In this study, ent-kaurenoic acid derivatives were obtained by microbial transformation methodologies and tested against breast cancer cell lines (MCF-7). A multivariate quantitative-structure activity relationship (QSAR) analysis was performed taking into account both microbial transformation derivatives and other analogues previously reported in literature to give some insight into the main features behind the cytotoxic activity displayed by kaurane-type diterpenes against MCF-7 cells. The partial least square regression (PLS) method was employed in the training set and the best PLS model was built with a factor describing 69.92% of variance and three descriptors (logP, εHOMO and εHOMO-1) selected by the Ordered Predictors Selection (OPS) algorithm. The QSAR model provided reasonable regression (Q2 = 0.64, R2 = 0.72, SEC = 0.29 and SEV = 0.33). The model was validated by leave-N-out cross-validation, y-randomization and external validation (R2pred = 0.89 and SEP = 0.27). The selected descriptors indicated that the activity was mainly related to electronic parameters (HOMO and HOMO-1 molecular orbital energies), as well as to logP. These findings suggest that higher activity values are directly related with both higher logP and frontier orbital energy values. The positive relationship between these orbitals and the activity suggests that the ent-kaurenoic acid analogues interaction with the target involves charge displacement, which is entirely consistent with the literature. Based on these findings, three compounds were proposed and one of them was synthesized and tested. The experimental result confirmed the activity predicted by the model.

中文翻译：

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对映贝壳杉烯酸衍生物对人乳腺癌细胞系的体外细胞毒性及构效关系研究

在这项研究中，通过微生物转化方法获得了对映贝壳杉烯酸衍生物，并针对乳腺癌细胞系 (MCF-7) 进行了测试。考虑到微生物转化衍生物和先前在文献中报道的其他类似物，进行了多变量定量-结构活性关系 (QSAR) 分析，以深入了解贝壳杉烷型二萜对 MCF-7 细胞显示的细胞毒性活性背后的主要特征. 在训练集中采用偏最小二乘回归 (PLS) 方法，并使用描述 69.92% 方差的因子和由有序预测变量选择 (OPS) 选择的三个描述符（logP、εHOMO 和 εHOMO-1）构建最佳 PLS 模型） 算法。QSAR 模型提供了合理的回归（Q2 = 0.64，R2 = 0.72，SEC = 0.29 和 SEV = 0.33）。该模型通过留存交叉验证、y 随机化和外部验证（R2pred = 0.89 和 SEP = 0.27）进行验证。选定的描述符表明活性主要与电子参数（HOMO 和 HOMO-1 分子轨道能量）以及 logP 相关。这些发现表明，较高的活动值与较高的 logP 和前沿轨道能量值直接相关。这些轨道与活性之间的正相关表明对映贝壳杉烯酸类似物与靶标的相互作用涉及电荷置换，这与文献完全一致。基于这些发现，提出了三种化合物，并合成并测试了其中一种。实验结果证实了模型预测的活性。