Synthesis and Testing of Novel Isomeric Mitochondriotropic Derivatives of Resveratrol and Quercetin

Resveratrol and quercetin are among the most studied plant polyphenols, and have many health-promoting actions. Strategies to accumulate them into mitochondria may be of therapeutic relevance, since these compounds are redox active and are well known to impact mitochondria and mitochondrial proteins. We report here the procedures to synthesize mitochondria-targeted resveratrol and quercetin derivatives; the synthetic strategies reported are however expected to be adaptable to other polyphenols with similar reactivity at the phenolic hydroxyls. Mitochondrial targeting can be achieved by conjugation with triphenylphosphonium, a lipophilic cation; this was linked via a butyl spacer forming an ether bond with one of the phenolic oxygens. The first step toward the synthesis of all mitochondriotropic derivatives described in this work is the production of a regiospecific -(4-O-chlorobutyl) derivative. Triphenylphosphonium (PPhI) is then introduced through two consecutive nucleophilic substitution steps: -Cl -> -I -> -PPhI. Pure mono-substituted chlorobutyl regioisomers are obtained by purification from the reaction mixture in the case of resveratrol, while specific protection strategies are required for quercetin to favor alkylation of one specific hydroxyl. Functionalization of the remaining hydroxyls can be exploited to modulate the physicochemical properties of the derivatives (i.e., water solubility, affinity for cell membranes); we report here synthetic protocols to obtain acetylated and methylated analogs. A brief description of some methods to assess the accumulation of the derivatives in mitochondria is also given; the proposed techniques are the use of a TPP-selective electrode (with isolated rat liver mitochondria) and fluorescence microscopy (with cultured cells).