The marine natural-derived inhibitors of glycogen synthase kinase-3beta phenylmethylene hydantoins: In vitro and in vivo activities and pharmacophore modeling.
The marine natural-derived inhibitors of glycogen synthase kinase-3beta phenylmethylene hydantoins: In vitro and in vivo activities and pharmacophore modeling.
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DOI：
10.1016/j.bmc.2009.06.054
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发表时间：
2009-08-15
影响因子：
3.5
通讯作者：
El Sayed, Khalid A.
中科院分区：
文献类型：
--
作者：
Khanfar, Mohammad A.;Abu Asal, Bilal;Mudit, Mudit;Kaddoumi, Amal;El Sayed, Khalid A.
关键词：
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-3beta (GSK-3β) similar to the well-known GSK-3β inhibitor I-5. Several PMHs showed potent in vitro GSK-3β inhibitory activity with an IC50 range of 4–20 µM. 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-3β inhibitors. The GSK-3β 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.
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影响因子：
5.6
作者：
Bertrand, JA;Thieffine, S;Flocco, M
通讯作者：
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影响因子：
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发表时间：
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影响因子：
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作者：
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通讯作者：
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影响因子：
3.5
作者：
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