Expression of calcitonin (CT) and its receptor (CTR) is elevated in advanced prostate cancer, and activated CT-CTR autocrine axis plays a pivotal role in tumorigenicity and metastatic potential of multiple prostate cancer cell lines. Recent studies suggest that CT promotes prostate cancer metastasis by reducing cell-cell adhesion through the disassembly of tight and adherens junctions and activation of B-catenin signaling. We attempted to identify a class of molecules that enhances cell-cell adhesion of prostate cells and reverses the disruptive actions of CT on tight and adherens junctions. Screening several compounds led to the emergence of phenyl-methylene hydantoin (PMH) as a lead candidate that can augment cell-cell adhesion and abolish disruptive actions of CT on junctional complexes. PMH reduced invasiveness of PC-3M cells and abolished proinvasive actions of CT. Importantly, PMH did not display significant cytotoxicity on PC-3M cells at the tested doses. I.p. administered PMH and its S-ethyl derivative remarkably decreased orthotopic tumor growth and inhibited the formation of tumor micrometastases in distant organs of nude mice. PMH treatment also reduced the growth of spontaneous tumors in LPB-Tag mice to a significant extent without any obvious cytotoxic effects. By virtue of its ability to stabilize cell junctions, PMH could reverse the effect of CT on junctional disruption and metastasis, which strengthens the possibility of using PMH as a potential drug candidate for CT-positive androgen-independent prostate cancers.
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 antiinvasive 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 IC 50 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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a b s t r a c tThe Red Sea sponge Hemimycale arabica afforded the known (Z)-5-(4-hydroxybenzylidene)-hydantoin (1), (R)-5-(4-hydroxybenzyl)hydantoin (2), and (Z)-5-((6-bromo-1H-indol-3-yl)methylene)-hydantoin (3). The natural phenylmethylene hydantoin (PMH) 1 and the synthetic (Z)-5-(4-(ethylthio)benzylidene)-hydantoin (4) showed potent in vitro anti-growth and anti-invasive properties against PC-3M prostate cancer cells in MTT and spheroid disaggregation assays. PMHs 1 and 4 also showed significant anti-invasive activities in orthotopic xenograft and transgenic mice models. To study the effect of electronic and lipophilic parameters on the activity, a wide array of several substituted aldehydes possessing electron-withdrawing (+r), lipophilic (+p), electron-donating (Àr), and less lipophilic substituents (Àp) were used to synthesize several PMHs. Few des-phenylmethylenehydantoins and 2-thiohydanoins were also synthesized and the anti-invasive activities of all compounds were evaluated. Comparative molecular field analysis (CoMFA) was then used to study the 3D QSAR. Predictive 3D QSAR model with conventional r 2 and cross validated coefficient (q 2 ) values up to 0.910 and 0.651 were established. In conclusion, PMH is a novel antimetastatic lead class with potential to control metastatic prostate cancer.
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