The beneficial effects of H2S-release and of COXs-inhibition have been exploited in the design of novel anti-inflammatory drugs, the H2S-releasing non-steroidal anti-inflammatory drugs (H2S-NSAIDs), showing promising potential for chemoprevention in cancers. Here, we evaluated the efficacy of a new H2S-releasing derivative of naproxen, named naproxen-4-hydroxybenzodithioate (naproxen-HBTA), in reducing metastatic melanoma features, both in vitro and in vivo. The novel H2S donor has been prepared following a synthetic scheme that provided high yields and purity. In particular, we investigated the effect of naproxen-HBTA in vitro on several metastatic features of human melanoma cells such as proliferation, migration, invasion, and colonies formation and in vivo in a model of cutaneous melanoma. Cell culture studies demonstrated that naproxen-HBTA induced caspase 3-mediated apoptosis and inhibited motility, invasiveness, and focus formation. Finally, daily oral treatment with naproxen-HBTA significantly suppressed melanoma growth and progression in mice. In conclusion, by using this dual approach we propose that the COX-2 and H2S pathways could be regarded as novel therapeutic targets/tools to generate new treatment options based on “combination therapy” for melanoma.

Helicobacter pylori (H. pylori) secretes the chaperone and serine protease high temperature requirement A (HtrA) that cleaves gastric epithelial cell surface proteins to disrupt the epithelial integrity and barrier function. First inhibitory lead structures have demonstrated the essential role of HtrA in H. pylori physiology and pathogenesis. Comprehensive drug discovery techniques allowing high-throughput screening are now required to develop effective compounds. Here, we designed a novel fluorescence resonance energy transfer (FRET) peptide derived from a gel-based label-free proteomic approach (direct in-gel profiling of protease specificity) as a valuable substrate for H. pylori HtrA. Since serine proteases are often sensitive to metal ions, we investigated the influence of different divalent ions on the activity of HtrA. We identified Zn ++ and cu ++ ions as inhibitors of H. pylori HtrA activity, as monitored by in vitro cleavage experiments using casein or E-cadherin as substrates and in the FRET peptide assay. Putative binding sites for Zn ++ and cu ++ were then analyzed in thermal shift and microscale thermophoresis assays. The findings of this study will contribute to the development of novel metal ion-dependent protease inhibitors, which might help to fight bacterial infections. Gastric cancer is associated with one of the highest mortality rates among all cancerous diseases in humans since efficient treatment options are still not available 1. Persistent infections with the gastric pathogen Helicobacter pylori (H. pylori) are a significant risk factor for the induction and progression of stomach cancer. Approximately 50% of the human population is infected with H. pylori, which can induce chronic gastritis, duodenal, and gastric ulcers and finally gastric adenocarcinoma or MALT (mucosa-associated lymphoid tissue) lymphoma 2,3. Accordingly, the complex network of cellular and molecular mechanisms of H. pylori-host interactions has been intensively investigated. The finding that the serine protease high temperature requirement A (HtrA) expressed by H. pylori targets cell surface proteins of infected host cells added an important aspect to the model of H. pylori pathogenesis. During infection, H. pylori secretes HtrA and cleaves off the ectodomain of the cell adhesion protein and tumor

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Background: Serotonin 1A (5-HT 1A) receptors are implicated in the pathogenesis of several psychiatric and neurodegenerative disorders motivating the development of suitable radiotracers for in vivo positron emission tomography (PET) neuroimaging. The gold standard PET imaging agent for this target is [carbonyl-11 C]WAY-100635, labeled via a technically challenging multi-step reaction that has limited its widespread use. While several antagonist and agonist-based PET radiotracers for 5-HT 1A receptors have been developed, their clinical translation has been hindered by methodological challenges and/or and non-specific binding. As a result, there is continued interest in the development of new and more selective 5-HT 1A PET tracers having a relatively easier and reliable radiosynthesis process for routine production and with favorable metabolism to facilitate tracer-kinetic modeling. The purpose of the current study was to develop and characterize a radioligand with suitable characteristics for imaging 5-HT 1A receptors in the brain. The current study reports the in vitro characterization and radiosyntheses of three candidate 5-HT 1A receptor antagonists, DF-100 (1), DF-300 (2) and DF-400 (3), to explore their suitability as potential PET radiotracers.