Lupeol and its esters: NMR, powder XRD data and in vitro evaluation of cancer cell growth

ABSTRACT The triterpene lupeol (1) and some of its esters are secondary metabolites produced by species of Celastraceae family, which have being associated with cytotoxic activity. We report herein the isolation of 1, the semi-synthesis of eight lupeol esters and the evaluation of their in vitro activity against nine strains of cancer cells. The reaction of carboxylic acids with 1 and DIC/DMAP was used to obtain lupeol stearate (2), lupeol palmitate (3) lupeol miristate (4), and the new esters lupeol laurate (5), lupeol caprate (6), lupeol caprilate (7), lupeol caproate (8) and lupeol 3’,4’-dimethoxybenzoate (9), with high yields. Compounds 1-9 were identified using FT-IR, 1H, 13C-NMR, CHN analysis and XRD data and were tested in vitro for proliferation of human cancer cell activity. In these assays, lupeol was inactive (GI50> 250µg/mL) while lupeol esters 2 -4 and 7 - 9 showed a cytostatic effect. The XRD method was a suitable tool to determine the structure of lupeol and its esters in solid state. Compound 3 showed a selective growth inhibition effect on erythromyeloblastoid leukemia (K-562) cells in a concentration-dependent way. Lupeol esters 4 and 9 showed a selective cytostatic effect with low GI50 values representing promising prototypes for the development of new anticancer drugs.

摘要 三萜类化合物羽扇豆醇（lupeol，1）及其部分酯类是卫矛科（Celastraceae）物种产生的次生代谢产物，该类化合物与细胞毒性活性密切相关。本文报道了羽扇豆醇（1）的分离方法、8种羽扇豆醇酯的半合成路线，以及它们对9株癌细胞的体外活性评价。通过羧酸与羽扇豆醇（1）在二环己基碳二亚胺/4-二甲氨基吡啶（DIC/DMAP）催化下的反应，以较高产率制备得到硬脂酸羽扇豆醇酯（2）、棕榈酸羽扇豆醇酯（3）、肉豆蔻酸羽扇豆醇酯（4），以及新型酯类：月桂酸羽扇豆醇酯（5）、癸酸羽扇豆醇酯（6）、辛酸羽扇豆醇酯（7）、己酸羽扇豆醇酯（8）和3’,4’-二甲氧基苯甲酸羽扇豆醇酯（9）。采用傅里叶变换红外光谱（FT-IR）、氢核磁共振谱（¹H NMR）、碳核磁共振谱（¹³C NMR）、碳氢氮元素分析（CHN分析）及X射线衍射（XRD）数据对化合物1~9进行结构鉴定，并开展了其对人体癌细胞增殖影响的体外实验。活性测试结果显示，羽扇豆醇（1）无明显细胞抑制活性（GI₅₀＞250μg/mL），而羽扇豆醇酯2~4及7~9均表现出细胞生长抑制活性。X射线衍射（XRD）是表征羽扇豆醇及其酯类固态结构的可靠分析手段。其中，棕榈酸羽扇豆醇酯（3）对红髓样白血病细胞（K-562）表现出浓度依赖性的选择性生长抑制效果。羽扇豆醇酯4和9的GI₅₀值较低，展现出良好的选择性细胞抑制活性，可作为新型抗癌药物开发的潜在先导化合物。