Synthesis And Cancer Chemoprevention Mechanism Of Isothiocyanates

Isothiocyanates(ITCs)derived from cruciferous vegetables,are a kind of important cancer chemoprevention agents,and thus have attracted much attention.The most widely studied and representative ITCs include sulforaphane(SFN),benzyl isothiocyanate(BITC)and phenethyl isothiocyanate(PEITC).In this thesis,to find a more active cancer chemoprevention agent with BITC and PEITC as the lead compounds,we selected a series of phenyl isothiocyanates,and investigated their cancer chemopreventive activitives,structure-activity relationships and mechanisms.These compounds are differentiated by placing various substituents(methyl,methoxy,hydroxyl,trifluoromethyl or fluoro)on the aromatic rings in the ortho-,meta-or para-position to the terminal isothiocyanate group.The main contents are as follows:(1)We started our studies with a comparison of the cytotoxicity of the above compounds on human breast cancer cells MDA-MB-231 by means of a classic SRB-based viability assay.It was found that among these compounds,4-hydroxyphenyl isothiocyanate was the most active and exhibited remarkably increased activity in comparison with BITC and PEITC.Cytotoxic mechanism research indicates that this compound could act as an electrophilic prooxidant to promote the generation of intracellular resctive oxygen species,which results in disruption of redox homeostasis,down-regulation of the ratio of Bcl-2/Bax,cytosolic release of cytochrome c,activation of caspase 9 and 3,and eventual apoptotic cell death.Additionally,it could induce a G2/M cell cycle arrest in MDA-MB-231 cells by decreasing the expression levels of the redox active proteins including p53,cyclins(cyclin A1 and B1)?cyclin-dependent kinase(Cdkl)and Cdc25c phosphatase which precisely regulate cell cycle progression.(2)As an electrophilic agent,menadione induces the intracellular oxidative stress,leading to the deaths of cell damage.Therefore,we preliminarily studied on the protective effect of 4-hydroxyphenyl isothiocyanate against menadione-induced oxidative death.of human normal liver cells L02.This compound was identified as an indirect antioxidant to protect the cells from oxidative death by inducing expression of the phase ? enzymes(heme oxygenase-1 and GCL)via the Keap1-Nrf2-ARE signaling pathways.