Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells,Journal of Medicinal Chemistry

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Platinum(IV) Derivatives of [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)] with Diclofenac Ligands in the Axial Positions: A New Class of Potent Multi-action Agents Exhibiting Selectivity to Cancer Cells
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-06-07 , DOI: 10.1021/acs.jmedchem.3c00269
Hana Kostrhunova ₁ , Brondwyn S McGhie ₂ , Lenka Markova ₁ , Olga Novakova ₁ , Jana Kasparkova _{1,

3} , Janice R Aldrich-Wright ₂ , Viktor Brabec ₁

Affiliation

The platinum(II) complex [Pt(1S,2S-diaminocyclohexane)(5,6-dimethyl-1,10-phenanthroline)]²⁺ (Pt^II56MeSS, 1) exhibits high potency across numerous cancer cell lines acting by a multimodal mechanism. However, 1 also displays side toxicity and in vivo activity; all details of its mechanism of action are not entirely clear. Here, we describe the synthesis and biological properties of new platinum(IV) prodrugs that combine 1 with one or two axially coordinated molecules of diclofenac (DCF), a non-steroidal anti-inflammatory cancer-selective drug. The results suggest that these Pt(IV) complexes exhibit mechanisms of action typical for Pt(II) complex 1 and DCF, simultaneously. The presence of DCF ligand(s) in the Pt(IV) complexes promotes the antiproliferative activity and selectivity of 1 by inhibiting lactate transporters, resulting in blockage of the glycolytic process and impairment of mitochondrial potential. Additionally, the investigated Pt(IV) complexes selectively induce cell death in cancer cells, and the Pt(IV) complexes containing DCF ligands induce hallmarks of immunogenic cell death in cancer cells.

中文翻译：

轴向位置带有双氯芬酸配体的[Pt(1S,2S-二氨基环己烷)(5,6-二甲基-1,10-菲咯啉)]的铂(IV)衍生物：一类新的具有癌症选择性的强效多作用药物细胞

铂 (II) 络合物 [Pt(1 S ,2S-二氨基环己烷)(5,6-二甲基-1,10-菲咯啉)] ²⁺ (Pt ^II 56MeSS, 1 ) 在多种癌细胞系中表现出高效能，通过作用多式联运机制。然而，1也表现出副作用和体内活性；其作用机制的所有细节尚不完全清楚。在这里，我们描述了新型铂（IV）前药的合成和生物学特性，该药物将1 个或两个双氯芬酸（DCF）轴向配位分子结合在一起，DCF 是一种非甾体抗炎癌症选择性药物。结果表明这些 Pt(IV) 配合物表现出 Pt(II) 配合物1的典型作用机制和 DCF，同时进行。Pt(IV) 复合物中 DCF 配体的存在通过抑制乳酸转运蛋白来促进1的抗增殖活性和选择性，从而导致糖酵解过程受阻并损害线粒体电位。此外，所研究的 Pt(IV) 复合物选择性诱导癌细胞中的细胞死亡，并且含有 DCF 配体的 Pt(IV) 复合物诱导癌细胞中免疫原性细胞死亡的标志。

更新日期：2023-06-07

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