Studies On Synthesis Of Derivatives Of Oleanolic Acids And Their Anti-Tumor Activity

Hunting for high-efficiency and low-toxic anti-tumor agents is one of hot topics in the research of new drugs.Seeking anti-tumor agents from traditional Chinese medicine,and structural modification and anti-tumor activity studies on natural products are not only the important part of modernization of Chinese medicine but also the major way of research in anti-tumor drugs.Oleanolic acid(OA)is oleanane type pentacyclic triterpene,which is abundant in the nature.This paper reviewed isolation and structural modifications of the triterpenoid as well as their pharmacological activities in recent 10 years,with an emphasis on their structure activity relationships(SAR).Biological and pharmacological activities of OA found to span a wide variety of ranges,such as antitumor,antiviral,anti-inflammatory,hepatoprotective,gastroprotective, antimicrobial,antidiabetic,hemolytic and many other properties.OA was oxidized into 3-oxooleanonic acid(3-oxo-OA),which exhibited markedly antitumor activity.3-oxo-OA was different from general cytotoxic medicines in that it showed anti-angiogenic activities and less toxicity to normal cells.Structural modifications on 3-oxo-OA maybe contribute to find efficient medicines for antitumor and other diseases.3-oxo-OA,however,has three disadvantages,firstly,lower water-solubility results in worse bioavailability.Secondly,the antitumor effect of 3-oxo-OA has a great way to a clinical antitumor drug.Thirdly,structural modifications of 3-oxo-OA mainly focused on A-,C-rings,and C-28 because of its less functional group.Therefore,this paper designed and synthesized three types of derivatives from OA:At first,we designed and synthesized six amino acid conjugates of 3-oxo-OA,and to determine their water solubility.Water solubility of conjugates showed various degrees of improvement than 3-oxo-OA.Antitumor activities in vitro showed amino acid conjugates of 3-oxo-OA bearing higher water solubility retained inhibitory activity,but inhibitory activity did not retain when the conjugates were prepared into their sodiums.Therefore,suitable partition coefficient of oil/water will need if improve or retain inhibitory activity of 3-oxo-OA.At second,jacaranone ethyl ester(JE)was connected to C-28 of 3-oxo-OA with different linkers in order that optimized 3-oxo-OA beneficial effects and minimized toxicity of jacaranone ethyl ester,and six compounds were obtained.The types of linkers include can be hydrolyzed by esterase and cannot be hydrolyzed by esterase in vivo.The lengths of linkers include four of 2～6 carbons. Two types of conjugates of JE and 3-oxo-OA with 4～6 carbons' linkers showed about tenfold cytotoxic than 3-oxo-OA.Therefore,JE was also connected to 3-oxoursolic acid,3-oxobetulinic acid and 3-oxoglycyrrhetinic acid by 4～6 carbons' linkers in order to optimized part of triterpene. Among them,conjugates of 3-oxoursolic acid and 3-oxobetulinic acid and JE showed stronger cytotoxicity than those of 3-oxo-OA.So,cytotoxic activity of conjugates could be improved further by changing part of triterpene.In addition,these conjugates could inhibit migration of vascular endothelial cell(ECV304). Higher inhibitory activity also needed longer linker.Conjugates of 3-oxoursolic acid and 3-oxobetulinic acid have higher inhibitory activity than that of conjugates of 3-oxo-OA.Among them,conjugate of 3-oxobetulinic acid showed the strongest inhibitory effects.At third,new natural 25-acetoxy-3α-hydroxyoleanolic acid,which exhibited moderate cytotoxicity against 39 human cancer cell lines,was semi-synthesized from OA,employing a photochemical reaction of nitrite for the introduction of C-25 substituting group.The sequence of synthesis was in an efficient manner(13 steps,20.5%yield).This paper reported the semi-synthesis the derivatives of 25-hydroxyolean-12-en-28-oic acid firstly.Based on the comparison of spectral data of product with reported natural compound,we found the structure in that paper was incorrectly assigned,and should be reassigned as 3α-acet-25-hydroxyolean-12-en-28-oic acid.This work not only provided a new example of derivatives on the "non-activated" positions in the synthesis of triterpenoids,but also opened up new avenues to explore the pharmacological activities of the 25-hydroxy triterpenoids.Therefore,the results of studies will benefit the further investigating on the structural modification and relationships of structures and activities of pentacyclic triterpenes.