The 3-phenylcoumarin derivative 6,7-dihydroxy-3-[3 ',4 '-methylenedioxyphenyl]-coumarin downmodulates the Fc gamma R- and CR-mediated oxidative metabolism and elastase release in human neutrophils: Possible mechanisms underlying inhibition of the formation and release of neutrophil extracellular traps

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Andrade, Micassio F. ; Kabeya, Luciana M. ; Bortot, Leandro O. ; dos Santos, Gabriela B. ; Santos, Everton O. L. ; Albiero, Lucineia R. ; Figueiredo-Rinhel, Andrea S. G. ; Carvalho, Camila A. ; Azzolini, Ana Elisa C. S. ; Caliri, Antonio ; Pupo, Monica T. ; Emery, Flavio S. ; Lucisano-Valim, Yara Maria

• Document type: Journal article
• Source: Free Radical Biology and Medicine; v. 115, p. 15-pg., 2018-02-01.

Abstract

In this study, we report the ability of a set of eight 3-phenylcoumarin derivatives bearing 6,7- or 5,7-dihydroxyl groups, free or acetylated, bound to the benzopyrone moiety, to modulate the effector functions of human neutrophils. In general, (i) 6,7-disubstituted compounds (5, 6, 19, 20) downmodulated the Fc gamma receptor-mediated neutrophil oxidative metabolism more strongly than 5,7-disubstituted compounds (21, 22, 23, 24), and (ii) hydroxylated compounds (5, 19, 21, 23) downmodulated this neutrophil function more effectively than their acetylated counterparts (6, 20, 22, 24, respectively). Compounds 5 (6,7-dihydroxy-3-[3',4'-methylenedioxyphenyl]-coumarin) and 19 (6,7-dihydroxy-3-[ 3', 4'-dihydroxyphenyl]-coumarin) effectively downmodulated the neutrophil oxidative metabolism elicited via Fc gamma and/or complement receptors. Compound 5 also downmodulated the immune complex-stimulated phagocytosis, degranulation of elastase, and production and release of neutrophil extracellular traps, as well as the human neutrophil chemotaxis towards n-formyl-methionylleucyl-phenylalanine, without altering the expression level of formyl peptide receptor type 1. Both compounds 5 and 19 did not impair the neutrophil capacity to recognize and kill Candida albicans. Docking calculations revealed that compounds 5 and 19 directly interacted with three catalytic residues - Gln-91, His-95, and Arg-239 - inside the myeloperoxidase active site. Together, these findings indicate that (i) inhibition of reactive oxygen species generation and degranulation of elastase are closely associated with downmodulation of release of neutrophil extracellular traps; and (ii) compound 5 can be a prototype for the development of novel immunomodulating drugs to treat immune complex-mediated inflammatory diseases. (AU)

• FAPESP's process: 10/19504-0 - Study of the antioxidant activity mechanism of Baccharis dracunculifolia(Asteraceae) in neutrophils and evaluation of this effect on rheumatoid arthritis model
• Grantee: Andréa Silva Garcia de Figueiredo Rinhel
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/23541-4 - In vitro evaluation of antioxidant and anti-inflammatory derivatives 3-phenylcoumarins in human neutrophils stimulated and in animal models of arthritis.
• Grantee: Micássio Fernandes de Andrade
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/20810-7 - Systematic study of the molecular mechanisms involved in the inhibition of the oxidative metabolism of the stimulated neutrophils by the Baccharis dracunculifolia, 3-phenylcoumarin derivatives and 3,5,7-triidroxiflavonaimplications on the RA therapeutics
• Grantee: Yara Maria Lucisano Valim
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/00927-7 - Molecular dynamics simulations for the identification of bioactive molecules: inhibitors of the interaction between the dengue virus envelope glycoprotein and cellular C-type lectins
• Grantee: Leandro Oliveira Bortot
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)