Rational discovery and development of a mitochondria-targeted antioxidant based on cinnamic acid scaffold

Abstract

A novel mitochondria-targeted antioxidant (TPP-OH) was synthesized by attaching the natural hydrophilic antioxidant caffeic acid to an aliphatic lipophilic carbon chain containing a triphenylphosphonium (TPP) cation. This compound has similar antioxidant activity to caffeic acid as demonstrated by measurement of DPPH/ABTS radical quenching and redox potentials, but is significantly more hydrophobic than its precursor as indicated by the relative partition coefficients. The antioxidant activity of both compounds was intrinsic related to the ortho-catechol system, as the methoxylation of the phenolic functions, namely in TPP-OCH₃ and dimethoxycinnamic acid, gave compounds with negligible antioxidant action. The incorporation of the lipophilic TPP cation to form TTP-OH and TPP-OCH₃ allowed the cinnamic derivatives to accumulate within mitochondria in a process driven by the membrane potential. However, only TPP-OH was an effective antioxidant: TPP-OH protected cells against H₂O₂ and linoleic acid hydroperoxide-induced oxidative stress. As mitochondrial oxidative damage is associated with a number of clinical disorders, TPP-OH may be a useful lead that could be added to the family of mitochondria-targeted antioxidants that can decrease mitochondrial oxidative damage.

Keywords::

• antioxidant
• caffeic acid
• lipophilic cation
• mitochondria
• TPP-OH
• TPP-OCH₃

This paper was first published online on Early Online on 22 February 2012.