Synthesis And Efficacy Of P450 2J2 Inhibitors

CYP450 (cytochrome pigment 450) is a kind of enzyme which belongs to hemoglobin. It is the most important oxidase of the microsomal mixed-function oxidase. CYP450 results in the xenobiotic metabolism developing to both deirections in chihens: metabolic detoxification and metabolic activation. Teratogenic effect and carcinogenic effect are even caused by the higher toxicity of the metabolic acitivation products. P450 2J2 participates in metabolism of drugs. It also catalyzes much activation process of procarcinogen and protoxin, inducing strong cancerigenic agant. It has proved that P450 2J2 can be inhibited by Ebstine.According to that, we sythesized a series of compounds which had the similar structure to Ebstine.The data of interfering with tumor cells of nude mouse in vitro an in vivo shows that, 4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-vinylphenyl)butan-1-one hydrochloride produces the best inhibitory effect of EETs which are the products of enzymatic reaction of P450 2J2, thus inhibiting the growth of human being tumor cells such as Tca-8113, Hela, A459, 435. The facts show that 4-(4-(hydroxydiphenylmethyl) piperidin-1-yl)-1-(4- vinylphenyl)butan-1-one hydrochloride displayed strong growth inhibitory effects on Tca-8113, Hela, A459, 435 tumor cells lines with 78%, 68%, 59%, 44% of inhibition rate after 24 h treatment by 10μM, respectivity, while the apoptosis rate is 90%. The volume and weight of solid tumor is obviously inhibited.The target products are synthesized by methods of Friedel-Crafts reaction, Stille coupling and Pd catalysis. The synthesis condition of 4-(4-(hydroxydiphenylmethyl) piperidin-1-yl)-1-(4-vinylphenyl)butan-1-one hydrochloride is discussed. The optimal condition is obtained.4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-vinylphenyl)butan-1-one hydro- chloride is synthesized by six-step process. The overall yield is 12.4%. The intermediat is characterized by IR. 4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-vinylphenyl) butan-1-one hydrochloride is characterized by IR, 1HNMR, MS.