title: 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.
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)benzo[d]isoxazole (PTB) was found to be the most potent antiproliferative agent with an IC50 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.
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India.
authors: Nanjundaswamy
authors: N
authors: Ashwini
authors: Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, 117 599, Singapore.
authors: Manoj
authors: M
authors: Garg
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India.
authors: Chakrabhavi Dhananjaya
authors: CD
authors: Mohan
authors: Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom.
authors: Julian E
authors: JE
authors: Fuchs
authors: Frontier Research Center for Post-genome Science and Technology Hokkaido University, Japan.
authors: Shobith
authors: S
authors: Rangappa
authors: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India.
authors: Sebastian
authors: S
authors: Anusha
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India.
authors: Toreshettahally Ramesh
authors: TR
authors: Swaroop
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India.
authors: Kodagahalli S
authors: KS
authors: Rakesh
authors: Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, 117 599, Singapore.
authors: Deepika
authors: D
authors: Kanojia
authors: Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, 117 599, Singapore.
authors: Vikas
authors: V
authors: Madan
authors: Centre for Molecular Science Informatics, Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, United Kingdom.
authors: Andreas
authors: A
authors: Bender
authors: Genomic Oncology Programme, Cancer Science Institute of Singapore, National University of Singapore, 117 599, Singapore.
authors: H Phillip
authors: HP
authors: Koeffler
authors: Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore 560001, India.
authors: Basappa
authors: Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India. Electronic address: rangappaks@yahoo.com.
authors: Kanchugarakoppal S
authors: KS
authors: Rangappa
mesh_terms: D000107:Acetylation; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056741:Cyclin D / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D014404:Tubulin / Q000378:metabolism*
chemical_list: C441200:1,2-benzisoxazole; D000970:Antineoplastic Agents; D056741:Cyclin D; D050759:Cyclin-Dependent Kinase Inhibitor p21; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D007555:Isoxazoles; D014230:Triazoles; D014404:Tubulin; D006655:Histone Deacetylases
keywords: 1,2,3-Triazoles; Acute myeloid leukemia; Histone 3 acetylation; Histone deacetylase