齐墩果酸C-3及C-28位衍生物的设计合成及抗肿瘤活性研究

Design,Synthesis,and Antitumor Activity of C-3 and C-28 Derivatives of Oleanolic Acid

设计及合成一系列新型齐墩果酸衍生物,并对其进行抗肿瘤活性及分子对接研究。以天然产物齐墩果酸为先导化合物,对其C-3羟基和C-28羧基进行结构修饰,合成新型齐墩果酸衍生物;采用MTT法测定化合物对人肺癌细胞(A549)和乳腺癌细胞(MCF-7)的体外抗肿瘤活性;利用计算机辅助药物设计方法分析所合成化合物关键基团与PI3K受体的作用方式。合成了12个未见文献报道的齐墩果酸衍生物,结构均经1HNMR、13 CNMR及MS谱确证。活性测试结果表明,化合物N-[3β-乙酰氧基-齐墩果烷-12-烯-28-酰]-2-氨基乙醇-4-三氟甲基苯甲酸酯(Ⅰ3)、3β-乙酰氧基-齐墩果烷-12-稀-28β-[N-(3-苯甲酰氨基丙基)]甲酰氨基(Ⅱ1)对肿瘤细胞的抑制活性明显高于母体齐墩果酸与阳性对照药Alpelisib相当。经过结构修饰后的齐墩果酸衍生物具有一定的抗肿瘤作用,值得进一步研究。

A series of novel derivatives of oleanolic acid were designed and synthesized,and their antitumor activity and molecular docking were investigated.Using natural oleanolic acid as lead compound,its C-3 hydroxyl and C-28 carboxyl groups were structurally modified to synthesize twelve novel derivatives of oleanolic acid,the structures of which were confirmed by 1HNMR,13 CNMR,and MS spectra.The antitumor activity against human lung cancer cells(A549)and breast cancer cells(MCF-7)was evaluated using the MTT assay.The interaction between the key functional groups of the synthesized compounds and the PI3K receptor was analyzed using computer-assisted drug design.The results demonstrated that compounds N-(3β-acetoxy-olean-12-ene-28-acyl)-2-amino ethanol-4-trifluorobenzoate(Ⅰ3)and 3β-acetoxy-olean-12-ene-28-acyl-[N-(3-benzoamidopropyl)]formamide(Ⅱ1)exhibited higher inhibitory activity against tumor cells compared to oleanolic acid and the positive control drug Alpelisib.These structurally modified derivatives of oleanolic acid possess certain anti-tumor effects warranting further investigation.