Gabriel E Büchel1, Susanne Kossatz2, Ahmad Sadique2, Peter Rapta3, Michal Zalibera3, Lukas Bucinsky3, Stanislav Komorovsky4, Joshua Telser5, Jörg Eppinger6, Thomas Reiner7, Vladimir B Arion8. 1. Division of Physical Sciences and Engineering, KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia and Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. 2. Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. 3. Slovak University of Technology, Institute of Physical Chemistry and Chemical Physics, Radlinského 9, 81237 Bratislava, Slovakia. peter.rapta@stuba.sk. 4. Institute of Inorganic Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, SK-84536 Bratislava, Slovakia. 5. Department of Biological, Chemical and Physical Sciences, Roosevelt University, 430 S. Michigan Avenue, Chicago, Illinois 60605, USA. jtelser@roosevelt.edu. 6. Division of Physical Sciences and Engineering, KAUST Catalysis Center, King Abdullah University of Science and Technology, Thuwal 23955-6900, Saudi Arabia. 7. Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA and Department of Radiology, Weill Cornell Medical College, New York, NY 10065, USA. 8. University of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Währinger Str. 42, A-1090 Vienna, Austria. vladimir.arion@univie.ac.at.
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-[PtCl2(NH3)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-[RuCl4(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-OsIIICl4(κN2-1H-ind)2]·(Na[1]) suggesting a route to the cis-isomer of NKP1339. The procedure involves heating (H2ind)[OsIVCl5(κN1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with the formation of cis-[OsIVCl4(κN2-1H-ind)2] ([1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from κN1 to κN2 and stabilization of the 1H-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 the formation of cis-[OsIIICl4(κN2-1H-ind)2]- ([1]-). Chemical reduction of [1] in methanol with NaBH4 followed by addition of nBu4NCl afforded the osmium(iii) complex nBu4N[cis-OsIIICl4(κN2-1H-ind)2] (nBu4N[1]). A metathesis reaction of nBu4N[1] with an ion exchange resin led to the isolation of the water-soluble salt Na[1]. The X-ray diffraction crystal structure of [1]·Me2CO was determined and compared with that of trans-[OsIVCl4(κN2-1H-ind)2]·2Me2SO (2·2Me2SO), also prepared in this work. EPR spectroscopy was performed on the OsIII complexes and the results were analyzed by ligand-field and quantum chemical theories. We furthermore assayed effects of [1] and Na[1] on cell viability and proliferation in comparison with trans-[OsIVCl4(κN1-2H-ind)2] [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.
The relationship between cis-trans isomerism and anticancer activity has been mainly addressed for square-planar n class="Chemical">metal complexes, in particular, for platinum(ii), e.g., cis- and trans-[PtCl2(NH3)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-[RuCl4(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-OsIIICl4(κN2-1H-ind)2]·(Na[1]) suggesting a route to the cis-isomer of NKP1339. The procedure involves heating (H2ind)[OsIVCl5(κN1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with the formation of cis-[OsIVCl4(κN2-1H-ind)2] ([1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from κN1 to κN2 and stabilization of the 1H-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 the formation of cis-[OsIIICl4(κN2-1H-ind)2]- ([1]-). Chemical reduction of [1] in methanol with NaBH4 followed by addition of nBu4NCl afforded the osmium(iii) complexnBu4N[cis-OsIIICl4(κN2-1H-ind)2] (nBu4N[1]). A metathesis reaction of nBu4N[1] with an ion exchange resin led to the isolation of the water-soluble salt Na[1]. The X-ray diffraction crystal structure of [1]·Me2CO was determined and compared with that of trans-[OsIVCl4(κN2-1H-ind)2]·2Me2SO (2·2Me2SO), also prepared in this work. EPR spectroscopy was performed on the OsIII complexes and the results were analyzed by ligand-field and quantum chemical theories. We furthermore assayed effects of [1] and Na[1] on cell viability and proliferation in comparison with trans-[OsIVCl4(κN1-2H-ind)2] [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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