Abstract

Since the beginning, natural products have represented an important source of bioactive molecules for cancer treatment. Among them, cardenolides attract the attention of different research groups due to their cardiotonic and antitumor activity. The observed biological activity is closely related to their Na⁺/K⁺-ATPase inhibition potency. Currently, the discovery of new compounds against cancer is an urgent need in modern pharmaceutical research. Thus, the aim of this work is to determine the physicochemical properties and substituent effects that module the antiproliferative activity of cardenolides on the human lung cancer cell line A549. We build and curate a library with results obtained from literature; molecular descriptors were calculated in PaDEL software, and SAR/QSAR analysis was performed. The SAR results showed that cardenolides were sensitive to modifications in C and D steroidal ring and required substituent groups with the function of hydrogen bond acceptor at the C3 position. QSAR models to doubly linked-type cardenolides indicated that properties as lipoaffinity and atoms with the capacity to be hydrogen bond acceptors are involved in the increment of antiproliferative activity on A549 cell line. In contrast, the presence and position of very electro-negative atoms on the molecule decreased the antiproliferative effect on A549 cells. These results suggest that the antiproliferative capacity of cardenolides on the cell line A549 is strongly related to substituent groups on the C3 position, which must not be carbohydrate. Additionally, the steroidal rings C and D must remain without modifications.

Graphic abstract

中文翻译：

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Cardenolides 对细胞系 A549 的抗增殖活性：构效关系分析。

摘要

从一开始，天然产物就代表了用于癌症治疗的生物活性分子的重要来源。其中，cardenolides因其强心和抗肿瘤活性而受到不同研究组的关注。观察到的生物活性与其Na ⁺ /K ^{+密切相关}-ATP酶抑制效力。目前，发现新的抗癌化合物是现代药物研究的迫切需要。因此，这项工作的目的是确定卡多内酯对人肺癌细胞系 A549 的抗增殖活性的物理化学性质和取代基效应。我们利用从文献中获得的结果建立和管理一个图书馆；在 PaDEL 软件中计算分子描述符，并进行 SAR/QSAR 分析。SAR结果表明，cardenolides对C和D甾体环的修饰敏感，需要在C3位具有氢键受体功能的取代基。QSAR 模型为双向链接型cardenolides 表明，脂亲和性和具有成为氢键受体能力的原子等性质与 A549 细胞系抗增殖活性的增加有关。相反，分子上极负电原子的存在和位置降低了对A549细胞的抗增殖作用。这些结果表明，cardenolides 对细胞系 A549 的抗增殖能力与 C3 位上的取代基密切相关，它一定不是碳水化合物。此外，甾体环 C 和 D 必须保持不变。

图形摘要