Novel Heme Oxygenase-1 (HO-1) Inducers Based on Dimethyl Fumarate Structure

International Journal of Molecular Sciences

ChiaraBianca Maria Platania¹  Claudio Bucolo¹  Loredana Salerno²  Valeria Sorrenti²  Luca Vanella²  Valeria Pittalಠ Khaled Greish³ 

[1] Department of Biomedical and Biotechnological Sciences, Section of Pharmacology, School of Medicine, University of Catania, Via Santa Sofia 97, 95123 Catania, Italy;Department of Drug Sciences, University of Catania, V.le A. Doria 6, 95125 Catania, Italy;Department of Molecular Medicine, College of Medicine and Medical Sciences, Princess Al-Jawhara Centre for Molecular Medicine, Arabian Gulf University, Manama 329, Bahrain;

关键词: heme oxygenase (HO);    HO-1 inducers;    dimethyl fumarate (DMF);    LX-2 cells;    hepatic fibrosis;   

DOI  :  10.3390/ijms21249541

来源: DOAJ

【 摘 要 】

Novel heme oxygenase-1 (HO-1) inducers based on dimethyl fumarate (DMF) structure are reported in this paper. These compounds are obtained by modification of the DMF backbone. Particularly, maintaining the α, β-unsaturated dicarbonyl function as the central chain crucial for HO-1 induction, different substituted or unsubstituted phenyl rings are introduced by means of an ester or amide linkage. Symmetric and asymmetric derivatives are synthesized. All compounds are tested on a human hepatic stellate cell line LX-2 to assay their capacity for modifying HO-1 expression. Compounds 1b, 1l and 1m stand out for their potency as HO-1 inducers, being 2–3 fold more active than DMF, and for their ability to reverse reactive oxygen species (ROS) production mediated using palmitic acid (PA). These properties, coupled with a low toxicity toward LX-2 cell lines, make these compounds potentially useful for treatment of diseases in which HO-1 overexpression may counteract inflammation, such as hepatic fibrosis. Docking studies show a correlation between predicted binding free energy and experimental HO-1 expression data. These preliminary results may support the development of new approaches in the management of liver fibrosis.

【 授权许可】

Unknown