Gabriel E. Büchel

Osmium complexes with osmium in different oxidation states (II, III, IV, and VI) have been reported to exhibit antiproliferative activity in cancer cell lines. Herein, we demonstrate unexplored opportunities offered by ¹⁸⁷ Os nuclear forward scattering (NFS) and nuclear inelastic scattering (NIS) of synchrotron radiation for characterization of hyperfine interactions and lattice dynamics in a benchmark Os(VI) complex, K ₂ [OsO ₂ (OH) ₄ ]. We determined the isomer shift [δ = 3.3(1) millimeters per second] relative to [Os ^IV Cl ₆ ] ²⁻ and quadrupole splitting [Δ E _Q = 12.0(2) millimeters per second] with NFS. We estimated the Lamb-Mössbauer factor [0.80(4)], extracted the density of phonon states, and carried out a thermodynamics characterization using the NIS data combined with first-principles calculations. Overall, we provide evidence that ¹⁸⁷ Os nuclear resonance scattering is a reliable technique for the investigation of hyperfine interactions and Os-specific vibrations in osmium(VI) species and is thus applicable for such measurements in osmium complexes of other oxidation states, including those with anticancer activity such as Os(III) and Os(IV).

A series of thiosemicarbazone-coumarin hybrids (HL¹-HL³ and H₂L⁴) has been synthesised in 12 steps and used for the preparation of mono- and dinuclear copper(II) complexes, namely Cu(HL¹)Cl₂ (1), Cu(HL²)Cl₂ (2), Cu(HL³)Cl₂ (3) and Cu₂(H₂L⁴)Cl₄ (4), isolated in hydrated or solvated forms. Both the organic hybrids and their copper(II) and dicopper(II) complexes were comprehensively characterised by analytical and spectroscopic techniques, i.e., elemental analysis, ESI mass spectrometry, 1D and 2D NMR, IR and UV–vis spectroscopies, cyclic voltammetry (CV) and spectroelectrochemistry (SEC). Re-crystallisation of 1 from methanol afforded single crystals of copper(II) complex with monoanionic ligand Cu(L¹)Cl, which could be studied by single crystal X-ray diffraction (SC-XRD). The prepared copper(II) complexes and their metal-free ligands revealed antiproliferative activity against highly resistant cancer cell lines, including triple negative breast cancer cells MDA-MB-231, sensitive COLO-205 and multidrug resistant COLO-320 colorectal adenocarcinoma cell lines, as well as in healthy human lung fibroblasts MRC-5 and compared to those for triapine and doxorubicin. In addition, their ability to reduce the tyrosyl radical in mouse R2 protein of ribonucleotide reductase has been ascertained by EPR spectroscopy and the results were compared with those for triapine.

The synthesis and characterization ofcis-[Os^IVCl₄(κN2-1H-indazole)₂] and its 1e-reduced analog are reported.

This protocol describes a new intraoperative imaging technique that uses a ruthenium complex as a source of chemiluminescent light...

Intraoperative imaging technologies recently entered the operating room, and their implementation is revolutionizing how physicians plan, monitor, and perform surgical interventions. In this work, we present a novel surgical imaging reporter system: intraoperative chemiluminescence imaging (ICI). To this end, we have leveraged the ability of a chemiluminescent metal complex to generate near‐infrared light upon exposure to an aqueous solution of Ce⁴⁺ in the presence of reducing tissue or blood components. An optical camera spatially resolves the resulting photon flux. We describe the construction and application of a prototype imaging setup, which achieves a detection limit as low as 6.9 pmol cm⁻² of the transition‐metal‐based ICI agent. As a proof of concept, we use ICI for the in vivo detection of our transition metal tracer following both systemic and subdermal injections. The very high signal‐to‐noise ratios make ICI an interesting candidate for the development of new intraoperative imaging technologies.

Since the discovery that nitric oxide (NO) is a physiologically relevant molecule, there has been great interest in the use of metal nitrosyl compounds as antitumor pharmaceuticals. Particularly interesting are those complexes which can deliver NO to biological targets. Ruthenium- and osmium-based compounds offer lower toxicity compared to other metals and show different mechanisms of action as well as different spectra of activity compared to platinum-based drugs. Novel ruthenium- and osmium-nitrosyl complexes with azole heterocycles were studied to elucidate their cytotoxicity and possible interactions with DNA. Apoptosis induction, changes of mitochondrial transmembrane potential and possible formation of reactive oxygen species were investigated as indicators of NO-mediated damage by flow cytometry. Results suggest that ruthenium- and osmium-nitrosyl complexes with the general formula (indazolium)[cis/trans-MCl₄(NO)(1H-indazole)] have pronounced cytotoxic potency in cancer cell lines. Especially the more potent ruthenium complexes strongly induce apoptosis associated with depolarization of mitochondrial membranes, and elevated reactive oxygen species levels. Furthermore, a slight yet not unequivocal trend to accumulation of intracellular cyclic guanosine monophosphate attributable to NO-mediated effects was observed.

A series of heteropentanuclear oxalate‐bridged Ru(NO)‐Ln (4d–4f) metal complexes of the general formula (nBu₄N)₅[Ln{RuCl₃(μ‐ox)(NO)}₄], where Ln=Y (2), Gd (3), Tb (4), Dy (5) and ox=oxalate anion, were obtained by treatment of (nBu₄N)₂[RuCl₃(ox)(NO)] (1) with the respective lanthanide salt in 4:1 molar ratio. The compounds were characterized by elemental analysis, IR spectroscopy, electrospray ionization (ESI) mass spectrometry, while1,2, and5were in addition analyzed by X‐ray crystallography,1by Ru K‐edge XAS and1and2by¹³C NMR spectroscopy. X‐ray diffraction showed that in2and5four complex anions [RuCl₃(ox)(NO)]²⁻are coordinated to Y^IIIand Dy^III, respectively, with formation of [Ln{RuCl₃(μ‐ox)(NO)}₄]⁵⁻(Ln=Y, Dy). While Y^IIIis eight‐coordinate in2, Dy^IIIis nine‐coordinate in5, with an additional coordination of an EtOH molecule. The negative charge is counterbalanced by fivenBu₄N⁺ions present in the crystal structure. The stability of complexes2and5in aqueous medium was monitored by UV/Vis spectroscopy. The antiproliferative activity of ruthenium‐lanthanide complexes2–5were assayed in two human cancer cell lines (HeLa and A549) and in a noncancerous cell line (MRC‐5) and compared with those obtained for the previously reported Os(NO)‐Ln (5d–4f) analogues (nBu₄N)₅[Ln{OsCl₃(ox)(NO)}₄] (Ln=Y (6), Gd (7), Tb (8), Dy (9)). Complexes2–5were found to be slightly more active than1in inhibiting the proliferation of HeLa and A549 cells, and significantly more cytotoxic than 5d–4f metal complexes6–9in terms of IC₅₀values. The highest antiproliferative activity with IC₅₀values of 20.0 and 22.4 μMwas found for4in HeLa and A549 cell lines, respectively. These cytotoxicity results are in accord with the presented ICP‐MS data, indicating five‐ to eightfold greater accumulation of ruthenium versus osmium in human A549 cancer cells.

A one-electron reduction of osmium(IV) complexes trans-[Os^IVCl₄(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^IIICl₄(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, ¹H 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].