Design, Synthesis And Biological Evaluation Of Benzo-chalcone Derivatives

Chalcones, which are considered to be precursors of flavonoids andisoflavonoids are one of the major classes of natural products withwidespread distribution in fruits, vegetables, spices, tea and soy basedfoodstuff. Chemically, chalcones or1,3-diaryl-2-propen-1-ones consistof open-chain flavonoids in which the two aromatic rings are joined by athree-carbon,unsaturated carbonyl system.Naturally occurring chalconesand their synthetic analogues display a wide spectrum of biologicalactivities. Such as antioxidant activity, anticancer activity,anti-inflammatory activity, anti–infective activity etc. For these reasons,chalcones became an object of continued interest in academia.CYP1A1/CYP1B1, are members of the cytochrome P450superfamily of enzymes. Observations have led to a great appreciationfor the role of CYPs in tumor formation and development. Targeting ofthese enzymes with natural or synthetic small molecules offers potentialbenefits in cancer prevention and therapy. General chemical strategies totarget these enzymes include: i) designing prodrugs that are activated bythe enzymes; ii) designing molecules that inhibit the enzymes.Several classes of agents are designed to be selectively activated byCYP1A1or CYP1B1to facilitate tumor-specific activation of prodrugsand are currently in preclinical evaluation, and part of them are chalcone analogues. Besides, some compounds extracting from natural plants,which have a structure of chalcone, show potent inhibition againstCYP1A1/CYP1B1.Based on this, we designed and synthesized a series of novelbenzochalcones, and further biological experiments showed most ofthem exhibited potent and selective inhibition against CYP1A1orCYP1B1compared with potent CYP1A inhibitor Resveratrol, especiallycompound (E)-3-(2-nitrophenyl)-1-(1,4,5,8-tetramethoxynaphthalen-2-yl)prop-2-en-1-one, with an IC50of0.00047μmol/L against CYP1B1, and (E)-1-(4-fluorophenyl)-3-(1,4,5,8-tetramethoxynaphthalen-2-yl)prop-2-en-1-one, with an IC50of0.017μmol/L against CYP1A1. The structure-activity relationships werealso discussed. And the results will provide experimental and theoreticalclues for designing of more potent anticancer agents.