Design And Synthesis Of Styrylnaphthalenes As Potent Inhibitors Of CYP1B1Enzyme

Human cytochrome P450(CYP)1B1could catalyze the bioactivationof certain procarcinogens and plays an important role in the carcinogenicaction of17-β-estradiol. It is known to be expessed at a high frequency invarious tumor organs, but not in normal ones. Besides, it is involved inanti-cancer drug resistance. These findings indicate that inhibition ofCYP1B1could be a new method in cancer prevention and therapy.In this work, according to the structure-activity relationships (SARs)of stilbenoids towards CYP1B1we designed and synthesized a series ofstyrylnaphthalenes taking CYP1B1as the target and resveratrol as the leadcompound. These compounds were prepared via the Horner-Wadsworth-Emmons reactions between naphthaldehydes containing methoxy groupsand phosphonates, includng β-(E)-styryl-1,4,5,8-tetramethoxynaphthalenes, α-(E)-styryl-4,5,8-trimethoxy naphthalenes, β-(E)-styryl-1,4,8-trimethoxy naphthalenes, β-(E)-styryl-1,5,6-trimethoxy naphthalenes and β-(E)-styryl-1,7-dimethoxy naphthalenes. Their chemical structureswere confirmed by1H-NMR.All the target compounds were evaluated for their inhibitory effectson CYP1B1-mediated EROD activity. The results suggested that most ofthese new compounds were more potent inhibitors of human CYP1B1enzyme than resveratrol. Compared with α-naphthoflavone, compounds (Ι6,Ι8, II2, II5) exhibited much higher potency and selectivity towardsCYP1B1inhibition. Among the tested ones, compound (E)-1-(4-fluorostyryl)-4,5,8-trimethoxynaphthalene (II5) exhibited the strongestinhibition effects with the IC50value of0.31nM.In conclusion, We found several new compounds with high potencyand selectivity towards CYP1B1inhibition and discussed the SARs ofthese candidates, which would have a significant effect on exploring newpotent and selective CYP1B1inhibitors.