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-(3,4-
dihydroxyphenyl)-(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.