Synthesis And Bioactivity Investigation Of Chlorogenic Acid Derivatives With Different Acetylation Degrees At Different Positions

Development and utilization of natural products has been occupying an important position in the history of drug discovery. A large proportion of presently used clinical drugs are natural products and their derivatives. Many natural products themselves have good in vitro biological activities. However, the special nature of the structures of some natural products hampered them to display bioactivities in vivo. Therefore, it is important to modify the chemical structures of these natural products by chemical or biological means in order to improve their in vivo bioactivity.Chlorogenic acid, a plant secondary metabolite, is widely distributed in nature. It has numerous excellent bioactivities, such as free radical scavenging, antisepsis and anti-inflammation, anti-viral, anti-diabetes, hypolipidemic, and hepatoprotective. Up till now, most researches on chlorogenic acid have been focused on the isolation, purification and pharmacological investigation of this compound from plants.The present research was carried out to use chlorogenic acid (5-0-caffeoylquinic acid) or its pentaketal derivative as starting materials to prepare their acetylated derivatives and to investigate the bioactivities of the prepared derivatives. Peracetylated derivatives were obtained by treatment of the starting materials with acetic anhydride/pyridine. Hydrolyzing peracetylated chlorogenic acid with HCl, Na2CO3 or lipase to obtain 1-acetyl chlorogenic acid,1,3-diacetyl chlorogenic acid,1,3,4-triacetyl chlorogenic acid and 1,3,4,3’-tetraacetyl chlorogenic acid. In these three hydrolysis conditions, Under these conditions, the acetyl groups in the phenolic hydroxyl were more easy to be hydrolyzed than those in the alcoholic hydroxyl of quinic acid part; The acetyl groups at position 3 and 4 were similarly sensitive to the hydrolysis condition using HCl or Na2CO3, compounds 1,3-diacetyl chlorogenic acid and 1,4-diacetyl chlorogenic acid being found in the experimental process; The acetyl group at C-1 was the most stable. Compound 1,3,4-triacetyl chlorogenic acid was obtained in all the three hydrolysis conditions with HCl, Na2CO3 or lipase. Lipase was the most selective in hydrolysis of the acetyl groups at the phenolic hydroxys. In addition, the enzyme hydrolysis was fast to obtain a single product, which made the post purification process simple, so lipase hydrolysis of peracetylated chlorogenic acid was a ideal method to prepare 1,3,4-triacetyl chlorogenic acid. The bioassay results showed that the partial acetylated chlorogenic acid derivatives maintained the ability to scavenge DPPH free radical while fully acetylated chlorogenic acid and fully acetylated ketal derivatives did not have this ability. Acetylated chlorogenic acid derivatives showed protection of oxidative damaged on HepG2 cells. The 1,7-(3-pentanone)-3,4,3’,4’-tetraacetyl chlorogenic acid ketal showed potent inhibitory activity on the proliferation of HepG2 cells. So acetylation of chlorogenic acid or its ketal derivatives at different positions in different degrees could result in chemical compounds of different bioactivities.