Fernandes Mariane B, Scotti Marcus T, Ferreira Marcelo J P, Emerenciano Vicente P
Instituto de Química, Universidade de São Paulo, Caixa Postal 26077, 05513-970, São Paulo, SP, Brazil.
Eur J Med Chem. 2008 Oct;43(10):2197-205. doi: 10.1016/j.ejmech.2008.01.003. Epub 2008 Jan 25.
Some sesquiterpene lactones (SLs) are the active compounds of a great number of traditionally medicinal plants from the Asteraceae family and possess considerable cytotoxic activity. Several studies in vitro have shown the inhibitory activity against cells derived from human carcinoma of the nasopharynx (KB). Chemical studies showed that the cytotoxic activity is due to the reaction of alpha,beta-unsaturated carbonyl structures of the SLs with thiols, such as cysteine. These studies support the view that SLs inhibit tumour growth by selective alkylation of growth-regulatory biological macromolecules, such as key enzymes, which control cell division, thereby inhibiting a variety of cellular functions, which directs the cells into apoptosis. In this study we investigated a set of 55 different sesquiterpene lactones, represented by 5 skeletons (22 germacranolides, 6 elemanolides, 2 eudesmanolides, 16 guaianolides and nor-derivatives and 9 pseudoguaianolides), in respect to their cytotoxic properties. The experimental results and 3D molecular descriptors were submitted to Kohonen self-organizing map (SOM) to classify (training set) and predict (test set) the cytotoxic activity. From the obtained results, it was concluded that only the geometrical descriptors showed satisfactory values. The Kohonen map obtained after training set using 25 geometrical descriptors shows a very significant match, mainly among the inactive compounds (approximately 84%). Analyzing both groups, the percentage seen is high (83%). The test set shows the highest match, where 89% of the substances had their cytotoxic activity correctly predicted. From these results, important properties for the inhibition potency are discussed for the whole dataset and for subsets of the different structural skeletons.
一些倍半萜内酯（SLs）是菊科大量传统药用植物的活性成分，具有相当强的细胞毒性活性。多项体外研究表明其对人鼻咽癌（KB）来源的细胞具有抑制活性。化学研究表明，细胞毒性活性是由于SLs的α,β-不饱和羰基结构与硫醇（如半胱氨酸）发生反应所致。这些研究支持了这样一种观点，即SLs通过对生长调节生物大分子（如控制细胞分裂的关键酶）进行选择性烷基化来抑制肿瘤生长，从而抑制多种细胞功能，使细胞进入凋亡状态。在本研究中，我们研究了一组由5种骨架代表的55种不同的倍半萜内酯（22种吉马烷型内酯、6种榄烷型内酯、2种桉烷型内酯、16种愈创木烷型内酯及其去甲衍生物和9种假愈创木烷型内酯）的细胞毒性特性。将实验结果和三维分子描述符提交给Kohonen自组织映射（SOM），以对细胞毒性活性进行分类（训练集）和预测（测试集）。从获得的结果得出结论，只有几何描述符显示出令人满意的值。使用25个几何描述符对训练集进行训练后得到的Kohonen映射显示出非常显著的匹配，主要在无活性化合物之间（约84%）。分析两组数据，匹配百分比很高（83%）。测试集显示出最高的匹配度，其中89%的物质的细胞毒性活性得到了正确预测。根据这些结果，讨论了整个数据集以及不同结构骨架子集的抑制效力的重要特性。
