A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using topomer CoMFA: model building studies and experimental verification.
A 3D QSAR study of betulinic acid derivatives as anti-tumor agents using topomer CoMFA: model building studies and experimental verification.
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使用TOPOMER COMFA：模型建筑研究和实验验证的3D QSAR研究将β酸衍生物作为抗肿瘤剂。
DOI：
10.3390/molecules180910228
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发表时间：
2013-08-22
期刊：
影响因子：
--
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Ding W;Sun M;Luo S;Xu T;Cao Y;Yan X;Wang Y
桦木酸（BA）是一种天然产物，通过触发线粒体凋亡途径，对多种恶性肿瘤发挥细胞毒性，且无副作用。桦木醇 (BE) 是 BA 的 28 个羟基类似物，大量存在于桦树外皮中（高达干重的 30%），并且与 BA 具有相同的五环三萜类核心，但没有表现出明显的细胞毒性。在本研究中，对 37 种 BA 和 BE 衍生物进行了 Topomer CoMFA 研究，及其针对 HT29 人结肠癌细胞的体外抗癌活性结果（报告为 IC50 值）。所有衍生物都共享一个共同的五环三萜类核心，并且考虑到结构多样性，通过在 C-3 和 C-28 位点切割将分子分成三部分。分析得出留一交叉验证 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）。等值线图表明，体积大且给电子的基团有利于 C-28 位点的活性，而 C-3 位点附近的中等体积且吸电子的基团将改善该活性。根据建模结果设计并合成了BE衍生物，在BE的C-28位直接引入大的电负性基团（马来酰基、邻苯二甲酰基和六氢邻苯二甲酰基）。给定类似物对HT29细胞的体外细胞毒性值与预测值一致，证明本拓扑异构体CoMFA模型是成功的，并且它有可能指导具有高抗癌活性的新型桦木酸衍生物的合成。这三种新化合物的 IC50 值也在其他五种肿瘤细胞系中进行了测定。 28-O-六氢邻苯二甲酰BE在所有细胞系（DU145细胞除外）中表现出最大的抗癌活性，其IC50值低于BA。
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.
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