title: Osmium(III) analogues of KP1019: electrochemical and chemical synthesis, spectroscopic characterization, X-ray crystallography, hydrolytic stability, and antiproliferative activity.
abstract: A one-electron reduction of osmium(IV) complexes trans-[Os(IV)Cl4(Hazole)2], where Hazole = 1H-pyrazole ([1](0)), 2H-indazole ([2](0)), 1H-imidazole ([3](0)), and 1H-benzimidazole ([4](0)), afforded a series of eight new complexes as osmium analogues of KP1019, a lead anticancer drug in clinical trials, with the general formula (cation)[trans-Os(III)Cl4(Hazole)2], where cation = H2pz(+) (H2pz[1]), H2ind(+) (H2ind[2]), H2im(+) (H2im[3]), Ph4P(+) (Ph4P[3]), nBu4N(+) (nBu4N[3]), H2bzim(+) (H2bzim[4]), Ph4P(+) (Ph4P[4]), and nBu4N(+) (nBu4N[4]). All complexes were characterized by elemental analysis, (1)H NMR spectroscopy, electrospray ionization mass spectrometry, UV-vis spectroscopy, cyclic voltammetry, while H2pz[1], H2ind[2], and nBu4[3], in addition, by X-ray diffraction. The reduced species [1](-) and [4](-) are stable in aqueous media in the absence of air oxygen and do not react with small biomolecules such as amino acids and the nucleotide 5'-dGMP. Cell culture experiments in five different human cancer cell lines (HeLa, A549, FemX, MDA-MB-453, and LS-174) and one noncancerous cell line (MRC-5) were performed, and the results were discussed and compared to those for KP1019 and cisplatin. Benzannulation in complexes with similar structure enhances antitumor activity by several orders of magnitude, implicating different mechanisms of action of the tested compounds. In particular, complexes H2ind[2] and H2bzim[4] exhibited significant antiproliferative activity in vitro when compared to H2pz[1] and H2im[3].
authors.affiliation: Faculty of Chemistry, Institute of Inorganic Chemistry, University of Vienna , Währinger Strasse 42, A-1090 Vienna, Austria.
authors.forename: Paul-Steffen
authors.initials: PS
authors.lastname: Kuhn
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: Büchel
authors.forename: Katarina K
authors.initials: KK
authors.lastname: Jovanović
authors.forename: Lana
authors.initials: L
authors.lastname: Filipović
authors.forename: Siniša
authors.initials: S
authors.lastname: Radulović
authors.forename: Peter
authors.initials: P
authors.lastname: Rapta
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D055664:Electrochemical Techniques; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D007191:Indazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009992:Osmium / Q000737:chemistry*; D017975:Ruthenium Compounds; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007191:Indazoles; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C499292:indazolium trans-(tetrachlorobis(1H-indazole)ruthenate (III)); D009992:Osmium