Antioxidant And Cancer Chemopreventive Activities Of [6]-shogaol Analogs And Resveratrol Metabolites

Cancer chemoprevention is defined as the use of naturally occurring or synthetic agents to reverse, suppress, or prevent carcinogenic progression, and has been a rational and appealing strategy in reducing the risk of cancer. The dissertation focused on this topic and systematically investigated antioxidant and cancer chemopreventive activities and mechanism of [6]-shogaol analogs and resveratrol metabolites. The main creative results are as follows:(1) [6]-Gingerol and [6]-shogaol are the major pungent components in the ginger with a variety of biological activities including antioxidant activity. To explore their structure determinants of as antioxidants, we synthesized eight compounds differentiated by their side chains We systematically characterized their antioxidant activity by the 2,2-diphenyl-1-picrylhydrazyl free radical-scavenging, ferric reducing antioxidant power, DNA strand breakage-inhibiting and human red blood cell hemolysis-protecting assays which are indicative of their formal hydrogen-transfer, electron-donating, and DNA damage- and lipid peroxidation-protecting abilities, respectively. Our results show that their antioxidant activity depends significantly on the side chain structures, the reaction mediums and substrates. Specifically, introduction of the C1-C2 double bond decreased their formal hydrogen-transfer and electron-donating abilities, whereas the existence of the 5-OH resulted in a significant increase in their DNA damage- and lipid peroxidation-protecting abilities. Besides, the chain length extension reduced remarkably their DNA strand breakage-inhibiting activity, but strengthened their anti-hemolysis activity.(2) From increasing electrophilicity point of view, we designed and synthesized a analogs of [6]-shogaol, [6]-dehydroshogaol characterized by introduction of the C1-C2 double bond. Compared to the parent molecule, [6]-dehydroshogaol shows remarkably increased antiproliferative, apoptosis-inducing and cell cycle arrest activities against HepG2 cells. The above activities are directly related to their Michael acceptor-dependent ability to promote intracellular ROS-generation which comes from their irreversible inhibition of thioredoxin reductase (TrxR), and the NADPH oxidase-like activity induced by their covalently modified TrxR. Intracellular ROS production is associated with disruption of redox homeostasis which could induce subsequently lipid peroxidation, increase of Ca2+ influx, collapse of mitochondrial membrane potential, activation of caspase-9 and 3, ultimately resulting in the cell apoptosis.(3) Resveratrol (3,5,4’-trihydroxystilbene, RES), a star among dietary polyphenols, shows a wide range of biological activities, but it is rapidly and extensively metabolized into its glucuronide and sulfate conjugates as well as to the corresponding reduced products. This begs the question of whether the metabolites of RES contribute to its in vivo biological activity. To explore this possibility, we synthesized its glucuronidation (3-GR and 4’-GR) and reduction (DHR) metabolites and evaluated influence of the structure modifications on its biological activities including binding ability with human serum albumin (HSA), antioxidant activity in homogeneous solutions and heterogeneous media, anti-inflammatory activity, and cytotoxicity against various cancer cells. Here we found that (ⅰ) 4’-GR, DHR and RES have nearly equal binding ability with HSA mainly through hydrogen bond, whereas 3-GR employs a remarkably different orientation mode upon the binding, resulting in the ability decrease; (ⅱ) 3-GR shows comparable and even equal ability to RES in the FRAP and AAPH-induced DNA strand breakage assays, respectively. DHR,3-GR and 4’-GR exhibit comparable anti-hemolysis activity, relative to RES; Additionally,3-GR and DHR remain some degree activity of the parent molecule in the DPPH·-scavenging and cupric ion-initiated oxidation of LDL assays, respectively; (ⅲ) compared to RES,4’-GR displays equipotent ability in the inhibition of COX-2, and DHR presents comparable activity in inhibiting NO production and growth of SMMC-7721 cells. Taken together, relative to RES, its glucuronidation and reduction metabolites could remain equal, comparable, or some degree of activity in the above assays depending on the specific compound and model used, which probably supports their roles in contributing to the in vivo biological activities of the parent molecule.