Cytochrome P450 enzymes are a versatile superfamily of heme containing proteins involved in the metabolism and detoxification of endogenous and exogenous compounds including environmental chemicals. In addition, these enzymes play an important role in the bioactivation of procarcinogenic compounds into their ultimate carcinogenic forms. Most recently, we have discovered that some ethynyl coumarin derivatives can inactivate certain P450 enzymes involved in carcinogenesis and DNA mutation. Flavones are also known natural substrates for a number of important P450 enzymes. Cytochrome P450 activity assays point out that the addition of certain functional groups such as the ethynyl group to the flavone backbone can cause inhibition activity towards certain P450s such as P450s 1A1 and 1A2. For this project, we utilized the results of our previous structural-activity relationship studies and the geometry of the active sites of P450 enzymes 1A1 and 1A2 to design and synthesize new and promising inhibitors with potential use as cancer chemo-preventive agents. Here we report the synthesis of four flavone propargyl ethers (2’-flavonyl propargyl ether, 5-flavonyl propargyl ether, 6-flavonyl propargyl ether, and 5-hydroxy-7-flavonyl propargyl ether) as potential inhibitors of P450s 1A1 and 1A2.

Design and synthesis of flavone propargyl ethers as potential inhibitors of human cytochrome P450 1A1 and 1A2 enzymes

249th National Meeting (2015)

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