Abstract
The antioxidant potency of 17β-estradiol and related polycyclic phenols has been well established. This property is an important component of the complex events by which these types of agents are capable to protect neurons against the detrimental consequences of oxidative stress. In order to relate their molecular structure and properties with their capacity to inhibit lipid peroxidation, a marker of oxidative stress, quantitative structure-activity relationship (QSAR) studies were conducted. The inhibition of Fe3+-induced lipid peroxidation in rat brain homogenate, measured through an assay detecting thiobarbituric acid reactive substances for about seventy compounds were correlated with various molecular descriptors. We found that lipophilicity (modeled by the logarithm of the n-octanol/water partition coefficient, logP) was the property that influenced most profoundly the potency of these compounds to inhibit lipid peroxidation in the biological medium studied. Additionally, the important contribution of the bond dissociation enthalpy of the phenolic O–H group, a shape index, the solvent-accessible surface area and the energy required to remove an electron from the highest occupied molecular orbital were also confirmed. Several QSAR equations were validated as potentially useful exploratory tools for identifying or designing novel phenolic antioxidants incorporating the structural backbone of 17β-estradiol to assist therapy development against oxidative stress-associated neurodegeneration.
Highlights
Oxidative stress (OS) has been implicated as a key factor to the initiation and/or progression of numerous pathological processes and premature aging [1]
Estrogens are unique among steroids in terms of having the phenolic A-ring that allows for eliciting antioxidant activity similar to that of simple phenolic antioxidants, such as vitamin E or butylated hydroxytoluene [6,7]
It has become evident that the ability of 17β-estradiol (E2, 1), the main human estrogen (Figure 1), to act as a direct free radical scavenging antioxidant is an important element in the cascade of neuroprotective events by which E2 provides protection against OS both in vitro [7,8,9] and in vivo [10,11,12], the latter is not without controversy [13]
Summary
Oxidative stress (OS) has been implicated as a key factor to the initiation and/or progression of numerous pathological processes and premature aging [1]. The high unsaturated lipid content of the brain, coupled with high oxygen utilization, elevated redox-active metal ions concentration and relatively poor antioxidant defense, makes this organ quite vulnerable to this process and the associated pathologies [4]. One of the most promising approaches to combat OS and, prevent the resultant LPO is the use of antioxidants that can either “catch” free radicals or chelate excessive redox metals that can provoke OS via the formation of reactive oxygen species (ROS) [5]. It has been shown that E2 and related compounds are able to directly scavenge free radicals and, thereby, alleviate OS independently of nuclear estrogen receptor (ER) activation [14,15].
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