Cytochrome P450 enzymes are involved in the metabolism of many procarcinogens, carcinogens, and pharmaceuticals such as polycyclic aromatic hydrocarbons (PAHs), arylamines, heterocyclic amines, sterols, fatty acids, vitamins, and steroids. P450s are expressed in many tissues including liver, kidney, and lung. The role of P450 enzymes in bioactivation, tumor formation and development makes them an attractive target for cancer prevention and treatment. Our earlier studies on anthraquinone/quinone inhibitors of P450 enzymes indicated that the presence of a methyl group adjacent to an amino group could be responsible for its mechanism-based inhibition of P450 enzymes 1A1 and 1A2. With the goal of finding new mechanism-based inhibitors for P450 enzymes 1A1 and 1A2, a 2D-pharmacophore-based database search was conducted for compounds containing 1-amino-2-methyl substituents on polyaromatic/heterocyclic core structure. A series of 12 compounds were selected from the database hits through docking studies and subjected to bioassay for P450 inhibition. Four of these compounds proved to be mechanism-based inhibitors of P450 enzyme 1A1. Further molecular modeling studies were conducted to understand the specificity and potency of these compounds.

Quest for new mechanism-based inhibitors of cytochrome P450 enzyme 1A1 and 1A2

245th National Meeting (2013)

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