School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK.
School of Pharmacy, University of Bradford, Bradford, BD7 1DP, UK.
Angew Chem Int Ed Engl. 2018 Jul 26;57(31):9799-9804. doi: 10.1002/anie.201805510. Epub 2018 Jul 3.
The ligands L and L both form separable dinuclear double-stranded helicate and mesocate complexes with Ru . In contrast to clinically approved platinates, the helicate isomer of [Ru (L ) ] was preferentially cytotoxic to isogenic cells (HCT116 p53 ), which lack the critical tumour suppressor gene. The mesocate isomer shows the reverse selectivity, with the achiral isomer being preferentially cytotoxic towards HCT116 p53 . Other structurally similar Ru -containing dinuclear complexes showed very little cytotoxic activity. This study demonstrates that alterations in ligand or isomer can have profound effects on cytotoxicity towards cancer cells of different p53 status and suggests that selectivity can be "tuned" to either genotype. In the search for compounds that can target difficult-to-treat tumours that lack the p53 tumour suppressor gene, [Ru (L ) ] is a promising compound for further development.
配体 L 和 L 均与 Ru 形成可分离的双核双链螺旋和中配位配合物。与临床批准的铂类药物不同，[Ru(L)]的螺旋异构体对缺乏关键肿瘤抑制基因的同基因细胞（HCT116 p53）具有优先的细胞毒性。中配位异构体表现出相反的选择性，手性异构体对 HCT116 p53 具有优先的细胞毒性。其他结构相似的含 Ru 双核配合物表现出很小的细胞毒性活性。这项研究表明，配体或异构体的改变对不同 p53 状态的癌细胞的细胞毒性有深远的影响，并表明选择性可以“调整”为任一种基因型。在寻找可以靶向缺乏 p53 肿瘤抑制基因的难治性肿瘤的化合物时，[Ru(L)]是一种很有前途的进一步开发的化合物。
