Non-nitric oxide based metallovasodilators: synthesis, reactivity and biological studies.

There is an increasing number of compounds developed to target one or more pathways involved in vasodilation. Some studies conducted with azaindole and indazole derivatives showed cardiovascular activity associated with these compounds. Fast and easy structural modification of these organic molecules can be achieved using metal complexes promoting a much larger spatial change than organic strategies, potentially leading to novel drugs. Here, we have prepared a series of complexes with a formula cis-[RuCl(L)(bpy)(2)]PF(6), where L = 7-azaindole (ain), 5-azaindole (5-ain), 4-azaindole (4-ain), indazole (indz), benzimidazole (bzim) or quinoline (qui), which were characterized by spectroscopic and electrochemical techniques (CV, DPV). These compounds showed reasonable stability exhibiting photoreactivity only at low wavelength along with superoxide scavenger activity. Cytotoxicity assays indicated their low activity preliminarily supporting in vivo application. Interestingly, vasodilation assays conducted in rat aorta exhibited great activity that largely improved compared to free ligands and even better than the well-studied organic compound (BAY 41-42272), with IC(50) reaching 55 nM. These results have validated this strategy opening new opportunities to further develop cardiovascular agents based on metallo-bicyclic rings.

Helicobacter pylori has an unprecedented nitric oxide detoxifying system.

AIMS: The ability of pathogens to cope with the damaging effects of nitric oxide (NO), present in certain host niches and produced by phagocytes that support innate immunity, relies on multiple strategies that include the action of detoxifying enzymes. As for many other pathogens, these systems remained unknown for Helicobacter pylori. This work aimed at identifying and functionally characterizing an H. pylori system involved in NO protection. RESULTS: In the present work, the hp0013 gene of H. pylori is shown to be related to NO resistance, as its inactivation increases the susceptibility of H. pylori to nitrosative stress, and significantly decreases the NADPH-dependent NO reduction activity of H. pylori cells. The recombinant HP0013 protein is able to complement an NO reductase-deficient Escherichia coli strain and exhibits significant NO reductase activity. Mutation of hp0013 renders H. pylori more vulnerable to nitric oxide synthase-dependent macrophage killing, and decreases the ability of the pathogen to colonize mice stomachs. INNOVATION: Phylogenetic studies reveal that HP0013, which shares no significant amino acid sequence similarity to the other so far known microbial NO detoxifiers, belongs to a novel family of proteins with a widespread distribution in the microbial world. CONCLUSION: H. pylori HP0013 represents an unprecedented enzymatic NO detoxifying system for the in vivo microbial protection against nitrosative stress.