Novel Caffeic Acid Phenethyl Ester (Cape) Analogues as Inducers of Heme Oxygenase-1

Background: Heme Oxygenase-1 (HO-1) is a metabolic enzyme strongly involved in processes including cytoprotection, modulation of inflammatory response, anti-oxidative functions, regulation of cellular proliferation, angiogenesis, cardiovascular homeostasis, and immuno-modulation. HO-1 induction and/ or activation is able to counterbalance, at least in part, oxidative stress and inflammation. For this reason, HO-1 can be regarded as an attractive target to ameliorate different stress-related pathologies. Caffeic acid phenethyl ester, a natural polyphenolic compound, behaves as HO-1 inducer and possesses a plethora of beneficial effects under oxidative stress conditions. Objectives: A small focused series of caffeic acid phenethyl ester (Cape) analogues was designed and synthesized with the aim of obtaining more potent HO-1 inducers. Method: The capacity of these new compounds to modify the levels of HO-1 was evaluated in human mesenchymal stem cells (hMSCs) derived from bone marrow. Results and conclusion: Some of tested compounds were found to be good HO-1 inducers and 3-(3,4dihydroxyphenyl)-( 2E)-2-propenoic acid 2-(3,4-dimethoxyphenyl) ethyl ester (VP961) was the most potent. VP961 tested to measure HO-1 protein expression and HO activity in in vitro system resulted more potent than the parent compound Cape both as inducer and as direct activator of the enzyme. VP961, selected as lead compound for further characterization, showed antioxidant properties in a model of H2O2-mediated ROS production and cytoprotective effects in a model of H2O2 cells viability impairment. To the best of our knowledge, VP961 is the first known compound able to activate directly HO-1 enzyme and to induce at the same time its protein expression.