Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation

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Ashwini, N. and Garg, M. and Mohan, C.D. and Fuchs, J.E. and Rangappa, S. and Anusha, S. and Swaroop, T.R. and Rakesh, K.S. and Kanojia, D and Madan, V. and Bender, A. and Koeffler, H.P. and Basappa, . and Rangappa, K.S. (2015) Synthesis of 1,2-benzisoxazole tethered 1,2,3-triazoles that exhibit anticancer activity in acute myeloid leukemia cell lines by inhibiting histone deacetylases, and inducing p21 and tubulin acetylation. Bioorganic and Medicinal Chemistry, 23 (18). pp. 6157-6165. ISSN 09680896

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Synthesis of 1,2-Benzisoxazole Tethered 1,2,3-Triazoles That Exhibit.pdf

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Official URL: https://doi.org/10.1016/j.bmc.2015.07.069

Abstract

1,2,3-Triazole-based heterocycles have previously been shown to possess significant anticancer activity in various tumor models. In the present study, we attached a 1,2,3-triazole moiety to the third position of a 1,2-benzisoxazole heterocycle via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with various alkynes and established for the title compounds significant antiproliferative effect against human acute myeloid leukemia (AML) cells. Among the tested compounds, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)benzodisoxazole (PTB) was found to be the most potent antiproliferative agent with an IC<inf>50</inf> of 2 μM against MV4-11 cells using MTT assay. Notably, PTB induced cytotoxicity in MOLM13, MOLM14 and MV4-11 cells with selectivity over normal bone marrow cells (C57BL/6). Furthermore, PTB was found to induce cytotoxicity by increasing apoptosis of AML cells (MOLM13, MOLM14 and MV4-11) as well as sub-G1 cell population and apoptotic cells at submicromolar concentrations, as shown by flow cytometry and Annexin-V staining, respectively. On the protein level we suggested histone deacetylases (HDACs) as the potential protein target of those compounds in silico, and the predicted target was next experimentally validated by measuring the variations in the levels of p21, cyclin D and acetylation of histone H3 and tubulin. Molecular docking analysis of the title compounds with the second deacetylase domain of HDAC6 displayed high degree of shape complementarity to the binding site of the enzyme, forming multiple molecular interactions in the hydrophobic region as well as a hydrogen bond to the phenol side-chain of Tyr-782. Thus, 1,2,3-triazole derivatives appear to represent a class of novel, biologically active ligands against histone deacetylases which deserve to be further evaluated in their applications in the cancer field. © 2015 Elsevier Ltd. All rights reserved.

Item Type: Article
Additional Information: cited By 0
Uncontrolled Keywords: (4 (3,5 bis(trifluoromethyl)phenyl) 1h 1,2,3 triazol 1 yl)benzodisoxazole; (4 (4 methoxyphenyl) 1h 1,2,3 triazol 1 yl)benzod isoxazole; (4 (4 tolyl) 1h 1,2,3 triazol 1 yl)benzodisoxazole; (4 phenyl 1h 1,2,3 triazol 1 yl)benzodisoxazole; 1,2 benzisoxazole; 1,2,3 triazole derivative; 3 (4 (3 methoxy 5 methylphenyl) 1h 1,2,3 triazol 1 yl) benzodisoxazole; 3 (4 (4 phenoxyphenyl) 1h 1,2,3 triazol 1 yl)benzod isoxazole; 3 (4 (4 phenoxyphenyl) 1h 1,2,3 triazol 1 yl)benzodisoxazole; antineoplastic agent; cyclin D; histone deacetylase; histone deacetylase 6; isoxazole derivative; lipocortin 5; protein p21; tubulin; tyrosine; unclassified drug, acute myeloblastic leukemia; animal cell; antineoplastic activity; antiproliferative activity; apoptosis; Article; binding site; bone marrow cell; cell cycle G1 phase; cell population; cell proliferation; computer model; controlled study; cycloaddition; cytotoxicity; flow cytometry; G2 phase cell cycle checkpoint; histone acetylation; human; human cell; hydrogen bond; IC50; leukemia cell line; molecular docking; molecular interaction; MOLM13 cell line; MOLM14 cell line; mouse; MTT assay; MV4 11 cell line; nonhuman; protein expression; protein targeting; synthesis
Subjects: Faculty of Science > Pure Sciences > Chemistry
Divisions: Jnana Bharathi / Central College Campus > Department of Chemistry
Depositing User: Mr. Kirana Kumar D
Date Deposited: 20 Apr 2016 11:20
Last Modified: 20 Apr 2016 11:20
URI: http://eprints-bangaloreuniversity.in/id/eprint/3250

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