Synthesis, in vitro and in silico studies of HO-1 inducers and lung antifibrotic agents

Abstract

Aim: Dimethyl fumarate (DMF) analogs were synthesized to obtain inducers of HO-1 and antifibrotic agents. Methods: HO-1 expression levels were measured on lung fibroblasts (MRC5). NMR and docking studies were performed. Heme oxygenase activity, gene levels and protein expression have been measured for the most active compound 1a. Collagen production by fibroblast after exposure to TGF-β was measured. Results: Compound 1a showed to be a strong HO-1 inducer. Its activity seems to be mediated by activation of nuclear factor erythroid 2 related factor 2 (Nrf2). TGF-β-induced collagen production was significantly decreased on MRC5, pretreated with DMF or 1a. DMF and 1a have a high potential for treatment of lung fibrotic injuries.

Keywords: Keap1; NMR; Nrf2; dimethyl fumarate; docking studies; fibrosis; heme oxygenase-1; lung.