Alkali Soil Natural Environmental Science Center, Northeast Forestry University/Key Laboratory of Saline-Alkali Vegetation Ecology Restoration in Oil Field, Ministry of Education, Harbin 150040, China.
Molecules. 2013 Aug 22;18(9):10228-41. doi: 10.3390/molecules180910228.
Betulinic acid (BA) is a natural product that exerts its cytotoxicity against various malignant carcinomas without side effects by triggering the mitochondrial pathway to apoptosis. Betulin (BE), the 28-hydroxyl analog of BA, is present in large amounts (up to 30% dry weight) in the outer bark of birch trees, and shares the same pentacyclic triterpenoid core as BA, yet exhibits no significant cytotoxicity. Topomer CoMFA studies were performed on 37 BA and BE derivatives and their in vitro anti-cancer activity results (reported as IC₅₀ values) against HT29 human colon cancer cells in the present study. All derivatives share a common pentacyclic triterpenoid core and the molecules were split into three pieces by cutting at the C-3 and C-28 sites with a consideration toward structural diversity. The analysis gave a leave-one-out cross-validation q² value of 0.722 and a non-cross-validation r² value of 0.974, which suggested that the model has good predictive ability (q² > 0.2). The contour maps illustrated that bulky and electron-donating groups would be favorable for activity at the C-28 site, and a moderately bulky and electron-withdrawing group near the C-3 site would improve this activity. BE derivatives were designed and synthesized according to the modeling result, whereby bulky electronegative groups (maleyl, phthalyl, and hexahydrophthalyl groups) were directly introduced at the C-28 position of BE. The in vitro cytotoxicity values of the given analogs against HT29 cells were consistent with the predicted values, proving that the present topomer CoMFA model is successful and that it could potentially guide the synthesis of new betulinic acid derivatives with high anti-cancer activity. The IC₅₀ values of these three new compounds were also assayed in five other tumor cell lines. 28-O-hexahydrophthalyl BE exhibited the greatest anti-cancer activities and its IC₅₀ values were lower than those of BA in all cell lines, excluding DU145 cells.
桦木酸（BA）是一种天然产物，通过触发线粒体凋亡途径，对各种恶性癌没有副作用地发挥细胞毒性。白桦脂（BE）是 BA 的 28-羟基类似物，大量存在于桦木的外树皮中（高达干重的 30%），与 BA 具有相同的五环三萜核心，但没有表现出显著的细胞毒性。对 37 种 BA 和 BE 衍生物及其在本研究中针对 HT29 人结肠癌细胞的体外抗癌活性结果（报告为 IC₅₀ 值）进行了拓扑构象 CoMFA 研究。所有衍生物都有一个共同的五环三萜核心，并且分子通过在 C-3 和 C-28 位点切割，考虑到结构多样性，被分为三个部分。分析得到的留一法交叉验证 q² 值为 0.722，非交叉验证 r² 值为 0.974，这表明该模型具有良好的预测能力（q²>0.2）。等高线图表明，在 C-28 位上，大的给电子基团是有利的，而在 C-3 位附近有一个适度大的吸电子基团会提高这种活性。根据建模结果设计并合成了 BE 衍生物，其中在 BE 的 C-28 位直接引入了大的电负性基团（马来酰基、邻苯二甲酰基和六氢邻苯二甲酰基）。所给类似物对 HT29 细胞的体外细胞毒性值与预测值一致，证明了本拓扑构象 CoMFA 模型是成功的，并且它可能指导具有高抗癌活性的新型桦木酸衍生物的合成。还在另外五个肿瘤细胞系中测定了这三种新化合物的 IC₅₀ 值。28-O-六氢邻苯二甲酰基 BE 表现出最大的抗癌活性，其 IC₅₀ 值在所有细胞系中均低于 BA，除 DU145 细胞外。
