Characterization of the antioxidant profiles of synthetic compounds derived from curcumin in human neuroblastoma cells. (Caratterizzazione del profilo antiossidante di analoghi sintetici derivati da curcumina in cellule di neuroblastoma umano)

In the last decades, due to the increase of life expectancy, the number of people affected by age-related diseases, such as neurodegenerative disorders, are increasing. Nowadays, the field of pharmacology and drug discovery is focusing on the research and development of multi-target drugs to slow down the onset and progression of age-related multifactorial disorders. In this regard, the use of natural compounds represents one of the most promising approaches. In particular, curcumin has been reported to exhibit anti-oxidant and anti-inflammatory activities in vivo and in vitro studies. However, curcumin is characterized by low bioavailability and adverse side effects that limits its use. Hence, several attempts have been focused on the synthesis of new molecules starting from the pharmacophoric moieties of natural compounds with the aim of improving their pharmacokinetic properties. The present project aims to study the antioxidant potential of new curcumin-derived compounds (i.e. compounds 1-6), synthesized in collaboration with the pharmaceutical group of chemists of the University of Bologna, by hybridizing the pharmacophoric elements of curcumin and diallyl sulfide. In particular, we focused on the effects of compounds on the modulation of the Nrf2/Keap1/ARE signaling pathway. In this project, we used human neuroblastoma SH-SY5Y cell line. These hybrids are characterized by the presence of (pro)-electrophilic motifs, such as Michael acceptor function and catechol moiety. The results obtained indicate that compounds 1-5 are able to modulate the Nrf2 signaling pathway by inducing an increase of the Nrf2 transcriptional levels, as a result of the presence of (pro)-electrophilic motifs. Another proof of this Nrf2-pathway electrophile-based modulation derives from the capability of compounds 1-5 to induce the Nrf2 nuclear translocation and ARE-dependent transcription of its target genes codifying cytoprotective enzymes (i.e. HO-1 and NQO1). The presence of Michael acceptor function and catechol moiety, either in combination or alone, appears to be essential to exert their antioxidant activities by inducing the complete activation of the Nrf2 pathway. In conclusion, through the evaluation and characterization in vitro of compounds 1-6, we obtained several and promising results about their antioxidant and cytoprotective effects. However, whether these profiles might result in better translational outcomes require further in vivo investigations to verify bioavailability issues and to determine the translational potentials of them.