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The marine natural-derived inhibitors of glycogen synthase kinase-3β phenylmethylene hydantoins: In vitro and in vivo activities and pharmacophore modeling

BIOORGANIC & MEDICINAL CHEMISTRY (2009)

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BIOORGANIC & MEDICINAL CHEMISTRY
卷 17, 期 16, 页码 6032-6039

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PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.06.054

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Marine natural products; Phenylmethylene hydantoins; Synthase kinase-3 beta (GSK-3 beta)inhibitors; Pharmacophore modeling; Molecular modeling; Cancer; Alzheimer's disease; Type-2 diabetes

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Biochemistry & Molecular Biology Chemistry, Medicinal Chemistry, Organic

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  1. Louisiana Biomedical Research Network

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The Red Sea sponge Hemimycale arabica afforded the known (Z)-5-(4-hydroxybenzylidene)-hydantoin (1). This natural phenylmethylene hydantoin (PMH) 1 and the synthetic (Z)-5-(4-(ethylthio)benzylidene)- hydantoin (2) showed potent in vitro and in vivo anti-growth and anti-invasive properties against PC-3M prostate cancer cells in MTT, spheroid disaggregation, and in mice models. To explore a possible molecular target of PMHs, the most potent synthetic analogue 2 has been virtually screened against various protein kinases. Molecular modeling study has shown that 2 can be successfully docked within the binding pocket of glycogen synthase kinase-3 beta (GSK-3 beta) similar to the well-known GSK-3 beta inhibitor 1-5. Several PMHs showed potent in vitro GSK-3b inhibitory activity with an IC50 range of 4-20 mu M. The most potent analogue 3 showed a significant increase in liver glycogen level at the 5, 15, and 25 mg/kg dose levels, in vivo. Pharmacophore model was built and validated using in-house database of active and inactive GSK-3b inhibitors. The GSK-3b inhibitory activity of PMHs entitles them to be potential leads for the treatment of cancer, Alzheimer's disease, bipolar disorders, stroke, different tau pathologies, and type-2 diabetes. (C) 2009 Elsevier Ltd. All rights reserved.

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