Free radical reactions of isoxazole and pyrazole derivatives of hispolon: kinetics correlated with molecular descriptors

Abstract

Hispolon (HS), a natural polyphenol found in medicinal mushrooms, and its isoxazole (HI) and pyrazole (HP) derivatives have been examined for free radical reactions and in vitro antioxidant activity. Reaction of these compounds with one-electron oxidant, azide radicals ([Formula: see text]) and trichloromethyl peroxyl radicals ([Formula: see text]), model peroxyl radicals, studied by nanosecond pulse radiolysis technique, indicated formation of phenoxyl radicals absorbing at 420 nm with half life of few hundred microseconds (μs). The formation of phenoxyl radicals confirmed that the phenolic OH is the active centre for free radical reactions. Rate constant for the reaction of these radicals with these compounds were in the order k ≅ k>k. Further the compounds were examined for their ability to inhibit lipid peroxidation in model membranes and also for the scavenging of 2,2'-diphenyl-1-picrylhydrazyl (DPPH) radical and superoxide ([Formula: see text]) radicals. The results suggested that HP and HI are less efficient than HS towards these radical reactions. Quantum chemical calculations were performed on these compounds to understand the mechanism of reaction with different radicals. Lower values of adiabatic ionization potential (AIP) and elevated highest occupied molecular orbital (HOMO) for HI and HP compared with HS controlled their activity towards [Formula: see text] and [Formula: see text] radicals, whereas the contribution of overall anion concentration was responsible for higher activity of HS for DPPH, [Formula: see text], and lipid peroxyl radical. The results confirm the role of different structural moieties on the antioxidant activity of hispolon derivatives.

Toxicity and Antigenotoxic Effect of Hispolon Derivatives: Role of Structure in Modulating Cellular Redox State and Thioredoxin Reductase

“…Recently, HS, HME, HP, and HMEP were reported for their abilities to scavenge ROS and to exhibit antioxidant activity in cell-free systems. 22 Additionally, observations of the present study that HP and HMEP maintain reductive environment within cells prompted us to hypothesize that such compounds can also be explored to protect cells from ROS-induced DNA damage, which is a prerequisite for developing any chemopreventive agent. 26 , 28 To address this issue, we employed CHO cells of epithelial origin.…”

“…8 , 11 − 16 This has led researchers to synthesize new derivatives of HS and to explore them for various pharmacological activities. 20 − 22 In the present study, four compounds namely HS, HME, HP, and HMEP have been evaluated for chemical stability, toxicities, and antigenotoxic effects to identify a potential lead phytochemical for cancer chemotherapy and chemoprevention.…”

“… 20 , 21 On similar lines, recently our group reported the abilities of HS and its derivatives such as hispolon pyrazole (HP), hispolon monomethyl ether (HME), and hispolon monomethyl ether pyrazole (HMEP) to scavenge reactive oxygen species (ROS) and to exhibit antioxidant activity in cell-free systems. 22 The exposure of carcinogenic agents such as radiation, pollutants, and xenobiotics are known to increase the intracellular levels of ROS, leading to oxidative damages. 23 , 24 Although DNA is a stable, well-protected molecule, it is the most critical subcellular target of ROS-induced oxidative damages and is believed to be responsible for the onset of cell death, mutagenesis, and carcinogenesis.…”

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“…% Scavenging activity = Acontrol -Aextract × 100/ Acontrol Here, A control and A extract are the absorbances in the absence and in the presence of extracts, respectively. The % scavenging was plotted as a function of the increasing concentrations of the extracts (CL-P, CL-C and CL-E) to estimate IC50 values (concentration of extracts required to decrease the absorbance of DPPH radicals to half of initial value) 40,41 .…”

“…The extent of lipid per oxidation was measured by estimating thiobarbituric acid reactive substances (TBARS) as reported in the literature 40,41 . In brief, 3 ml of soy lecithin liposomal solution (1 mg/ml) in 5 mM pH 7 phosphate buffer with and without extracts (50 mg/ml) like CL-P, CL-C, and CL-E was saturated with N2O and air in the ratio of 4:1 and then irradiated with 60 °C γ-radiation at a dose of 270 Gy.…”