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      cis-Tetrachlorido-bis(indazole)osmium(IV) and its osmium(III) analogues: paving the way towards the cis-isomer of the ruthenium anticancer drugs KP1019 and/or NKP1339

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          Abstract

          The relationship between cis-trans isomerism and anticancer activity has been mainly addressed for square-planar metal complexes, in particular, for platinum(II), e.g., cis- and trans-[PtCl 2(NH 3) 2], and a number of related compounds, of which, however, only cis-counterparts are in clinical use today. For octahedral metal complexes, this effect of geometrical isomerism on anticancer activity has not been investigated systematically, mainly because the relevant isomers are still unavailable. An example of such an octahedral complex is trans-[RuCl 4(Hind) 2] , which is in clinical trials now as its indazolium (KP1019) or sodium salt (NKP1339), but the corresponding cis-isomers remain inaccessible. We report the synthesis of Na[ cis-Os IIICl 4(κN2-1 H-ind) 2] (Na[ 1]) to show that cis-isomer of NKP1339 can in principle be prepared as well. The procedure involves heating (H 2ind)[Os IVCl 5(κN1-2 H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with formation of cis-[Os IVCl 4(κN2-1 H-ind) 2] ([ 1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from κN1 to κN2 and stabilization of the 1 H-indazole tautomer. Fully reversible spectroelectrochemical reduction of [ 1] in acetonitrile at 0.46 V vs NHE is accompanied by a change in electronic absorption bands indicating formation of cis-[Os IIICl 4(κN2-1 H-ind) 2] ([ 1] ). Chemical reduction of [ 1] in methanol with NaBH 4 followed by addition of nBu 4NCl afforded the osmium(III) complex nBu 4N[ cis-Os IIICl 4(κN2-1 H-ind) 2] ( nBu 4N[ 1]). Metathesis reaction of nBu 4N[ 1] with an ion exchange resin led to isolation of the water-soluble salt Na[ 1]. The X-ray diffraction crystal structure of [ 1]·Me 2CO was determined and compared with that of trans-[Os IVCl 4(κN2-1 H-ind)]·2Me 2SO ( 2·2Me 2SO), also prepared in this work. EPR spectroscopy was performed on the Os III complexes and the results analyzed by ligand-field and quantum chemical theories. We furthermore assayed effects of [ 1] and Na[ 1] on cell viability and proliferation in comparison to trans-[Os IVCl 4(κN1-2 H-ind)] [ 3] and cisplatin and found a strong reduction of cell viability at concentrations between 30 and 300 µM in different cancer cell lines (HT29, H446, 4T1 and HEK293). HT-29 cells are less sensitive to cisplatin than 4T1 cells, but more sensitive to [ 1] and Na[ 1], as shown by decreased proliferation and viability as well as an increased late apoptotic/necrotic cell population.

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          The synthesis and characterization of unprecedented cis-[Os IVCl 4(κN2-1 H-ind) 2] and Na[ cis-Os IIICl 4(κN2-1 H-ind) 2] is reported. Even though the analogous cis-isomers of trans-Ru III complexes KP1019/NKP1339 remain unknown, their synthesis appears to be imminent giving an opportunity that deserves to be exploited in the search for more effective metal-based anticancer drugs than those currently in clinical trials.

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          Author and article information

          Journal
          101176026
          31991
          Dalton Trans
          Dalton Trans
          Dalton transactions (Cambridge, England : 2003)
          1477-9226
          1477-9234
          7 September 2017
          12 September 2017
          12 September 2018
          : 46
          : 35
          : 11925-11941
          Affiliations
          [# ]Division of Physical Sciences and Engineering, KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia
          [§ ]Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA
          []Slovak University of Technology, Institute of Physical Chemistry and Chemical Physics, Radlinského 9, 81237 Bratislava, Slovakia
          []Institute of Inorganic Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-84536, Slovakia
          []Department of Biological, Chemical and Physical Sciences, Roosevelt University, 430 S. Michigan Avenue, Chicago, Illinois 60605, USA
          [Δ ]Department of Radiology, Weill Cornell Medical College, New York, NY 10065, USA
          []University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Währinger Str. 42, A-1090 Vienna, Austria
          Author notes
          Article
          PMC5605806 PMC5605806 5605806 nihpa903634
          10.1039/c7dt02194a
          5605806
          28850133
          613075ad-310f-41b6-90a8-72f684c05f1e
          History
          Categories
          Article

          Osmium(IV),osmium(III),1H-indazole,cis/trans isomerism,solvatochromism,antiproliferative activity,EPR spectra

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