Extraordinary Radical Scavengers: 4‐Mercaptostilbenes

Abstract

In the past decade, there was a great deal of interest and excitement in developing more active antioxidants and cancer chemoprevention agents than resveratrol, a naturally occurring stilbene. In this work, eight resveratrol-directed 4-mercaptostilbenes were constructed based on the inspiration that thiophenol should be a stronger radical scavenger than phenol, and their reaction rates with galvinoxyl (GO(.)) and 2,2-diphenyl-1-picrylhydrazyl (DPPH(.)) radicals in methanol and ethyl acetate were measured by using stopped-flow UV/Vis spectroscopy at 25 °C. Kinetic analysis demonstrates that 4-mercaptostilbenes are extraordinary radical scavengers, and the substitution of the 4-SH group for the 4-OH group in the stilbene scaffold is an important strategy to improve the radical-scavenging activity of resveratrol. Surprisingly, in methanol, some of the 4-mercaptostilbenes are 10(4)-times more active than resveratrol, dozens of times to hundreds of times more effective than known antioxidants (α-tocopherol, ascorbic acid, quercetin, and trolox). The detailed radical-scavenging mechanisms were discussed based on acidified-kinetic analysis. Addition of acetic acid remarkably reduced the GO(.) and DPPH(.) radical-scavenging rates of the 4-mercaptostilbenes in methanol, a solvent that supports ionization, suggesting that the reactions proceed mainly through a sequential proton loss electron transfer mechanism. In contrast, an interesting acid-promoted kinetics was observed for the reactions of the 4-mercaptostilbenes with DPPH(.) in ethyl acetate, a solvent that weakly supports ionization. The increased ratio in rates is closely correlated with the electron-rich environment in the molecules, suggesting that the acceleration could benefit from the contribution of the electron transfer from the 4-mercaptostilbenes and DPPH(.). However, the addition of acetic acid had no influence on the GO(.)-scavenging rates of the 4-mercaptostilbenes in ethyl acetate, due to the occurrence of the direct hydrogen atom transfer. Our results show that the radical-scavenging activity and mechanisms of 4-mercaptostilbenes depends significantly on the molecular structure and acidity, the nature of the attacking radical, and the ionizing capacity of the solvent.

Toward an understanding of the role of a catechol moiety in cancer chemoprevention: The case of copper- ando-quinone-dependent Nrf2 activation by a catechol-type resveratrol analog

“…It has been previously pointed out that the 4′‐OH in RES is important for its antioxidant and biological activities . In our continuing search for RES‐directed antioxidants , prooxidants , and cancer chemopreventive agents , we have found that introducing the electron donating groups into the stilbene skeleton in the ortho ‐ or para ‐position of 4′‐OH of RES could significantly improve its radical‐scavenging and cancer chemopreventive activities . As an extension of our previous studies , to find more active Nrf2 activators and phase II detoxifying enzyme inducers than RES, we selected RES and its hydroxyled analogs to perform a structure‐activity relationship (SAR) analysis for cytoprotection in HepG2 cells challenged by tert ‐butyl hydroperoxide ( t ‐BHP), a model of oxidative stress.…”

“…In our continuing search for RES‐directed antioxidants , prooxidants , and cancer chemopreventive agents , we have found that introducing the electron donating groups into the stilbene skeleton in the ortho ‐ or para ‐position of 4′‐OH of RES could significantly improve its radical‐scavenging and cancer chemopreventive activities . As an extension of our previous studies , to find more active Nrf2 activators and phase II detoxifying enzyme inducers than RES, we selected RES and its hydroxyled analogs to perform a structure‐activity relationship (SAR) analysis for cytoprotection in HepG2 cells challenged by tert ‐butyl hydroperoxide ( t ‐BHP), a model of oxidative stress. These compounds include 4‐hydroxy‐ trans ‐stilbene (4‐HS) and 3,5‐dihydroxy‐ trans ‐stilbene (3,5‐DHS), where 4′‐hydroxy and 3,5‐dihydroxy groups of RES are respectively retained, as well as 3,4‐dihydroxy‐ trans ‐stilbene (3,4‐DHS), 4,4′‐dihydroxy‐ trans ‐stilbene (4,4′‐DHS), and 4‐hydroxy‐3‐methoxy‐ trans ‐stilbene (3‐MeO‐4‐HS), where not only the active 4′‐OH group of RES is remained but also an electron‐donating hydroxyl or methoxy group is placed on the stilbene skeleton in ortho ‐ or para ‐position of 4′‐OH.…”

Synthesis and antioxidant activity of hydroxylated phenanthrenes as cis-restricted resveratrol analogues

“…The structural simplicity of this molecule has prompted interest in designing novel analogues with improved antioxidant potency (Amorati et al, 2004;Fukuhara et al, 2008;Murias et al, 2005). In this connection, we have also demonstrated that the introduction of electron-donating groups at positions ortho and para to the 4-OH or 4 0 -OH group in the stilbene scaffold (Fang & Zhou, 2008;Shang et al, 2009), construction of the hydroxylated stilbene-chroman hybrids (Yang et al, 2010), the insertion of additional double bonds between two aromatic rings (Tang et al, 2011) and the substitution of 4-SH for 4-OH in the stilbene scaffold (Cao et al, 2012) could effectively improve antioxidant activity of this parent molecule.…”

Thiophenols, Promising Scavengers of Peroxyl Radicals: Mechanisms and kinetics

“…Santagelo proposed that the thiol group could regulate the inflammatory response that occurs as a consequence of OS . Although many bioassays have proved the pharmaceutical, antibacterial, and antifungal activities of a few thiophenolic compounds, their antioxidant properties have not been studied, with the exception of some thiostilbenes . It is possible to assume that these compounds possess positive and desirable properties, and therefore their antioxidant properties must also be studied.…”