relatively new class of heterocyclic compounds that exhibit a wide variety of biological actions, including anticancer properties. Here, we used caspase enzyme activity assays, flow cytometry analysis of propidium iodide (PI)-stained cells, and a DNA laddering assay to investigate the mechanisms of cell death triggered by the MM -compounds ( MM134 , -6 , -7 , and -9 ). Due to inconsistent results in caspase activity assays, we have performed a bromodeoxyuridine (BrdU) incorporation assay, colony formation assay, and gene expression profiling. The compounds' cytotoxic and pro-oxidative properties were also assessed. Additionally, computational studies were performed to demonstrate the potential of the scaffold for future drug discovery endeavors. MM-compounds exhibited strong micromolar (0.06-0.35 µM) anti-proliferative and pro-oxidative activity in two cancer cell lines (BxPC-3 and PC-3). Activation of caspase 3/7 was observed following a 24-h treatment of BxPC-3 cells with IC 50 concentrations of MM134 , -6, and -9 compounds. However, no DNA fragmentation characteristics for apoptosis were observed in the flow cytometry and DNA laddering analysis. Gene expression data indicated up-regulation of BCL10, GADD45A, RIPK2, TNF, TNFRSF10B, and TNFRSF1A (TNF-R1) following treatment of cells with the MM134 compound. Moreover, in silico studies indicated AKT2 kinase as the primary target of compounds. MM -compounds exhibit strong cytotoxic activity with pro-oxidative, pro-apoptotic, and possibly pro-necroptotic properties that could be employed for further drug discovery approaches. |
