Study On Anti - Gout Effect Of Berberine And Its Derivatives

Gout is a painful disease that is mainly caused by the deposition of monosodium uratecrystals in joints. Various factors are suggested to contribute to the sustained elevation of theuric acid (UA) level in blood, termed hyperuricemia. Normally, UA is dissolved in blood. Asa result of hyperuricemia, insoluble UA forms microscopic crystals in the capillary vessels ofjoints. These crystals cause inflammation and sharp pain, which is termed acute goutyarthritis or acute gout, and result in a significant degradation in the quality of life of patients.Moreover, some epidemiologic studies suggest that hyperuricemia is an independent riskfactor for cardiovascular diseases such as myocardial infarction and cerebral infarction.Berberine is a quaternary protoberberine isoquinoline alkaloid and is a major constituent ofmany medicinal plants of families Papaveraceae, Berberidaceae, Fumariaceae,Menispermaceae, Ranunculaceae, Rutaceae etc. In this study, berberine, as an attractive leadcompound, a series of berberine derivatives were synthesized to improve the XO inhibitoryactivities. Structural modifications at C-9of berberine was done by converting the methoxygroup to hydroxyl to obtain berberrubine in80%yield using microwave irradiation. The nextstep involved acylation of berberrubine in a polar aprotic solvent using various acid chlorides.The desired berberine-9-O-esters BBR-1to BBR-7were obtained in quantitative yield.13-(substituted benzyl) berberine and berberrubine derivatives were synthesized by means of theintroduction of various aromatic groups. For the synthesis of the derivatives, acetonyl-berberine used as a key intermediate was obtained by condensation of berberine with acetone.Then the desired derivatives were obtained by treating with various benzyl bromides andsodium iodide. By introducing various amino methyl groups into12-position of berberruine,a series of12-(sbustituted aminomethyl) berberrubine derivatives were synthesized bytreating the berberrubine with the appropriate aliphatic amino or aryl amine andformaldehyde.All the synthesized derivatives were evaluated for their xanthine oxidase inhibitoryativity. Four BBR-7(IC50=6.36μmol/L)， BBR-15(IC50=7.15μmol/L)， BBR-16(IC50=6.53μmol/L)，BBR-17(IC50=5.28μmol/L)out of20synthesized molecules in thisclass showed good inhibition against xanthine oxidase, which were more potent than allopurinol (IC50=8.51μmol/L) based on their respective IC50values. The experimentalanimal model of hyperuricemia was developed by intraperitoneal iniection of potassiumoxonate. The mouse serum uric acid level and liver xanthine oxidase activity were used toevaluate anti-gout effects in vivo of the four berberine derivatives. All the four derivativescould significantly reduce contents of uric acid and inhibit activities of liver xanthine oxidasein model rats of hyperuricemia, BBR-17showed the most potent xanthine oxidase inhibitoryactivity which might be a new nonpurine class of xanthine oxidase inhibitors that havepotential to be more efficacious to treat gout.