Effective and scalable mechanochemical synthesis of platinum(ii) heteroleptic anticancer complexes†

With global cancer cases and their associated costs steadily increasing, there is an imperative for sustained research efforts to improve health outcomes and mitigate its socio-economic impact. Several treatments have been developed over the last few decades to alleviate these issues. Among them, platinum(II) and(IV)(Pt(II) and(IV)) heteroleptic complexes show promise in the field of cancer treatment. However, the design of innovative derivatives towards enhanced cancer therapies is hindered by the limited number of synthetic methods currently available. Mechanochemistry is rapidly emerging as a powerful alternative to traditional synthetic routes. In this context, it not only offers a fast, efficient and scalable synthesis with a reduced environmental footprint but also renders a new conceptual synthetic framework in materials science and pharmaceuticals. Herein, we demonstrate proof-of-concept that Pt(II) heteroleptic complexes can be readily synthesised using a solvent-free milling and kneading mechanochemical method. Using PHENSS as an example, the synthesis was readily scaled up by 6.7-fold, whilst maintaining high yield and purity. The newly developed method significantly reduced reaction time by 8-fold and energy consumption by 28.8-fold, in comparison to the traditional route. Further, the environmental footprint was notably reduced when mechanochemistry was employed (i.e., ∼700-fold reduction in the environmental factor (E-factor) and ∼200-fold in the process mass intensity (PMI)). This work also determined that the mechanochemical method did not alter the in vitro growth inhibition activity. This study provides new insights into the mechanochemical synthesis of six Pt(II) heteroleptic complexes: PHENSS, 56MESS, 47MESS, 4MESS, 3478MESS and 5ClSS, and sets the foundation for scalable and sustainable routes towards heteroleptic metal complexes with potential applications across diverse fields.