Abstract：
Herein, we describe the general design, synthesis, characterization, and biological activity of new multitargeting Pt(IV) prodrugs that combine antitumor cisplatin and dasatinib, a potent inhibitor of Src kinase. These prodrugs exhibit impressive antiproliferative and anti-invasive activities in tumor cell lines in both two-dimensional (2D) monolayers of cell cultures and three-dimensional (3D) spheroids. We show that the cisplatin moiety and dasatinib in the investigated Pt(IV) complexes are both involved in the mechanism of action in MCF7 breast cancer cells and act synergistically. Thus, combining dasatinib and cisplatin into one molecule, compared to using individual components in a mix, may bring several advantages, such as significantly higher activity in cancer cell lines and higher selectivity for tumor cells. Most importantly, Pt(IV)-dasatinib complexes hold significant promise for potential anticancer therapies by targeting epithelial-mesenchymal transition, thus preventing the spread and metastasis of tumors, a value unachievable by a simple combination of both individual components.
摘要：
在这里，我们描述了总体设计，合成，表征，结合抗肿瘤顺铂和达沙替尼的新型多靶向Pt（IV）前药的生物活性，Src激酶的有效抑制剂。这些前药在细胞培养物的二维（2D）单层和三维（3D）球体中的肿瘤细胞系中均表现出令人印象深刻的抗增殖和抗侵袭活性。我们表明，所研究的Pt（IV）复合物中的顺铂部分和达沙替尼都参与了MCF7乳腺癌细胞的作用机制，并协同作用。因此，将达沙替尼和顺铂联合成一个分子，与在混合物中使用单个组分相比，可能会带来几个优点，例如在癌细胞系中明显更高的活性和对肿瘤细胞更高的选择性。最重要的是,Pt（IV）-达沙替尼复合物通过靶向上皮-间质转化为潜在的抗癌疗法，具有重要的前景。从而防止肿瘤的扩散和转移，两个单独组件的简单组合无法实现的值。
