Naphthalene Exchange in [Re(η6-napht)2]+ with Pharmaceuticals Leads to Highly Functionalized Sandwich Complexes [M(η6-pharm)2]+ (M=Re/99mTc)

Bis-arene sandwich complexes are generally prepared by the Fischer-Hafner reaction, which conditions are incompatible with most O- and N- functional groups. We report a new way for the synthesis of sandwich type complexes [Re(η⁶-arene)₂]⁺ and [Re(η⁶-arene)(η⁶-benzene)]⁺ from [Re(η⁶-napht)₂]⁺ and [Re(η⁶-napht)(η⁶-benzene)]⁺, with functionalized arenes and pharmaceuticals. N-methylpyrrolidine (NMP) facilitates the substitution of naphthalene with the incoming arene. A series of fully characterized rhenium sandwich complexes with simple arenes, such as aniline, as well as with active compounds like lidocaine and melatonin are presented. With these rhenium compounds in hand, the radioactive sandwich complexes [^99mTc(η⁶-pharm)₂]⁺ (pharm=pharmaceutical) can be unambiguously confirmed. The direct labelling of pharmaceuticals with ^99mTc through η⁶-coordination to phenyl rings and the confirmation of the structures with the rhenium homologues opens a path into molecular theranostics.     

Harnessing Endogenous Formate for Antibacterial Prodrug Activation by in cellulo Ruthenium-Mediated Transfer Hydrogenation Reaction

The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination-directed 3-component assembly to prepare a library of 768 unique Ru–Arene Schiff-base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites.     

Cell-specific and nuclear targeting with [M(CO)(3)](+) (M=(99m)Tc, Re)-based complexes conjugated to acridine orange and bombesin

Receptor-specific nuclear targeting requires trifunctional metal complexes. We have synthesized [M(L(2)-pept)(L(1)-acr)(CO)(3)] (pept=peptide; acr=acridine-based agent) in which the fac-[M(CO)(3)](+) moiety (1st function, M=(99m)Tc, Re) couples an acridine-based nuclear-targeting agent (2nd function, L(1)-acr) and the specific cell-receptor-binding peptide bombesin (3rd function, L(2)-pept). The metal-mediated coupling is based on the mixed ligand [2+1] principle. The nuclear targeting agents have been derivatised with an isocyanide group for monodentate (L(1)) and bombesin (BBN) with a bidentate ligand (L(2)) for complexation to fac-[M(CO)(3)](+). For nuclear uptake studies, the model complexes [Re(L(2))(L(1)-acr)(CO)(3)] (L(2)=pyridine-2-carboxylic acid and pyridine-2,4-dicarboxylic acid) were synthesized and structurally characterized. We selected acridine derivatives as nuclear-targeting agents, because they are very good nucleus-staining agents and exhibit strong fluorescence. Despite the bulky metal complexes attached to acridine, all [Re(L(2))(L(1)-acr)(CO)(3)] showed high accumulation in the nuclei of PC3 and B16F1 cells, as evidenced by fluorescence microscopy. For radiopharmaceutical purposes, the (99m)Tc analogues have been prepared and radioactivity distribution confirmed the fluorescence results. Coupling of BBN to L(2) gave the receptor-selective complexes [M(L(2)-BBN)(L(1)-acr)(CO)(3)]. Whereas no internalization was found with B16F1 cells, fluorescence microscopy on PC3 cells bearing the BBN receptor showed high and rapid uptake by receptor-mediated endocytosis into the cytoplasm, but not into the nucleus.     

Coordination Chemistry of Organoruthenium Compounds with Benzoylthiourea Ligands and their Biological Properties

Benzoylthiourea derivatives feature several donor atoms capable of coordinating to metal centers. We report here a series of Ru(η⁶‐p‐cymene) complexes employing benzoylthiourea derivatives as ligands. Such ligands often coordinate to metal centers through their S and O donor atoms. We isolated complexes where the ligands were mono‐ or bidentately coordinated to Ru involving the S donor atom and surprisingly in bidentate coordination mode a deprotonated thiourea nitrogen resulting in a 4‐membered ring structure around the metal center. DFT calculations were used to explain the differences in coordination behavior. These were complemented by stability studies and biological investigations of the compounds as anticancer agents. Several of the synthesized derivatives exhibited significant cell growth inhibitory activity, with the complexes featuring bidentate ligands being more potent than their monodentate counterparts. This can be explained by the higher stability of the former under the conditions employed in cell culture assays.     

Chemistry at High Dilution: Dinuclear 99 mTc Complexes

The formation of di- or polynuclear complexes at nanomolar concentrations is generally too slow to be observed with ^99mTc. It is reported in this communication that an appropriate choice of potentially bridging ligands, herein thiols HS-R, accelerates the dimerization reaction to an extent that dinuclear complexes are formed at very high dilution. The dinuclear nature of [^99mTc₂(μ₂-SR)₃(CO)₆]⁻ is shown by chromatographic comparison, not only with its rhenium homologue as commonly done, but also with the true ⁹⁹Tc analogue.     

A Multitargeted Approach: Organorhodium Anticancer Agent Based on Vorinostat as a Potent Histone Deacetylase Inhibitor

The combination of more than one bioactive moiety in a multitargeted anticancer agent may result in synergistic activity of its components. Using this concept, bioorganometallic compounds were designed to feature a metal center, a 2‐pyridinecarbothioamide (PCA), and a hydroxamic acid, which is found in the anticancer drug vorinostat (SAHA). The organometallics showed inhibitory activity in the nanomolar range against histone deacetylases (HDACs) as the key target for SAHA. In particular, the Rh complex was a potent inhibitor of HDAC6 over HDAC1 and HDAC8. Whereas this complex was highly cytotoxic in human cancer cells, it showed low toxicity in hemolysis studies and zebrafish, demonstrating the role of the metal center. For this complex a slightly reduced expression of vascular endothelial growth factor receptor 2 (VEGFR2) was established, which was upregulated by SAHA. This finding indicates that the new organometallics display different modes of action than their bioactive components.     

[(C C)Au(N N)]+ Complexes as a New Family of Anticancer Candidates: Synthesis,Characterization and Exploration of the Antiproliferative Properties

A library of eleven cationic gold(III) complexes of the general formula [(C C)Au(N N)]⁺ when C C is either biphenyl or 4,4’-ditertbutyldiphenyl and N N is a bipyridine, phenanthroline or dipyridylamine derivative have been synthesized and characterized. Contrasting effects on the viability of the triple negative breast cancer cells MDA-MB-231 was observed from a preliminary screening. The antiproliferative activity of the seven most active complexes were further assayed on a larger panel of human cancer cells as well as on non-cancerous cells for comparison. Two complexes stood out for being either highly active or highly selective. Eventually, reactivity studies with biologically meaningful amino acids, glutathione, higher order DNA structures and thioredoxin reductase (TrxR) revealed a markedly different behavior from that of the well-known coordinatively isomeric [(C N C)Au(NHC)]⁺ structure. This makes the [(C C)Au(N N)]⁺ complexes a new class of organogold compounds with an original mode of action.     

Harnessing Endogenous Formate for Antibacterial Prodrug Activation by in cellulo Ruthenium‐Mediated Transfer Hydrogenation Reaction

The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination‐directed 3‐component assembly to prepare a library of 768 unique Ru–Arene Schiff‐base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites.     

Impact of the Metal Center and Leaving Group on the Anticancer Activity of Organometallic Complexes of Pyridine-2-carbothioamide

Ru^II(cym)Cl (cym = η⁶-p-cymene) complexes of pyridinecarbothioamides have shown potential for development as orally active anticancer metallodrugs, underlined by their high selectivity towards plectin as the molecular target. In order to investigate the impact of the metal center on the anticancer activity and their physicochemical properties, the Os(cym), Rh- and Ir(Cp*) (Cp* = pentamethylcyclopentadienyl) analogues of the most promising and orally active compound plecstatin 2 were prepared and characterized by spectroscopic techniques and X-ray diffraction analysis. Dissolution in aqueous medium results in quick ligand exchange reactions; however, over time no further changes in the ¹H NMR spectra were observed. The Rh- and Ir(Cp*) complexes were investigated for their reactions with amino acids, and while they reacted with Cys, no reaction with His was observed. Studies on the in vitro anticancer activity identified the Ru derivatives as the most potent, independent of their halido leaving group, while the Rh derivative was more active than the Ir analogue. This demonstrates that the metal center has a significant impact on the anticancer activity of the compound class.