Bioisosteric modification of known fucosidase inhibitors to discover a novel inhibitor of a-L-fucosidase

Bathula, Chandramohan and Ghosh, Shreemoyee and Hati, Santanu and Tripathy, Sayantan and Singh, Shailja and Chakrabarti, Saikat and Sen, Subhabrata (2017) Bioisosteric modification of known fucosidase inhibitors to discover a novel inhibitor of a-L-fucosidase. The Royal Society of Chemistry Advances, 7. pp. 3563-3572.

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    Abstract

    Bioisosteric modification of known fucosidase inhibitors A and B, resulted in three new types of molecules, 4b, 5c and 6a (belonging to furopyridinedione, thiohydantoin and hydantoin chemotypes) that could potentially bind to a-L-fucosidase (bovine kidney origin). Molecular docking revealed and compared the putative binding interaction between 4b, 5c and 6a with A and B against the active site of a homology model of a-L-fucosidase. Based on this initial investigation, design and synthesis of a library of small molecules based on furopyridinedione, thiohydantoin and hydantoin, followed by their in vitro screening against a-L-fucosidase (bovine kidney origin) generated a potent inhibitor (compound 4e) with IC50 of �0.7 mM. Compound 4e possessed no cytotoxic properties when tested against healthy mammalian COS-1 cells. Reaction kinetics study suggested it to be a mixed inhibitor. Finally compounds 4a, b, e and f, bearing the furopyridinedione motif also exhibited substantial inhibition of the proliferation of MCF 7 breast cancer cells.

    Item Type: Article
    URI: http://www.eprints.iicb.res.in/id/eprint/2603
    Subjects: Structural Biology & Bioinformatics
    Divisions: Indian Institute of Chemical Biology
    Depositing User: Ms Sutapa Ganguly
    Date Deposited: 16 Mar 2017 12:09
    Last Modified: 02 May 2017 12:54
    Official URL: http://dx.doi.org/10.1039/c6ra24939f
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