Roda A, Cerrè C, Manetta A C, Cainelli G, Umani-Ronchi A, Panunzio M
Dipartimento di Scienze Farmaceutiche, Università di Bologna, Italy.
J Med Chem. 1996 May 24;39(11):2270-6. doi: 10.1021/jm9508503.
New analogs of cyclic amino acid-conjugated bile acids were synthesized, and their physicochemical and biological properties were compared with those of natural analogs. Ursodeoxycholic acid was amidated with D-proline, L-proline, 4-hydroxy-L-proline, and 4-methoxy-L-proline. Hyocholic and hyodeoxycholic acids were amidated with L-proline. The physicochemical properties were similar to those of the natural analogs. All of them were highly stable toward enzymatic C-24 amide bond hydrolysis and 7-dehydroxylation. Their transport, metabolism, and effect on biliary lipid secretion were evaluated in bile fistula rat after intravenous infusion. All the analogs were secreted in bile unmodified. The 4-methoxy-L-proline derivative produced the highest secretion rate, much higher than those of all the other natural and synthetic analogs. This was associated with a selective reduction of cholesterol secretion with normal phospholipid secretion and choleresis. When coinfused, all the analogs were able to prevent the hepatotoxicity induced by intravenous taurochenodeoxycholic acid, as revealed by normal choleresis, alkaline phosphatase, and lactate dehydrogenase values in bile. Considering the overall data, 4-methoxy-L-proline, 4-hydroxy-L-proline, and L-proline derivatives of ursodeoxycholic acid were more potent than the natural analogs.
合成了环状氨基酸共轭胆汁酸的新类似物，并将其物理化学性质和生物学性质与天然类似物进行了比较。熊去氧胆酸与D-脯氨酸、L-脯氨酸、4-羟基-L-脯氨酸和4-甲氧基-L-脯氨酸进行酰胺化反应。猪胆酸和猪去氧胆酸与L-脯氨酸进行酰胺化反应。其物理化学性质与天然类似物相似。所有这些类似物对酶促C-24酰胺键水解和7-脱羟基反应都具有高度稳定性。静脉输注后，在胆瘘大鼠中评估了它们的转运、代谢以及对胆汁脂质分泌的影响。所有类似物均未修饰地分泌到胆汁中。4-甲氧基-L-脯氨酸衍生物的分泌率最高，远高于所有其他天然和合成类似物。这与胆固醇分泌选择性降低、磷脂分泌正常以及胆汁分泌增加有关。当共同输注时，所有类似物都能够预防静脉注射牛磺鹅去氧胆酸诱导的肝毒性，这可通过胆汁中胆汁分泌正常、碱性磷酸酶和乳酸脱氢酶值来表明。综合所有数据，熊去氧胆酸的4-甲氧基-L-脯氨酸、4-羟基-L-脯氨酸和L-脯氨酸衍生物比天然类似物更有效。
