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

Abstract

We report here the synthetic procedures to obtain mitochondria-targeted resveratrol and quercetin derivatives. These two compounds were selected among plant polyphenols because both are well studied and have many health-promoting actions. The synthetic strategies reported here are however expected to be adaptable to other polyphenols with similar reactivity at the phenolic hydroxyls.

Mitochondrial targeting can be achieved by incorporating in the molecule an “electrophoretic” membrane-permeant, triphenylphosphonium cation. We have generally chosen to link it 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 (P⁺Ph₃I⁻) is then introduced through two consecutive nucleophilic substitution steps: -Cl→-I→-P⁺Ph₃I⁻. 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.

Physicochemical properties of the derivatives (i.e., water solubility, affinity for cell membranes) can be furthermore modulated by functionalization of the remaining hydroxyls; we report here synthetic protocols to obtain acetylated and methylated analogs.

We also briefly describe how to assess mitochondrial accumulation of the derivatives; the proposed techniques are the use of a TPP⁺-selective electrode (with isolated rat liver mitochondria) and fluorescence microscopy (with cultured cells).