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

Handle URI:
http://hdl.handle.net/10754/625813
Title:
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
Authors:
Büchel, Gabriel E. ( 0000-0002-5055-7099 ) ; Kossatz, Susanne; Sadique, Ahmad; Rapta, Peter; Zalibera, Michal ( 0000-0002-6527-1982 ) ; Bucinsky, Lukas; Komorovsky, Stanislav ( 0000-0002-5317-7200 ) ; Telser, Joshua ( 0000-0003-3307-2556 ) ; Eppinger, Jorg ( 0000-0001-7886-7059 ) ; Reiner, Thomas; Arion, Vladimir B. ( 0000-0002-1895-6460 )
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-(OsCl4)-Cl-III(kappa N2-1H-ind)(2)] . (Na[1]) suggesting a route to the cis-isomer of NKP1339. The procedure involves heating (H(2)ind)[(OsCl5)-Cl-IV(kappa N1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with the formation of cis-[(OsCl4)-Cl-IV(kappa N2-1H-ind)(2)] ([1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from kappa N1 to kappa N2 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-[(OsCl4)-Cl-III(kappa N2-1H-ind)(2)](-) ([1](-)). Chemical reduction of [1] in methanol with NaBH4 followed by addition of nBu(4)NCl afforded the osmium(III) complex nBu(4)N[cis-(OsCl4)-Cl-III(kappa N2-1H-ind)(2)] (nBu(4)N [1]). A metathesis reaction of nBu(4)N[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-[(OsCl4)-Cl-IV(kappa N2-1H-ind)(2)] . 2Me(2)SO (2 . 2Me(2)SO), also prepared in this work. EPR spectroscopy was performed on the Os-III 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-[(OsCl4)-Cl-IV(kappa N1-2H-ind)(2)] [3] and cisplatin and found a strong reduction of cell viability at concentrations between 30 and 300 mu M 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.
KAUST Department:
KAUST Catalysis Center (KCC); Physical Sciences and Engineering (PSE) Division
Citation:
Büchel GE, Kossatz S, Sadique A, Rapta P, Zalibera M, et al. (2017) 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. Dalton Trans 46: 11925–11941. Available: http://dx.doi.org/10.1039/c7dt02194a.
Publisher:
Royal Society of Chemistry (RSC)
Journal:
Dalton Trans.
Issue Date:
15-Aug-2017
DOI:
10.1039/c7dt02194a
Type:
Article
ISSN:
1477-9226; 1477-9234
Sponsors:
We thank Alexander Roller for collecting X-ray diffraction data for compound 4.2Me<INF>2</INF>SO. The financial support from the Slovak Grant Agency VEGA (Contract No. 1/0598/16 and 1/0416/17) and the Slovak Research and Development Agency (Contract No. APVV-15-0053, APVV-15-0079 and APVV-15-0726) is duly acknowledged. The work has also received financial support from the SASPRO Program (Contract no. 1563/03/02), co-financed by the European Union and the Slovak Academy of Sciences. The computational resources for this project have been provided by the NOTUR high-performance computing program [grant number NN4654 K] and by the HPC center at STU (SIVVP Project, ITMS code 26230120002). We thank Prof. Brian M. Hoffman, Northwestern University, for use of the low temperature X and Q-band EPR spectrometers, which is supported by the United States NIH (GM 111097 to B.M.H.). The authors thank the support of Memorial Sloan Kettering Cancer Center's Flow Cytometry Core Facility. This work was supported by National Institutes of Health grants NIH R01CA204441 (T. R.), R21CA191679 (T. R.) and P30 CA008748. The authors thank the Tow Foundation and Memorial Sloan Kettering Cancer Center's Center for Molecular Imaging & Nanotechnology (S. K.). Financial support by King Abdullah University of Science and Technology is also gratefully acknowledged (G. B., J. E.).
Additional Links:
http://pubs.rsc.org/en/Content/ArticleLanding/2017/DT/C7DT02194A#!divAbstract
Appears in Collections:
Articles; Physical Sciences and Engineering (PSE) Division; KAUST Catalysis Center (KCC)

Full metadata record

DC FieldValue Language
dc.contributor.authorBüchel, Gabriel E.en
dc.contributor.authorKossatz, Susanneen
dc.contributor.authorSadique, Ahmaden
dc.contributor.authorRapta, Peteren
dc.contributor.authorZalibera, Michalen
dc.contributor.authorBucinsky, Lukasen
dc.contributor.authorKomorovsky, Stanislaven
dc.contributor.authorTelser, Joshuaen
dc.contributor.authorEppinger, Jorgen
dc.contributor.authorReiner, Thomasen
dc.contributor.authorArion, Vladimir B.en
dc.date.accessioned2017-10-05T12:47:09Z-
dc.date.available2017-10-05T12:47:09Z-
dc.date.issued2017-08-15en
dc.identifier.citationBüchel GE, Kossatz S, Sadique A, Rapta P, Zalibera M, et al. (2017) 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. Dalton Trans 46: 11925–11941. Available: http://dx.doi.org/10.1039/c7dt02194a.en
dc.identifier.issn1477-9226en
dc.identifier.issn1477-9234en
dc.identifier.doi10.1039/c7dt02194aen
dc.identifier.urihttp://hdl.handle.net/10754/625813-
dc.description.abstractThe 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-(OsCl4)-Cl-III(kappa N2-1H-ind)(2)] . (Na[1]) suggesting a route to the cis-isomer of NKP1339. The procedure involves heating (H(2)ind)[(OsCl5)-Cl-IV(kappa N1-2H-ind)] in a high boiling point organic solvent resulting in an Anderson rearrangement with the formation of cis-[(OsCl4)-Cl-IV(kappa N2-1H-ind)(2)] ([1]) in high yield. The transformation is accompanied by an indazole coordination mode switch from kappa N1 to kappa N2 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-[(OsCl4)-Cl-III(kappa N2-1H-ind)(2)](-) ([1](-)). Chemical reduction of [1] in methanol with NaBH4 followed by addition of nBu(4)NCl afforded the osmium(III) complex nBu(4)N[cis-(OsCl4)-Cl-III(kappa N2-1H-ind)(2)] (nBu(4)N [1]). A metathesis reaction of nBu(4)N[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-[(OsCl4)-Cl-IV(kappa N2-1H-ind)(2)] . 2Me(2)SO (2 . 2Me(2)SO), also prepared in this work. EPR spectroscopy was performed on the Os-III 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-[(OsCl4)-Cl-IV(kappa N1-2H-ind)(2)] [3] and cisplatin and found a strong reduction of cell viability at concentrations between 30 and 300 mu M 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.en
dc.description.sponsorshipWe thank Alexander Roller for collecting X-ray diffraction data for compound 4.2Me<INF>2</INF>SO. The financial support from the Slovak Grant Agency VEGA (Contract No. 1/0598/16 and 1/0416/17) and the Slovak Research and Development Agency (Contract No. APVV-15-0053, APVV-15-0079 and APVV-15-0726) is duly acknowledged. The work has also received financial support from the SASPRO Program (Contract no. 1563/03/02), co-financed by the European Union and the Slovak Academy of Sciences. The computational resources for this project have been provided by the NOTUR high-performance computing program [grant number NN4654 K] and by the HPC center at STU (SIVVP Project, ITMS code 26230120002). We thank Prof. Brian M. Hoffman, Northwestern University, for use of the low temperature X and Q-band EPR spectrometers, which is supported by the United States NIH (GM 111097 to B.M.H.). The authors thank the support of Memorial Sloan Kettering Cancer Center's Flow Cytometry Core Facility. This work was supported by National Institutes of Health grants NIH R01CA204441 (T. R.), R21CA191679 (T. R.) and P30 CA008748. The authors thank the Tow Foundation and Memorial Sloan Kettering Cancer Center's Center for Molecular Imaging & Nanotechnology (S. K.). Financial support by King Abdullah University of Science and Technology is also gratefully acknowledged (G. B., J. E.).en
dc.publisherRoyal Society of Chemistry (RSC)en
dc.relation.urlhttp://pubs.rsc.org/en/Content/ArticleLanding/2017/DT/C7DT02194A#!divAbstracten
dc.rightsThis Open Access Article is licensed under a Creative Commons Attribution 3.0 Unported Licenceen
dc.rights.urihttp://creativecommons.org/licenses/by/3.0/en
dc.titlecis-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 NKP1339en
dc.typeArticleen
dc.contributor.departmentKAUST Catalysis Center (KCC)en
dc.contributor.departmentPhysical Sciences and Engineering (PSE) Divisionen
dc.identifier.journalDalton Trans.en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionDepartment of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, , United Statesen
dc.contributor.institutionSlovak University of Technology, Institute of Physical Chemistry and Chemical Physics, Radlinského 9, Bratislava, 81237, , Slovakiaen
dc.contributor.institutionInstitute of Inorganic Chemistry, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava, SK-84536, , Slovakiaen
dc.contributor.institutionDepartment of Biological, Chemical and Physical Sciences, Roosevelt University, 430 S. Michigan Avenue, Chicago, IL, 60605, , United Statesen
dc.contributor.institutionDepartment of Radiology, Weill Cornell Medical College, New York, NY, 10065, , United Statesen
dc.contributor.institutionUniversity of Vienna, Faculty of Chemistry, Institute of Inorganic Chemistry, Währinger Str. 42, Vienna, A-1090, , Austriaen
kaust.authorBüchel, Gabriel E.en
kaust.authorEppinger, Jorgen
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