HOCL SCAVENGING STRUCTURES IN LIBRARIES OF NITRONES AND DITERPENES

J BORQUEZ; G ÁLVAREZ; N GONZALEZ; D COSTA; GOMEZ MEJIBA, SE; ER VERNI ; L THOMPSON; L CELANO; H CERECETTO; M SIMIRGIOTIS; P COSTA; E AGUILERA; N CATALDO; AG DIAS; RAMIREZ DC

Congreso; SAIC; 2016

th: 0px; ">Neutrophilic inflammation results from activation of neutrophilsat sites of chronic or acute inflammation. Activated neutrophilsrelease myeloperoxidase (MPO), the unique enzyme that usesH2O2 to oxidize chloride anions to the powerful oxidant HOCl.HOCl damaged proteins are seen and involved in a number ofinflammatory diseases. Thus the search for inhibitors of MPOand/or scavengers of HOCl is of vital importance for the treat- -ment of neutrophilic inflammation. The aim of this work is thesearch for highly characterized synthetic or natural structuresthat react with HClO/ClO- (hypochlorous acid/hypochlorite, Ka= 7.58). We searched HOCl scavenging activity in 55 syntheticand natural compounds: 47 nitrones and 8 natural diterpenes.For this purpose, we used a screening assay to evaluate theability to reduce luminescence caused by reaction of HClO withluminol. The variables were optimized and the method wasdeveloped for a concentration of 10 µM luminol and 50 µM HClO.Compound dilutions were prepared (0, 0.1, 1, 5, 10 and 25 µM,corresponding ?0? to a HClO solution only) and then HClO andluminol solutions were added. Results showed that from the 8diterpenes compounds, only one lessened the signal below 1µM concentration. The rest of them probed to have this activityjust above that value. Whereas, nitrones showed interestingproperties: 13 showed inhibitory activity in the range of 5-10 µM,28 compounds in 1-5 µM, 4 compounds between 0.1 and 1 µM,and finally two nitrones showed an interesting activity below 100nM. Scavenging HOCl at sites of neutrophilic inflammation maybe an interesting bioactivity forfinding new leader structures indrug discovery. Further studies aimed at determining toxicity, cellpermeability, mechanism of action and in vivo activity are guaranteed for leading compounds. Supported by PROICO 2-3214& PICT-2014-3369 (to DCR), PROICO 10-0414 (To SEGM) andPIP2015-2017 112215-0100603CO (To DCR, SEA & SEGM).