BACKGROUND AND PURPOSEShogaols are reported to possess anti-inflammatory and anticancer activities. However, the antimetastatic potential of shogaols remains unexplored. This study was performed to assess the effects of shogaols against breast cancer cell invasion and to investigate the underlying mechanisms. EXPERIMENTAL APPROACHThe anti-invasive effect of a series of shogaols was initially evaluated on MDA-MB-231 breast cancer cells using the matrigel invasion assay. The suppressive effects of 6-shogaol on phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP-9) gelatinolytic activity and nuclear factor-kB (NF-kB) activation were further determined. KEY RESULTSShogaols (6-, 8-and 10-shogaol) inhibited PMA-stimulated MDA-MB-231 cell invasion with an accompanying decrease in MMP-9 secretion. 6-Shogaol was identified to display the greatest anti-invasive effect in association with a dose-dependent reduction in MMP-9 gene activation, protein expression and secretion. The NF-kB transcriptional activity was decreased by 6-shogaol; an effect mediated by inhibition of IkB phosphorylation and degradation that subsequently led to suppression of NF-kB p65 phosphorylation and nuclear translocation. In addition, 6-shogaol was found to inhibit JNK activation with no resulting reduction in activator protein-1 transcriptional activity. By using specific inhibitors, it was demonstrated that ERK and NF-kB signalling, but not JNK and p38 signalling, were involved in PMA-stimulated MMP-9 activation. CONCLUSIONS AND IMPLICATIONS6-Shogaol is a potent inhibitor of MDA-MB-231 cell invasion, and the molecular mechanism involves at least in part the down-regulation of MMP-9 transcription by targeting the NF-kB activation cascade. This class of naturally occurring small molecules thus have potential for clinical use as antimetastatic treatments. AbbreviationsAP-1, activator protein-1; ECM, extracellular matrix; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; IKK, IkB kinase; IkBa, inhibitor of kBa; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-kB, nuclear factor-kB; PMA, phorbol 12-myristate 13-acetate BJP British Journal of Pharmacology

Phenylmethylenehydantoins (PMHs) and their des-phenyl analogues were synthesized and evaluated for anticonvulsant activity using the maximal electroshock seizure (MES) assay. The phenyl rings of PMHs were substituted with a wide spectrum of groups, and the selection of substituents was guided by Craig's plot. Phenylmethylenehydantoins substituted with alkyl (2, 3, 5, 6, 12, 14), halogeno (35, 38, 41), trifluoromethyl (11), and alkoxyl (23) groups at the phenyl ring were found to exhibit good anticonvulsant activity with ED(MES(2.5)) ranging from 28 to 90 mg/kg. Substitution of polar groups such as -NO(2), -CN, and -OH was found to be less active or inactive on PMHs. Replacement of the phenyl ring with heteroaromatic rings reduced or caused the loss of anticonvulsant activity. The study identified two PMHs, 14 (ED(MES(2.5)) = 28 +/- 2 mg/kg) and 12 (ED(MES(2.5)) = 39 +/- 4 mg/kg), to be the most active candidates of the series, which are comparable to phenytoin (55, ED(MES(2.5)) = 30 +/- 2 mg/kg) in their protection against seizure. Multivariate analysis performed on the whole series of 54 PMHs further supported the finding that the alkylated phenylmethylenehydantoins are the best acting compounds. The SAR model derived on the basis of 12 of the most active phenylmethylenehydantoins demonstrated good predicting ability (root-mean-square error of prediction (RMSEP) = 0.134; RMSEE = 0.057) and identified LUMO energy and the log P as critical parameters for their anticonvulsant activity.

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a b s t r a c tA catalyst-free highly efficient synthesis of 3(5)-amino-5(3)-(het)aryl-1,2,4-triazoles in aqueous medium was performed using conventional heating and microwave irradiation. The tautomerism in the products was investigated using NMR spectroscopy and X-ray crystallography. The effects of the substitution, temperature, solvents, and concentration on the tautomerism were studied. The triazoles were found to exist in 1H-forms, the 4H-form was not observed either in solid state or in solution. In general, 5-amino-1,2,4-triazoles were electronically preferred in the tautomeric equilibrium, but some exceptions from the established relationship were also identified.

The developed multifunctional nanoparticles hold potential to treat malignant integrin-expressing cancers.