Curcumin analogs as multi-target antioxidants: focus on mitochondria.

Many lines of evidence suggest that oxidative stress and mitochondria impairment have a central role in age-related neurodegenerative diseases such as Alzheimer’s disease (AD). In addition, the recent understanding that mitochondria are at the intersection of the life and death of a cell, particularly through the involvement of mitochondrial oxidative stress, has made mitochondria a promising target for drug discovery and therapeutic interventions. Thus, considering the oxidative stress as a crucial event on the degenerative cascade, we designed a series of compounds presenting a constrained curcumin-like moiety. Curcumin and its constrained analogs have currently received remarkable interest as they have a unique conjugated structure which shows a pleiotropic biological profile. Actually, beside the well-known direct antioxidant activity, curcumin displays a wide range of properties including anti-inflammatory and anti-amyloidogenic activities. Moreover, dietary antioxidants, like curcumin, have recently been demonstred in vitro to be neuroprotective through the activation of heme oxigenase 1 pathway, showing an additional indirect antioxidant behaviour. On the basis of the consideration that mitochondria are a major source of ROS and are particularly vulnerable to oxidative stress, it is convincible that antioxidants that alleviate mitochondrial dysfunction could be beneficial in AD. This prompted us to design mitochondria-targeted antioxidants by connecting curcumin analogs to different polyamine chains. Polyamines might deliver the corresponding conjugates into the cell with active polyamine transporters and, acting as lipophilic cations, drive the antioxidant moiety selectively into mitochondria in a membrane potential-dependent manner across the inner membrane. In order to validate if such compounds were preferentially taken up by mitochondria, a fluorescent probe was designed by combining the phenyl benzothiazole group with the polyamine residue.