Valeria Pittalà1, Luca Vanella1, Chiara Bianca Maria Platania2, Loredana Salerno1, Marco Raffaele1, Emanuele Amata1, Agostino Marrazzo1, Giuseppe Floresta1, Giuseppe Romeo1, Khaled Greish3, Sebastiano Intagliata4, Claudio Bucolo2, Valeria Sorrenti1. 1. Department of Drug Sciences, University of Catania, Viale A. Doria 6, Sicily, 95125, Italy. 2. Department of Biomedical & Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, Via Santa Sofia n. 97, Sicily, 95123, Italy. 3. College of Medicine and Medical Sciences, Department of Molecular Medicine, and Nanomedicine Unit, Princess Al-Jawhara Center for Molecular Medicine, Arabian Gulf University, Building 61, King Abdulaziz Avenue, Block 328, Manama, Kingdom of Bahrain. 4. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Medical Science Building, 1345 Center Drive, Gainesville, FL 32610, USA.
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.
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.