Structure-hepatoprotective activity relationship of 3,4-dihydroxycinnamic acid (caffeic acid) derivatives.

3,4-Dihydroxycinnamic acid (caffeic acid, CAF) is a natural product containing a catechol group with an alpha,beta-unsaturated carboxylic acid chain that has shown hepatoprotective properties. The aim of this work was to determine the importance of the 4-hydroxy, 3-hydroxy, 3,4-dihydroxy substituents and the double bond moiety on the hepatic pharmacological effects of the molecule. We compared the ability of the caffeic, 4-hydroxycinnamic, 3-hydroxycinnamic, cinnamic and 3,4-dihydroxyhydrocinnamic (a caffeic acid analogue without the double bond) acids at a dose of 50 mg kg(-1), p.o., to reduce the liver damage produced by CCl(4) (4 g kg(-1), p.o.) intoxication in the rat. Cinnamic acid, the non-hydroxylated analogue, only modestly protected the experimental animals challenged with CCl(4), suggesting that hydroxyl groups participate in the pharmacological properties of CAF. The 3,4-dihydroxyhydrocinnamic derivative did not show any significant differences when compared with the CAF effect in this model, suggesting that the double bond does not account for the liver pharmacological properties of CAF. In contrast, the 4-hydroxy substituent seems to be very important for hepatoprotective activity because the 4-hydroxy analogue improved almost every hepatic injury marker altered by CCl(4), and in a better way than CAF did.