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

• Published in: Journal of inorganic biochemistry Vol. 129; pp. 127 - 134
• Main Authors: Shtemenko, Natalia I., Chifotides, Helen T., Domasevitch, Konstantin V., Golichenko, Alexander A., Babiy, Svetlana A., Li, Zhanyong, Paramonova, Katherina V., Shtemenko, Alexander V., Dunbar, Kim R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-12-2013
• Subjects: Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cisplatin - chemistry; Cisplatin - pharmacology; Combination therapy; Crystallography, X-Ray; Dirhenium; DNA cleavage; DNA, Neoplasm - chemistry; DNA, Neoplasm - metabolism; Drug Screening Assays, Antitumor; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Oxidation-Reduction; Rats; Rats, Wistar; Rhenium - chemistry; Rhenium - pharmacology; Tumor suppression; DNA cleavage; Tumor suppression; Combination therapy; Dirhenium
• DOI: 10.1016/j.jinorgbio.2013.09.001
• EISSN: 1873-3344
• ISSN: 0162-0134

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 2.2×103M−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.
Herein 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. [Display omitted]