Preclinical Anticancer Activity of an Electron-Deficient Organoruthenium(II) Complex.,ChemMedChem

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Preclinical Anticancer Activity of an Electron-Deficient Organoruthenium(II) Complex.
ChemMedChem ( IF 3.6 ) Pub Date : 2020-04-01 , DOI: 10.1002/cmdc.202000096
Joan J Soldevila-Barreda ₁ , Maria Azmanova ₁ , Anaïs Pitto-Barry ₁ , Patricia A Cooper ₂ , Steven D Shnyder ₂ , Nicolas P E Barry ₁

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Ruthenium compounds have been shown to be promising alternatives to platinum(II) drugs. However, their clinical success depends on achieving mechanisms of action that overcome Pt‐resistance mechanisms. Electron‐deficient organoruthenium complexes are an understudied class of compounds that exhibit unusual reactivity in solution and might offer novel anticancer mechanisms of action. Here, we evaluate the in vitro and in vivo anticancer properties of the electron‐deficient organoruthenium complex [(p ‐cymene)Ru(maleonitriledithiolate)]. This compound is found to be highly cytotoxic: 5 to 60 times more potent than cisplatin towards ovarian (A2780 and A2780cisR), colon (HCT116 p53 +/+ and HCT116 p53 −/−), and non‐small cell lung H460 cancer cell lines. It shows no cross‐resistance and is equally cytotoxic to both A2780 and A2780cisR cell lines. Furthermore, unlike cisplatin, the remarkable in vitro antiproliferative activity of this compound appears to be p53‐ independent. In vivo evaluation in the hollow‐fibre assay across a panel of cancer cell types and subcutaneous H460 non‐small cell lung cancer xenograft model hints at the activity of the complex. Although the impressive in vitro data are not fully corroborated by the in vivo follow‐up, this work is the first preclinical study of electron‐deficient half‐sandwich complexes and highlights their promise as anticancer drug candidates.

中文翻译：

电子缺乏型有机钌（II）配合物的临床前抗癌活性。

钌化合物已被证明是铂（II）药物的有前途的替代品。但是，它们的临床成功取决于实现克服Pt耐药机制的作用机制。缺电子的有机钌络合物是一类未被充分研究的化合物，它们在溶液中表现出异常的反应性，并可能提供新颖的抗癌作用机理。在这里，我们评估了缺电子的有机钌配合物[（p- Cymene）Ru（马来三硫代硫酸盐）]的体外和体内抗癌性能。该化合物具有高度细胞毒性：对卵巢（A2780和A2780cisR），结肠（HCT116 p53 + / +和HCT116 p53）的毒性是顺铂的5至60倍-/-）和非小细胞肺癌H460癌细胞系。它没有交叉抗性，并且对A2780和A2780cisR细胞系均具有细胞毒性。此外，与顺铂不同，该化合物的显着体外抗增殖活性似乎与p53无关。中空纤维测定法对一系列癌细胞类型和皮下H460非小细胞肺癌异种移植模型的体内评估提示了复合物的活性。尽管体内随访结果并不能完全证实令人印象深刻的体外数据，但这项工作是对缺乏电子的半三明治复合物的首次临床前研究，并突显了它们作为抗癌药物的前景。

更新日期：2020-04-01

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