Anticancer Water-Soluble Organoruthenium Complexes: Synthesis and Preclinical Evaluation.
Anticancer Water-Soluble Organoruthenium Complexes: Synthesis and Preclinical Evaluation.
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DOI：
10.1002/cbic.202200259
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发表时间：
2022-09-16
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本文报道了5种含不同膦配体的顺丁烯二腈二硫醇基金属配合物的合成、表征及其对两种卵巢癌细胞(A2780和A2780cisR)、一种非小细胞肺癌细胞系(H460)和一种正常前列腺细胞系(PNT2)的体外细胞毒性( )。这些18电子配合物被设计为含有四个水溶性膦配体，以增加相应的在 体外承诺中表现出很大的电子缺乏的Ru络合物的水溶性，并与三苯基膦进行比较。与16电子前体相比，三苯基膦-3，3‘，3’-三磺酸和三苯基膦的配合物具有相似的细胞毒性，对A2780和A2780cisR具有相同的细胞毒性。对作用机制的提示提示了一种基于活性氧(ROS)产生的细胞凋亡途径。在A2780和A2780cisR皮下移植模型中，这两种化合物在 活体初步试验中没有观察到毒性，并有一些肿瘤生长延迟的证据。将膦配体与[(η，6-对-伞花烃)Ru(顺丁烯二硫酸酯)]配位，得到亲水性不同的Ru(II)配合物。对两种卵巢癌细胞系、一种非小细胞肺癌细胞系和一种正常前列腺细胞系的体外 细胞毒性进行了鉴定和评价。提出了一种基于产生活性氧而导致细胞凋亡的作用机制。体内评估表明，有一些证据表明肿瘤生长迟缓。
The synthesis, characterisation, and evaluation of the in vitro cytotoxicity of five maleonitriledithiolate‐based ruthenium metal complexes bearing various phosphine ligands towards two ovarian cancer cell lines (A2780 and A2780cisR), one non‐small‐cell lung cancer cell line (H460) and one normal prostate cell line (PNT2) are presented herein. These 18‐electron complexes were designed with four water‐soluble phosphine ligands to increase the water‐solubility character of the corresponding electron‐deficient ruthenium complex which showed great in vitro promises, and triphenylphosphine for comparison. The complexes with triphenylphosphine‐3,3′,3′′‐trisulfonic acid and triphenylphosphine present similar cytotoxicity compared to the 16‐electron precursor, with equal cytotoxicity to both A2780 and A2780cisR. Hints at the mechanism of action suggest an apoptotic pathway based on reactive oxygen species (ROS) production. No toxicity was observed in preliminary in vivo pilot studies for these two complexes in subcutaneous A2780 and A2780cisR xenograft models, with some evidence of tumour growth delay. Phosphine ligands are coordinated to [(η6‐p‐cymene)Ru(maleonitriledithiolate)] to obtain ruthenium(II) complexes with different hydrophilicities. Characterisation and evaluation of the in vitro cytotoxicity towards two ovarian, one non‐small‐cell lung cancer cell lines and one normal prostate cell line are presented. A mechanism of action based on reactive oxygen species production leading to apoptosis is suggested. In vivo evaluation suggests some evidence of tumour growth delay.
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