ABSTRACT
Pterocarpanquinone (+/-)-LQB-118 presents antineoplastic and antiparasitic properties and also shows great inhibitory effect on TNF-α release in vitro. Here, its anti-inflammatory activity was evaluated in a lipopolysaccharide (LPS)-induced lung inflammation model in C57BL/6 mice. LPS inhalation induced a marked neutrophil infiltration to the lungs which was reduced by intraperitoneal treatment with (+/-)-LQB-118 in a similar manner to that of dexamethasone and even better than that of acetylsalicylic acid. Moreover, (+/-)-LQB-118 administration resulted in decrease of NF-κB activation and KC level in lungs, with a pronounced inhibitory effect on TNF-α release, measured in bronchoalveolar lavage fluid. Trying to understand the anti-inflammatory mechanism by which (+/-)-LQB-118 acts, we performed a molecular modeling analysis, including docking to estrogen receptors α and ß. Results suggested that (+/-)-LQB-118 may bind to both receptors, with a similar orientation to 17-ß-estradiol. Together, these results showed that (+/-)-LQB-118 exhibits an anti-inflammatory effect, most likely by inhibiting TNF-α release and NF-κB activation, which may be related to the estrogen receptor binding.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Naphthoquinones/pharmacology , Pterocarpans/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Disease Models, Animal , Hydrogen Bonding , Inflammation/drug therapy , Lung Diseases/drug therapy , Male , Mice , Mice, Inbred C57BL , NF-kappa B/metabolism , Naphthoquinones/chemistry , Naphthoquinones/therapeutic use , Pterocarpans/chemistry , Pterocarpans/therapeutic use , Receptors, Estrogen/drug effects , ThermodynamicsABSTRACT
A new pterocarpanquinone (5a) was synthesized through a palladium catalyzed oxyarylation reaction and was transformed, through electrophilic substitution reaction, into derivatives 5b-d. These compounds showed to be active against human leukemic cell lines and human lung cancer cell lines. Even multidrug resistant cells were sensitive to 5a, which presented low toxicity toward peripheral blood mononuclear cells (PBMC) cells and decreased the production of TNF-alpha by these cells. In the laboratory these pterocarpanquinones were reduced by sodium dithionite in the presence of thiophenol at physiological pH, as NAD(P)H quinone oxidoredutase-1 (NQO1) catalyzed two-electron reduction, and the resulting hydroquinone undergo structural rearrangements, leading to the formation of Michael acceptors, which were intercepted as adducts of thiophenol. These results suggest that these compounds could be activated by bioreduction.
