title: Structure-activity relationships among 9-N-alkyl derivatives of erythromycylamine and their effect on the oxidative burst of human neutrophils in vitro.
abstract: Macrolide antibiotics have recently triggered much interest owing to the immunomodulatory potential of some derivatives, particularly in the field of inflammatory diseases. Among the possible mechanisms underlying these anti-inflammatory effects, macrolide-induced inhibition of oxidant production by phagocytes has attracted much attention. We and others have previously reported that erythromycin A-derived macrolides impair the phagocyte oxidative burst, a property linked to the presence of L-cladinose. However, we have also demonstrated that other substituents can be involved in the modulation of phagocyte function. Here we have extended the analysis of structure-activity relationships by studying the effects of five 9-N-alkyl derivatives of erythromycylamine on oxidant production by human neutrophils in vitro. LY211397 (2-methoxyethyl derivative) neither altered cell viability nor superoxide anion production. LY281389 (n-propyl derivative) did not alter cell viability and was slightly more inhibitory than erythromycylamine for the production of superoxide anion; its IC50 (concentration that inhibits 50% of the neutrophil response) was about 18 and 24 microM (versus 72 and 74 pM for erythromycylamine) after 60 min of incubation following fMLP and PMA stimulation, respectively. LY80576 (N-phenyl-3-indolylmethyl derivative), LY281981 (3-phenyl-n-propyl derivative) and LY57843 (benzyl derivative) all displayed cellular toxicity at high pharmacological concentrations after 30 to 60 min of incubation. Interestingly, these latter three drugs exhibited a rapid (5 min incubation) and strong inhibitory effect on the neutrophil oxidative burst from either stimulus, with IC50 values of 3 to 10 pM. Further in-vitro and in-vivo investigations are required to analyze the anti-inflammatory potential of these three derivatives.
authors.affiliation: Faculté des Science I, Ain Chock, Casablanca, Morrocco.
authors.forename: H
authors.initials: H
authors.lastname: Abdelghaffar
authors.forename: H
authors.initials: H
authors.lastname: Kirst
authors.forename: A
authors.initials: A
authors.lastname: Soukri
authors.forename: C
authors.initials: C
authors.lastname: Babin-Chevaye
authors.forename: M T
authors.initials: MT
authors.lastname: Labro
mesh_terms: D002470:Cell Survival / Q000187:drug effects*; D004917:Erythromycin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000378:metabolism; D016897:Respiratory Burst / Q000187:drug effects; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism*
chemical_list: D013481:Superoxides; C007626:erythromyclamine; D004917:Erythromycin; D007770:L-Lactate Dehydrogenase