Synthesis And Preliminary In Vitro Antitumor Activity Of Asiatic Acid Derivatives

Asiatic acid(AA)is the main component of the traditional Chinese medicine Centella asiatica.It has shown various biological activities such as antihypertensive,nootropic,antimicrobial and antitumor in preclinical studies.Bcl-xL protein is an anti-apoptotic protein,which is widely expressed in tumor cells and promotes tumor proliferation,migration and drug resistance.By inhibiting the activity of Bcl-xL protein,it can promote tumor cell apoptosis.Therefore,Bcl-xL protein is a potential target for tumor therapy.In this paper,on the basis of the structure-activity relationship of Asiatic acid summarized in the early stage of the research group,using computer-aided design and molecular docking simulation,using the three-dimensional crystal structure of Bcl-xL protein(PDB:3WIX)as the target,40 new products were designed.A total of 10target compounds in two categories were finally screened and synthesized for the derivatives of asiatic acid.With AA as the lead compound,the three hydroxyl groups on the A ring are oxidized and condensed to form a ring.At the same time,the C-28 carbox yl group is acylated to form an amide to obtain 6 2,3-hydropyrazine rings-23-c arbonyl-ursane-type-12-ene-28-Amide compound and 4 2?-nicotinoyloxy-3?,23-O-isopropylene-ursane-type-12-ene-28-Amide compounds.Their structures have bee n confirmed by ¹H-NMR,and there are no new compounds reported in the lite rature.Using the MTT method,SGC7901 and A549 cells were used as target cel ls,and Navitoclax(Bcl-xL inhibitor)was used as a positive control drug to tes t the in vitro anti-tumor activity of compounds of class I and class II.The ex perimental results showed that the inhibitory effects of all target compounds on tumor cells A549 and SGC7901 were stronger than the parent volume of Asia tic acid.Among them,compounds I₂and II₃showed better tumor inhibitory eff ects and had stronger anti-tumor effects than the positive control drug Navitocl ax.Tumor activity.The inhibitory rates of compounds I₂and?₃on the human gastric cancer SGC7901 cell line were 72.39%and 65.32%,respectively,and the IC₅₀values were 5.71?mol·L^-1and 5.43?mol·L^-1,respectively.The inhibit ory rates of compounds I₂and?₃on the human lung cancer A549 cell line w ere 73.62%and 68.65%,respectively,and the IC₅₀values were 2.66?mol·L^-1and 4.79?mol·L^-1,respectively.The molecular docking results showed that co mpounds I₂and II₃interact with multiple amino acid residues in the Bcl-xL pr otein structure to form hydrogen bonds,?-?conjugates,and hydrophobic bond s,thereby stabilizing the binding.This article provides a reference for further research on the structure modification and anti-tumor activity of asiatic acids and pentacyclic triterpenoids.