Design, Activity And Mechanism Of Stilbene-inspired Antioxidants And Cancer Chemopreventive Agents: Introduction Of Mercapto And Michael Addition Acceptor

Resveratrol, a naturally occurring stilbene, is the subject of intense research as an antioxidant and cancer chemopreventive agent. In the past decade, there was a great deal of interest and excitement in developing more active antioxidants and cancer chemoprevention agents than this parent molecule. In this thesis, more than seventy stilbene compounds were designed and synthesized by introducing mercapto and Michael addition acceptor on the stilbene scaffold, and their antioxidant and cancer chemopreventive activities and the related mechanisms were investigated. The main creative results.are as follows:1. Radical-scavenging activity and mechanisms of the 4-mercaptostilbenes.Eight 4-mercaptostilbenes with different substituents at different positions on the aromatic ring were constructed based on the inspiration that thiophenol should be a stronger radical scavenger than phenol, and the fact that 4’-OH group of resveratrol is responsible for its radical-scavenging activity. Their reaction rates with galvinoxyl (GO) and 2,2-diphenyl-l-picrylhydrazyl (DPPH·) radicals in methanol and ethyl acetate were measured by using stopped-flow UV/Vis spectroscopy at 25℃. 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,4,4’-DMS、4’-MeO-4-MS and 3’,4’-DMeO-4-MS are 104-times more active than resveratrol, dozens of times to hundreds of times more effective than known antioxidants (a-tocopherol, ascorbic acid, quercetin, and trolox). The detailed radical-scavenging mechanisms were discussed based on acidified-kinetic analysis. 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.2. Cancer chemoprevention activity and mechanism of the stilbene compounds containing a Michael addition acceptor.Dietary constituents with an electrophilic Michael acceptor usually display promising cancer chemopreventive activity by redox intervention. Thus, dozens of the stilbene compounds containing a Michael addition acceptor were constructed by introducing aldehyde, ester, carboxyl and cyano groups on the olefinic bridge. The stilbene aldehydes were screened for cytotoxicity at different cancer cells and a compound SA-5, surfaced as an important lead compound which displaying remarkable cytotoxicity at submicromolar concentrations. Besides, treatment of NCI-H460 cells with this compound at submicromolar concentrations resulted in a clear block of cells in G2/M phase and the occurrence of apoptosis. Quite unexpectedly, this activity was not mediated by Michael acceptor-dependent redox modulation such as promoting intracellular ROS-generation. Further research indicates that one of the likely targets of this compound is tubulin and it could enhance microtubule polymerization as a microtubule-stabilizing agent causing cell cycle arrest, just like paclitaxel does.