Reconocimiento y Encapsulación Molecular, Universidad Católica San Antonio de Murcia Campus los Jerónimos, 30107 Murcia, Spain.
Int J Mol Sci. 2020 Jul 3;21(13):4741. doi: 10.3390/ijms21134741.
Although Pt(II)-based drugs are widely used to treat cancer, very few molecules have been approved for routine use in chemotherapy due to their side-effects on healthy tissues. A new approach to reducing the toxicity of these drugs is generating a prodrug by increasing the oxidation state of the metallic center to Pt(IV), a less reactive form that is only activated once it enters a cell. We used theoretical tools to combine the parent Pt(IV) prodrug, oxoplatin, with the most recent FDA-approved anti-cancer drug set published by the National Institute of Health (NIH). The only prerequisite imposed for the latter was the presence of one carboxylic group in the structure, a chemical feature that ensures a link to the coordination sphere via a simple esterification procedure. Our calculations led to a series of bifunctional prodrugs ranked according to their relative stabilities and activation profiles. Of all the designed molecules, the combination of oxoplatin with aminolevulinic acid as the bioactive ligand emerged as the most promising strategy by which to design enhanced dual-potency oncology drugs.
尽管基于铂(II)的药物被广泛用于治疗癌症，但由于它们对健康组织的副作用，很少有分子被批准常规用于化疗。减少这些药物毒性的一种新方法是通过增加金属中心的氧化态至 Pt(IV)来生成前药，Pt(IV)是一种反应性较低的形式，只有进入细胞后才被激活。我们使用理论工具将母体 Pt(IV)前药奥沙利铂与美国国立卫生研究院 (NIH) 发布的最新 FDA 批准的抗癌药物集结合起来。对后者唯一的要求是结构中存在一个羧酸基团，这种化学特征可确保通过简单的酯化程序与配位体连接。我们的计算得出了一系列根据其相对稳定性和激活特性排列的双功能前药。在所设计的所有分子中，奥沙利铂与作为生物活性配体的氨基乙酰丙酸的组合成为设计增强双重效力的肿瘤药物的最有前途的策略。
