Synthesis Of Water-soluble Pentacyclic Dihydroxyterpene Carboxylic Acid Derivatives Coupled Amino Acids And Their Biological Activity Study

Maslinic acid and corosolic acid,a kind of pentacyclic triterpene carboxylic acid,widely existing in natural plants,with high efficiency and low side effect as well as hypoglycemic,anti-inflammatory and other biological activities have been gotten a widespread attention currently.Corosolic was known as"plant insulin"due to it exhibit a similar biological activity with insulin and it has been developed into a variety of domestic and foreign health care products.However,the low bioavailability in the organisms of maslinic acid and corosolic acid was attributed to their poor water solubility.There is an urgent need for modifying their structure to increase their hydrophilicity,thereby improving their bioavailability.With maslinic acid and corosolic acid as the precursors,a series of water-soluble pentacyclic triterpene carboxylic acid coupled amino acid derivatives were synthesized by coupling with different L-amino acids at the A-ring dihydroxy site or the single site of C-28 carboxyl group and the structures of the derivatives were elucidated by standard spectroscopic methods including ¹H NMR,¹³C NMR and HRMS.Thea-glucosidase inhibitory activities of the present compounds were evaluated in vitro.The solubility and inhibitory activity of ?-glucosidase assays reveal that some of the derivatives exhibit a bettera-glucosidase inhibitory activity than that of acarbose in the test conditions of ethanol-water solution and DMSO;Secondly,most of the derivatives exhibit better water solubility than that of the precursors,however,all of the derivatives possess lower inhibitory properties ofa-glucosidase than those of the precursors in the measurement system of DMSO solution.Derivatives with free hydroxyl group at the C-28 amide side chain(9d:IC₅₀=998mm and 9h:IC₅₀=1321mm)showed similar inhibitory activity as derivatives without the hydroxyl group on the amide side chain(e.g.9a for IC₅₀=987mm,9g for IC₅₀=1000mm and 9k for IC₅₀=993mm),indicating that a hydroxyl group at the C-28 amide side chain could not enhance the inhibition ofa-glucosidase in despite of the superior water solubility of the former.The derivatives with two free carboxyl groups on the C-28 amide side chain(9f:IC₅₀=382mm,9e:IC₅₀=495mm and 10f:IC₅₀=364mm)possessed better inhibitory activities than those of the derivatives with only one free carboxyl group on the C-28 amide side chain(e.g.9i:IC₅₀=608mm,9j:IC₅₀=798mm).Besides,the inhibitory activities of CA derivatives are generally lower than those of MA derivatives?e.g.9a vs 10a,9d vs 10d?.It is worth noting that maslinic acid and corosolic acid derivatives coupled aspartic acid(9f:IC₅₀=382mM and 10f:IC₅₀=364mM,respectively)have the best water solubility and present higher inhibitory activity than that of acarbose(IC₅₀=484mM).Moreover,the kinetic inhibition studies indicate that 9f and10f are non-competitive inhibitor.In addition,the anti-inflammatory activities of some derivatives were evaluated in vitro.The results show that the derivatives 15a?IR=69.3%?and 16a?IR=61.3%?introduced glycine on the A-ring bishydroxyl site exhibit stronger inhibitory activity against LPS-induced NO production than indomethacin at 10mM;simultaneously,the inhibitory activities of the derivatives 15b and 15c are similar to that of indomethacin and most of derivatives show weak inhibitory activity.Finally,structure–activity relationships of the derivatives are also discussed.