Development of hydroxybenzoic-based platforms as a solution to deliver dietary antioxidants to mitochondria

Abstract

Oxidative stress and mitochondrial dysfunction have been associated with metabolic and age-related diseases. Thus, the prevention of mitochondrial oxidative damage is nowadays a recognized pharmacological strategy to delay disease progression. Epidemiological studies suggested an association between the consumption of polyphenol-rich diet and the prevention of different pathologies, including diseases with a mitochondrial etiology. The development of mitochondrial-targeted antioxidants based on dietary antioxidants may decrease mitochondrial oxidative damage. Herein, we report the design and synthesis of two new mitochondriotropic antioxidants based on hydroxybenzoic acids (AntiOxBENs). The results obtained showed that the novel antioxidants are accumulated inside rat liver mitochondria driven by the organelle transmembrane electric potential and prevented lipid peroxidation, exhibiting low toxicity. Some of the observed effects on mitochondrial bioenergetics resulted from an increase of proton leakage through the mitochondrial inner membrane. The new derivatives present a higher lipophilicity than the parent compounds (protocatechuic and gallic acids) and similar antioxidant and iron chelating properties. AntiOxBENs are valid mitochondriotropic antioxidant prototypes, which can be optimized and used in a next future as drug candidates to prevent or slow mitochondrial oxidative stress associated to several pathologies.

Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors

“…The reaction was followed by TLC [silica gel, ethyl acetate:methanol (9:1) and dichloromethane:methanol (9:1)]. The procedure was adapted from the literature (Brown et al, 2007 ; Teixeira et al, 2017b ).…”

“…DPPH • radical scavenging activity was evaluated as previously described (Teixeira et al, 2017b ). The IC 50 values were determined in triplicate from the dose-response inhibition curves and are expressed as mean ± standard deviation (SD).…”

“…Voltammetric studies were performed using an Autolab PGSTAT12 potentiostat/galvanostat (Metrohm Autolab, Netherland) and a one-compartment glass electrochemical cell. Voltammetric curves were recorded at room temperature using a three-electrode system, according the conditions previously described (Teixeira et al, 2017b ).…”

“…The design and synthesis of two mitochondriotropic antioxidants based on HBAc ( AntiOxBEN 1 and AntiOxBEN 2 , Figure 1 ), in which PA and GA were covalently bound to a triphenylphosphonium cation (TPP + ) through a six-carbon aliphatic chain has been previously reported (Teixeira et al, 2017b ). AntiOxBENs effectively accumulated in rat liver mitochondria, driven by the negative-inside organelle transmembrane electric potential (ΔΨ), and prevented lipid peroxidation while exhibiting low toxicity (Teixeira et al, 2017b ). AntiOxBENs presented higher lipophilicity than the parent compounds (PA and GA), and similar antioxidant and iron chelating properties.…”

Metabolic and Phenotypic Characterization of Human Skin Fibroblasts After Forcing Oxidative Capacity

“…Mitochondria are considered the powerhouses of the cell, because they enclose important energy-producing metabolic pathways (Pereira et al, 2009;Picard et al, 2016). Besides ATP production, mitochondria display other important roles, including intracellular calcium (Ca 2þ ) regulation (Arduino et al, 2017), as well as redox and apoptotic signaling pathways (Smith et al, 2012;Teixeira et al, 2017). Decline in mitochondrial function has been associated with a wide range of human pathologies (Wallace et al, 2010), while alterations caused by drug toxicity have been extensively demonstrated (Marroquin et al, 2007;Masubuchi et al, 2006;Ong et al, 2007;Swiss and Will, 2011;Tirmenstein et al, 2002).…”