HOCL SCAVENGING STRUCTURES IN LIBRARIES OF NITRONES AND DITERPENES

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

MZA

Congreso; SBC; 2016

Neutrophilic inflammation results from activation ofneutrophils at sites of chronic and acute inflammation. Activated neutrophilsrelease myeloperoxidase (MPO), the unique enzyme that uses H2O2to oxidize chloride anions to the powerful oxidant HOCl. HOCl damaged proteinsare seen and involved in a number of inflammatory diseases. Thus the search forinhibitors of MPO and/or scavengers of HOCl is of vital importance for thetreatment of neutrophilic inflammation. The aim of this work is the search forhighly characterized synthetic or natural structures that react with HClO/ClO-. We searched HOCl scavenging activity in 55synthetic and natural compounds: 47 nitrones and 8 natural diterpenes. For thispurpose, we used a screening assay to evaluate the ability to reduceluminescence caused by reaction of HClO with luminol. To avoid luminescent-probe-associatedunspecific reactions, a chlorotyrosine assay was performed. Results showed thatfrom the 8 diterpenes compounds, only one lessened the signal below 1 µMconcentration. In the case of nitrones, 13 probed to have inhibitory activityin 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 100 nM. ScavengingHOCl at sites of neutrophilic inflammation may be an interesting bioactivityfor finding new leader structures in drug discovery. Further studies aimed atdetermining toxicity, cell permeability, mechanism of action and in vivoactivity are guaranteed for leading compounds. Supported by PROICO 2-3214 & PICT-2014-3369 (to DCR), PROICO 10-0414(To SEGM) and PIP2015-2017-112215-0100603CO (To DCR, SEGM & SEGM).