Synthesis, cytotoxic, proapoptotic evaluation, and molecular docking study of some new sulfonyl-3-indolyl heterocycles | ||||
| Egyptian Pharmaceutical Journal | ||||
| Volume 14, Issue 1, January 2015, Page 15-29 PDF (1.26 MB) | ||||
| DOI: 10.4103/1687-4315.154695 | ||||
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| Authors | ||||
| Eslam R. El-Sawy; Heba M. Abo-Salem; Shaymaa M. Yahya; Manal S. Ebaid; Adel H. Mandour | ||||
| Abstract | ||||
| Background and objectives Apoptosis, also called programmed cell death, is a fundamental biological phenomenon that plays a crucial role in processes such as immune regulation, embryogenesis, and general tissue homeostasis. B-cell lymphocyte/leukemia-2 () family members are key regulators of apoptosis. The ability of the indole derivative to disrupt microtubule assembly and induce G2/M arrest, polyploidy, and apoptosis through mitochondrial pathways in COLO 205 cell has been reported; in addition, it reduced the levels of procaspase-3, procaspase-9, -xL, and -2 gene. The aim of this study is to describe the synthesis of some new -substituted sulfonyl-3-indolyl heterocycles and to study their cytotoxic and proapoptotic effects. In addition, a molecular docking study of the most biologically active compounds against the -2 protein is discussed. Materials and methods A new series of triazolopyridines , diaminopyridines , acetamides , triazolo[1,5-] pyridines , pyrido[1,2-][1,2,4]triazines , , pyrazoles , , and pyrimidine derivatives were prepared by an initial reaction of 2-((-substituted sulfonyl-1-indol-3-yl)methylene) malononitriles with different reagents. The newly synthesized compounds were tested for their cytotoxic activity against the HepG2 cell line. The compounds that showed promising IC values were chosen for the study of their proapoptotic effect on the -2 gene, which is an antiapoptotic factor, and they significantly inhibited the expression levels of the -2 gene. The binding mode of the most promising proapoptotic compounds was assessed by docking studies with the CHIMAERIC -XL protein (PDB ID: 2W3L). Results and conclusion From the data obtained, the most active compounds against the HepG2 cancer cell line were in the descending order of , whereas compounds , , , , and 5c showed moderate to slight growth inhibition. Compounds , , , , , and significantly inhibited the expression levels of the -2 gene. Docking results showed that compounds and showed good fitting within the pocket site of the protein molecular surface and had a minimum binding energy of −20.29 and −18.98 kJ/mol, respectively, in comparison with the co-crystallized ligand, which is in agreement with the experimental result of a proapoptotic effect. | ||||
| Keywords | ||||
| Cytotoxic and proapoptotic activities; indole-3-carboxaldehyde; Molecular docking; pyrazole; Pyridine; Pyrimidine | ||||
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