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

Sorrenti, Valeria; Vanella, Luca; Platania, Chiara Bianca Maria; Greish, Khaled; Bucolo, Claudio; Pittalà, Valeria; Salerno, Loredana

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.

DIMETHYL fumarate; PALMITIC acid; HEME; LIVER cells; HEPATIC fibrosis; REACTIVE oxygen species

International Journal of Molecular Sciences, 2020, Vol 21, Issue 24, p9541

1661-6596

Academic Journal

10.3390/ijms21249541