Prompted by the antineoplastic properties of cisplatin, a plethora of platinum(II)-based complexes have been synthesized in the past decades. At present, their rational design is based on a number of structure–activity relationships involving the nature of the ligands initially coordinated to platinum(II): either non-labile (acting as a carrier) or labile (undergoing substitution). The coordinate bond strength of the labile ligand plays a key role in the first step of the drug mechanism of action, i.e., the hydrolysis process, which is associated to the retention time of the medicine in the body. Therefore, an accurate determination of the metal–ligand bond strength becomes highly relevant as it will help the rational design of novel chemotherapeutic agents. Herein, we challenge the recently developed intrinsic bond strength index (IBSI) as a rapid and practical tool to assess the ligand lability in Pt(II) complexes. In a first stage, given the importance of the trans-effect in synthetic strategies of cisplatin-based drugs, the effect of eleven trans-directing ligands T is quantified in two sets of complexes [Pt(NH₃)₂(H₂O)T]ⁿ⁺ and [PtCl₂(NH₃)T]^m+ where T = H₂O, F⁻, NH₃, Cl⁻, Br⁻, I⁻, SO₃²⁻, CH₃⁻, CN⁻, CO, and H⁻. An essential outcome of this work is a novel index IBSI^trans = IBSI^σ + IBSI^π able to rank the directing ligands by their trans-effect according to their σ-donation and π-backbonding electronic contributions. In a second stage, we apply the IBSI score to a panel of eleven case studies, comprising mostly antineoplastic agents, such as cisplatin, carboplatin, lobaplatin etc., in order to quantify the coordinate bond strength of the ligands, providing insights about the hydrolysis process. The obtained results, in good agreement with experimental data and reported theoretical studies, demonstrate that the IBSI score is able to deliver a rapid and reliable picture of the coordinate bond strength, representing a chemically intuitive tool helpful for the development of novel anticancer agents prior to synthetic efforts.

中文翻译：

---

精确预测铂基抗癌药物中键强度和配体不稳定性的新颖方法。

在过去的几十年中，由于顺铂的抗肿瘤特性，已经合成了过多的基于铂（II）的配合物。目前，他们的合理设计是基于许多结构-活性关系，涉及最初与铂（II）配位的配体的性质：不稳定（充当载体）或不稳定（正在进行取代）。不稳定配体的配位键强度在药物作用机理的第一步中起着关键作用，即水解过程，这与药物在体内的保留时间有关。因此，准确确定金属-配体的结合强度变得非常重要，因为这将有助于合理设计新型化学治疗剂。在本文中，我们挑战最近开发的固有键强度指数（IBSI），作为评估Pt（II）配合物中配体不稳定性的快速实用工具。在第一阶段，考虑到反式作用在基于顺铂的药物合成策略中的重要性，在两组复合物中[Pt（NH ₃）₂（H ₂ O）”中定量了十一种反式配体T的作用T] ^{n +}和[PtCl₂（NH ₃）T]^米+其中T = H ₂ O，F ^-，NH ₃，氯^- ，溴^- ，我^-，SO ₃ ^2-，CH ₃ ^-，CN ^-，CO和H ^- 。本工作的一个重要结果是一种新颖的索引IBSI^反式= IBSI ^σ + IBSI ^π能够通过他们的排名所述引导配体反根据它们的σ贡献和π反向键电子贡献。在第二阶段，我们将IBSI分数应用于一组11个案例研究中，主要包括抗肿瘤药，例如顺铂，卡铂，洛巴铂等，以定量配体的配位键强度，从而提供有关水解的见解处理。获得的结果与实验数据和报道的理论研究高度吻合，表明IBSI得分能够提供快速而可靠的配位键强度图，代表化学上直观的工具，有助于在开发新型抗癌剂之前综合努力。