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Ruthenium Carbonyl Complexes with Azole Heterocycles – Synthesis, X‐ray Diffraction Structures, DFT Calculations, Solution Behavior, and Antiproliferative Activity
Author(s) -
Kuhn PaulSteffen,
Meier Samuel M.,
Jovanović Katarina K.,
Sandler Isolde,
Freitag Leon,
Novitchi Ghenadie,
González Leticia,
Radulović Siniša,
Arion Vladimir B.
Publication year - 2016
Publication title -
european journal of inorganic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.667
H-Index - 136
eISSN - 1099-0682
pISSN - 1434-1948
DOI - 10.1002/ejic.201501393
Subject(s) - chemistry , imidazole , indazole , ruthenium , electrospray ionization , medicinal chemistry , benzimidazole , stereochemistry , formic acid , acetamide , pyrazole , mass spectrometry , organic chemistry , catalysis , chromatography
The reactions of (H 2 azole)[ trans ‐RuCl 4 (Hazole) 2 ] [Hazole = 1 H ‐pyrazole (Hpz), 1 H ‐indazole (Hind), 1‐methylindazole (1‐Me‐ind), or 1 H ‐benzimidazole (Hbzim)] with 1:1 mixtures of 12 M HCl and formic acid resulted in the formation of trans ‐[RuCl 4 (CO)(Hazole)] – complexes, which were isolated and identified by X‐ray diffraction as n Bu 4 N[ trans ‐RuCl 4 (CO)(Hpz)] ( 1a ), n Bu 4 N[ trans ‐RuCl 4 (CO)(Hind)] ( 2a ), [(Hind) 2 H][ trans ‐RuCl 4 (CO)(Hind)] ( 2b ), n Bu 4 N[ trans ‐RuCl 4 (CO)(1‐Me‐ind)] ( 3a ), and n Bu 4 N[ trans ‐RuCl 4 (CO)(Hbzim)] ( 6a ), whereas a prolonged reaction with 1 H ‐benzimidazole afforded ( n Bu 4 N) 2 [ trans ‐RuCl 5 (CO)] ( 7a ). The reactions of [(DMSO) 2 H][ trans ‐RuCl 4 (CO)(DMSO)] with different azole heterocycles in dichloromethane afforded five similar complexes, which were isolated as azolium salts (H 2 azole)[ trans ‐RuCl 4 (CO)(Hazole)] [Hazole = 1 H ‐indazole ( 2 ), 1‐methylindazole ( 3 ), 2‐methylindazole ( 4 ), 1 H ‐imidazole ( 5 ), and 1 H ‐benzimidazole ( 6 )]. Complexes 2 – 6 were characterized by elemental analysis, high‐resolution electrospray ionization (ESI) mass spectrometry, UV/Vis spectroscopy, and IR spectroscopy, and 3 was also characterized by X‐ray diffraction. The pH of the solution was crucial for the stability of the obtained compound series. The interactions of 2 – 4 with the model proteins myoglobin and ubiquitin and the influence of the indazole tautomer identity on those processes were investigated by high‐resolution mass spectrometry. The ruthenium(III) complexes interact with the proteins to form protein–Ru II (CO) adducts, that is, metal reduction appears to be responsible for the release of the azole heterocycle but not CO. Moreover, the binding of the Ru II (CO) unit to myoglobin reduces the observed global charge state of the adduct with respect to that of free myoglobin, which suggests that the Ru(CO) fragment can cross‐link the protein backbone. Complexes 2 – 6 show low antiproliferative activity against the human cancer cell lines HeLa and MDA‐MB‐231 and the noncancerous cell line MRC‐5, and this activity correlates with the low stability of complexes in aqueous media, especially at neutral or basic pH. The results are compared to previously reported data on ruthenium nitrosyl analogues and KP1019.