Synthesis, X-ray structure, interactions with DNA, remarkable in vivo tumor growth suppression and nephroprotective activity of cis-tetrachloro-dipivalato dirhenium(III)

In this study we report the synthesis, the X-ray crystal structure and the in vivo tumor growth suppression and nephroprotective activity of bis-dimethylsulfoxide-cis-tetrachlorodi-μ-pivalatodirhenium(III), cis-Re2[(CH3)3CCOO]2Cl4 · 2(CH3)2SO (I). The interactions of I with DNA were also investigated by electrophoretic mobility shift assays, electronic absorption titrations, ΔTm and viscosity measurements, which indicate that compound I interacts relatively strongly with the DNA (Kb 2.2 × 103 M− 1), most likely by forming covalent interstrand cross-links, and by kinking and unwinding supercoiled DNA; moreover, DNA cleavage by I is enhanced in the presence of redox-active species. The in vivo antitumor activity of I is considerable and is accompanied by significant elimination of red blood cell and kidney damage. Remarkably, compound I in combination with cisplatin (combined Re–Pt antitumor system) led to suppression of tumor growth or complete tumor elimination. The antihemolytic and nephroprotective abilities of I only or as a part of the Re–Pt antitumor system were established and a possible mechanism for the influence of I on these properties, involving erythropoietin production, is proposed.

Graphical abstractHerein we report the synthesis, the X-ray crystal structure of cis-Re2[(CH3)3CCOO]2Cl4·2DMSO (I). Compound I cleaves, covalently binds and unwinds supercoiled DNA. Remarkably, I and I + cisplatin suppressed tumor growth or completely eliminated the tumors, and exhibited considerable antihemolytic and nephroprotective abilities, in in vivo studies.Figure optionsDownload full-size imageDownload as PowerPoint slide