Ruthenium-Containing Linear Helicates and Mesocates with Tuneable p53-Selective Cytotoxicity in Colorectal Cancer Cells
作者:Simon J. Allison、David Cooke、Francesca S. Davidson、Paul I. P. Elliott、Robert A. Faulkner、Hollie B. S. Griffiths、Owen J. Harper、Omar Hussain、P. Jane Owen-Lynch、Roger M. Phillips、Craig R. Rice、Samantha L. Shepherd、Richard T. Wheelhouse
DOI:10.1002/anie.201805510
日期:2018.7.26
The ligands L1 and L2 both form separable dinuclear double‐stranded helicate and mesocate complexes with RuII. In contrast to clinically approved platinates, the helicate isomer of [Ru2(L1)2]4+ 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
配体L 1和L 2都与Ru II形成可分离的双核双链螺旋和介旋配合物。与临床批准的铂酸盐相反,[Ru 2(L 1)2 ] 4+的螺旋状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。中消旋异构体显示出相反的选择性,非手性异构体优先对HCT116 p53 + / +具有细胞毒性。其他结构相似的茹二世含双核复合物的细胞毒活性很小。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具有深远的影响,并表明选择性可以“调节”到任一基因型。在寻找可以靶向缺乏p53抑癌基因的难以治疗的肿瘤的化合物时,[Ru 2(L 1)2 ] 4+是有希望发展的化合物。