利用猪脱氧胆酸合成细胞核肝X受体激动剂

Synthesis of liver X receptor agonists from hydeoxycholic acid

利用来自畜牧业的丰富原料猪脱氧胆酸为甾体骨架研究细胞核肝X受体(LXR)激动剂,合成了3个胆酸衍生物;在体外培养的人胚胎肾细胞HEK293内,使用双荧光报告基因法测定目标物调节LXR的能力。结果显示,合成的3个化合物中,化合物1、2可以激活LXRα和LXRβ,而化合物3有亚型选择性,只对LXRα有激活作用。这类化合物有望成为调控体内胆固醇代谢的临床药物。

Liver X receptor（LXRs） are members of nuclear receptor superfamily, responsible for the regula- tion of cholesterol metabolism. Dysfunction in cholesterol metabolism may result in cardio- and cerebral-vas- cular diseases, such as ischemic stroke, coronary artery atherosclerosis and Alzheimer＇s disease. Hyodeoxy- cholic acid, an abundant by-product from livestock industry, is used as steroidal scaffold to synthesize LXR modulators. Three bile acid analogs were synthesized and evaluated in an in vitro biological assay using the human embryonic kidney cell line HEK293 and a commercial dual-luciferase reporter gene method. 4-（ （3R, 5R ,6S, 10R, 13R ） -3,6-dihydroxy-lO, 13-dimethylhexadecahydro-1H-cyclopenta [ a I phenanthren-17-yl）-N, N-dimethylpentanamide （ 1 ） and 4-（ （ 3R, 5R, 6S, 10R, 13R ） -3,6-dihydroxy-10,13-dimethylhexadecahydro- 1H-cyclopenta [a] phenanthren-17-yl） -N-methyl-N- （3,4,5-trimethoxybenzyl） pentanamide （ 2 ） showed ago- nist activity toward both LXRa and LXR/3, while 2-（ （3R,5R,6S, 10R, 13S） -3,6-dihydroxy-10,13-dimeth- ylhexadecahydro-1H-cyclopenta [a] phenanthren-17-yl ） -N-（ 3,4,5-trimethoxybenzyl ） propanamide （ 3 ） de- monstrated LXR sub-type selectivity and only activated LXRα. Further analysis is needed to develop these bile acid analogs and their derivatives into clinically useful LXR regulators.