ORIGINAL ARTICLE
Year : 2015  |  Volume : 14  |  Issue : 1  |  Page : 15-29

Synthesis, cytotoxic, proapoptotic evaluation, and molecular docking study of some new N-substituted sulfonyl-3-indolyl heterocycles


1 Department of Natural Compounds Chemistry, National Research Centre, Dokki, Giza, Egypt
2 Department of Hormones, National Research Centre, Dokki, Giza, Egypt

Correspondence Address:
Eslam R El-Sawy
Chemistry Department of Natural Compounds, National Research Centre, Dokki 12311, Giza
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1687-4315.154695

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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 (BCL-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, BCL-xL, and BCL-2 gene. The aim of this study is to describe the synthesis of some new N-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 BCL-2 protein is discussed. Materials and methods A new series of triazolopyridines 3a-c , diaminopyridines 4a-c , acetamides 5a-c , triazolo[1,5-a]pyridines 6a-c-8a-c , pyrido[1,2-b][1,2,4]triazines 9a-c , 10a-c , pyrazoles 11a-c, 12a-c , and pyrimidine derivatives 13a-c-15a-c were prepared by an initial reaction of 2-((N-substituted sulfonyl-1H-indol-3-yl)methylene) malononitriles 2a-c with different reagents. The newly synthesized compounds were tested for their cytotoxic activity against the HepG2 cell line. The compounds that showed promising IC 50 values were chosen for the study of their proapoptotic effect on the BCL-2 gene, which is an antiapoptotic factor, and they significantly inhibited the expression levels of the BCL-2 gene. The binding mode of the most promising proapoptotic compounds was assessed by docking studies with the CHIMAERIC BCL2-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 10b>4c>10a>10c , whereas compounds 3c , 6c , 9c , 4b , and 5c showed moderate to slight growth inhibition. Compounds 4c , 5c , 9c , 10a , 10b , and 10c significantly inhibited the expression levels of the BCL-2 gene. Docking results showed that compounds 5c and 9c 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.


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