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  • Title: Design, synthesis and biological evaluation of 3'-benzylated analogs of 3'-epi-neoponkoranol as potent α-glucosidase inhibitors.
    Author: Liu D, He W, Wang Z, Liu L, Wang C, Zhang C, Wang C, Wang Y, Tanabe G, Muraoka O, Wu X, Wu L, Xie W.
    Journal: Eur J Med Chem; 2016 Mar 03; 110():224-36. PubMed ID: 26840363.
    Abstract:
    A group of 3'-epi-neoponkoranol analogs with different hydrophobic substituents attached at 3'-position of side chain moiety were designed and synthesized in order to further improve the inhibitory activities against α-glucosidases. Biological evaluation of these compounds revealed that sulfonium salts attached with ortho-substituted benzyl groups showed best α-glucosidase inhibitory activities. The most potent compound 10i showed greater inhibitory activities than all natural products. Moreover, docking studies on 10i with ntMGAM presented a new binding mode, indicating that amino residue Asp542 should be the key interacting point for strong inhibitory activity of small molecules against α-glucosidase enzymes. The strongest α-glucosidase inhibitory activity of 10i could be rationalized by van der Waals interactions between the 3'-attached substituent and particularly the ortho-substituted trifluoromethyl on benzyl group with the adjacent hydrophobic amino residues. Cytotoxicity evaluation assay demonstrated a high level of safety profile of the synthesized sulfonium salts against normal cell line. The enzyme kinetic studies showed a fully competitive inhibition of these sulfonium salts on each α-glucosidase.
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