Abstract：
The impact of kinetic lability or reactivity on in vitro cytotoxicity, stability in plasma, in vivo tumor and tissue accumulation, and antitumor efficacy of functional platinum(II) (Pt) anticancer agents containing a O˄O β-diketonate leaving ligand remain largely unexplored. To investigate this, we synthesized Pt complexes [(NH3 )2 Pt(L1-H)]NO3 and [(DACH)Pt(L1-H)]NO3 (L1=4,4,4-trifluoro-1-ferrocenylbutane-1,3-dione, DACH=1R,2R-cyclohexane-1,2-diamine) containing an electron deficient [L1-H]- O˄O leaving ligand and [(NH3 )2 Pt(L2-H)]NO3 and [(DACH)Pt(L2-H)]NO3 (L2=1-ferrocenylbutane-1,3-dione) containing an electron-rich [L2-H]- O˄O leaving ligand. While all four complexes have comparable lipophilicity, the presence of the electron-withdrawing CF3 group was found to dramatically enhance the reactivity of these complexes toward nucleophilic biomolecules. In vitro cellular assays revealed that the more reactive complexes have higher cellular uptake and higher anticancer potency as compared to their less reactive analogs. But the scenario is opposite in vivo, where the less reactive complex showed improved tissue and tumor accumulation and better anticancer efficacy in mice bearing ovarian xenograft when compared to its more reactive analog. Finally, in addition to demonstrating the profound but contrasting impact of kinetic lability on in vitro and in vivo antitumor potencies, we also described the impact of kinetic lability on the mechanism of action of this class of promising antitumor agents.
摘要：
动力学不稳定性或反应性对体外细胞毒性的影响，在等离子体中的稳定性，体内肿瘤和组织积聚，和含有OOβ-二酮酸盐离开配体的铂（II）（Pt）抗癌剂的抗肿瘤功效仍未被探索。为了调查这一点，我们合成了Pt配合物[（NH3）2Pt（L1-H）]NO3和[（DACH）Pt（L1-H）]NO3（L1=4,4,4-三氟-1-二茂铁基丁烷-1,3-二酮，DACH=1R,2R-环己烷-1,2-二胺），含有缺电子的L1-HOO离开配体和[（NH3）2Pt（L2-H）]NO3和[（DACH）Pt（L2-H）]NO3（L2=1-二茂铁基丁烷-1,3-二酮），其中含有富电子的L2-HOO离开。虽然所有四种复合物都具有相当的亲脂性，发现吸电子CF3基团的存在显着增强了这些复合物对亲核生物分子的反应性。体外细胞测定显示,与其较低反应性的类似物相比,更具反应性的复合物具有更高的细胞摄取和更高的抗癌效力。但在体内情况正好相反，与活性较高的类似物相比，活性较低的复合物在带有卵巢异种移植的小鼠中显示出改善的组织和肿瘤积累以及更好的抗癌功效。最后,除了证明动力学不稳定性对体外和体内抗肿瘤效力的深刻但对比的影响，我们还描述了动力学不稳定性对这类配合物作用机理的影响。
