Synthesis, X-ray structure, interactions with DNA, remarkable in vivo tumor growth suppression and nephroprotective activity of cis-tetrachloro-dipivalato dirhenium(III) Natalia I. Shtemenko a, ⁎, Helen T. Chifotides d , Konstantin V. Domasevitch b , Alexander A. Golichenko c , Svetlana A. Babiy a , Zhanyong Li d , Katherina V. Paramonova a , Alexander V. Shtemenko c , Kim R. Dunbar d a Department of Biophysics and Biochemistry, Dnipropetrovs'k National University, Gagarin Ave. 72, Dnipropetrovs'k 49050, Ukraine b Department of Inorganic Chemistry, Taras Shevchenko University, Kiev 01033, Ukraine c Department of Inorganic Chemistry, State Higher Education Establishment “Ukrainian State University of Chemical Technology”, Gagarin Ave. 8, Dnipropetrovs'k 49005, Ukraine d Department of Chemistry, Texas A&M University, PO Box 30012, College Station, TX 77842-3012, USA abstract article info Article history: Received 18 April 2013 Received in revised form 5 August 2013 Accepted 2 September 2013 Available online 11 September 2013 Keywords: Dirhenium DNA cleavage Tumor suppression Combination therapy 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-Re 2 [(CH 3 ) 3- CCOO] 2 Cl 4 · 2(CH 3 ) 2 SO (I). The interactions of I with DNA were also investigated by electrophoretic mobility shift assays, electronic absorption titrations, ΔT m and viscosity measurements, which indicate that compound I interacts relatively strongly with the DNA (K b 2.2 × 10 3 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. © 2013 Elsevier Inc. All rights reserved. 1. Introduction Since the discovery of the anticancer properties of cisplatin, various strategies have been applied for the design of novel transition-metal- containing drugs in an effort to obtain improved toxicological profiles [1–5]. It is notable that the many attributes of metal complexes as com- pared to organic compounds, especially their versatile redox chemistry, should be exploited in the development of more efficient anticancer drugs. It is worth mentioning the paradigms of new promising antitumor pharmaceuticals, namely dinuclear metal–metal bonded complexes of rhodium, ruthenium and rhenium with ‘lantern-type’ structures [6–12]. It has been postulated that these complexes bind to DNA, inhibit DNA replication and protein synthesis in a manner similar to cisplatin [11]. In particular, the DNA purine bases have been shown to bind to the dimetallic units in a bridging fashion via the nucleobase heteroatoms or exocyclic groups involved in DNA hydrogen bonding [6–9,11,12]. Among the compounds with metal–metal bonds, dirhenium(III) ad- ducts are especially promising candidates for clinical development due to their very low toxicity [13]. The low toxicity of dirhenium compounds is notable in light of the severe limitations for clinical use of several anticancer agents such as cisplatin owing to their neuro- hemato- hepato- and nephrotoxicities [14–16]. Despite the reported promising antitumor activity of dirhenium complexes, systematic studies of their in vivo activity have not been performed yet. In our previous work, a new rhenium–platinum antitumor system (Re–Pt antitumor system) was presented [17–19], the introduction of which led to practically full reduction in the rate of tumor growth and significant reduction of cisplatin toxicity against red blood cells. These previous studies [17–19] and other ongoing studies from our laboratories revealed the dependence of the rhenium cluster anticancer activity on the identity and orientation of the ligands in the coordination sphere of the Re 2 (III, III) core. This is in contrast to our earlier conclusion that the main factor for the antitumor activity of dirhenium compounds is merely the presence of a quadruple Re–Re bond. In this respect, system- atic studies of structure–activity relationships among dirhodium com- plexes have provided insight into the molecular characteristics that control their activity [11,20–24]. In particular, a study performed on a se- ries of dirhodium carboxylate derivatives that exhibit cytostatic activity against the Ehrlich ascites tumor, leukemia L1210, and sarcoma 180 cells, revealed that the activity of this series increases with the lipophilic- ity of the bridging carboxylate alkyl groups but that further lengthening of the carboxylate group beyond the pentanoate reduces their therapeutic efficacy [11]. Taking this into account as well as the fact that dirhenium isobutyrate analogs are anticancer active [17], we synthesized and Journal of Inorganic Biochemistry 129 (2013) 127–134 ⁎ Corresponding author. Fax: +380 562 470672. E-mail address: n.shtemenko@i.ua (N.I. Shtemenko). 0162-0134/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jinorgbio.2013.09.001 Contents lists available at ScienceDirect Journal of Inorganic Biochemistry journal homepage: www.elsevier.com/locate/jinorgbio