Interaction of a ruthenium hexacationic prism with amino acids and biological ligands: ESI mass spectrometry and NMR characterisation of the reaction products

Reactions between the cationic triangular metallaprism [(p-cymene)6Ru6(tpt)2(dhnq)3]6+ ([1]6+) [tptis2,4,6-tri(pyridine-4-yl)-1,3,5-triazine; dhnqis5,8-dihydroxy-1,4-naphthoquinonato] and Arg, His, Lys, ascorbic acid, lactic acid and glutathione (GSH) have been studied at 37°C in aqueous solution at pD 7 using NMR spectroscopy and electrospray ionisation mass spectrometry. Coordination to the imidazole nitrogen atom of His or to the basic NH/NH2 groups in Arg and Lys slowly displaces the dhnq and tpt ligands from the (p-cymene)Ru units, and subsequently additional coordination to the amino and carboxylato groups forms stable N,N,O metallacycles. Compared with our previously reported study with the analogous metallaprism [(p-cymene)6Ru6(tpt)2(dhbq)3]6+ ([2]6+) (dhbqis2,5-dihydroxy-1,4-benzoquinonato), the larger metallaprism [1]6+ appears to be significantly more stable, and disassembled in the presence of Arg, His and Lys after only 12h of incubation. Moreover, the reaction with His is not complete, since only 14% of His reacted after more than 1week of incubation. Solutions of [1]6+ are also able to catalyse oxidation of the thiol group of Cys and GSH to give the corresponding disulfides and of ascorbic acid to give the corresponding dehydroascorbic acid. However, the results are markedly different from those obtained with metallaprism [2]6+: the oxidation of Cys and ascorbic acid is not complete, and the formation of intermediate adducts could be evidenced. On the other hand, the oxidation of GSH remains fast and is completed after only 12h. Oxidation of GSH to give the corresponding disulfide may explain its higher in vitro anticancer activity as compared with [2]6+. Our results suggest that metallaprism [1]6+ is more robust than [2]6+, may remain intact in the bloodstream and, therefore, may enter cancer cells undamaged, thus confirming the drug delivery potential for such water-soluble organometallic cage

The DEPTQ+ Experiment: Leveling the DEPT Signal Intensities and Clean Spectral Editing for Determining CHn Multiplicities

We propose a new 13C DEPTQ+ NMR experiment, based on the improved DEPTQ experiment, which is designed to unequivocally identify all carbon multiplicities (Cq, CH, CH2, and CH3) in two experiments. Compared to this improved DEPTQ experiment, the DEPTQ+ is shorter and the different evolution delays are designed as spin echoes, which can be tuned to different 1JCH values; this is especially valuable when a large range of 1JCH coupling constants is to be expected. These modifications allow (i) a mutual leveling of the DEPT signal intensities, (ii) a reduction in J cross‐talk in the Cq/CH spectrum, and (iii) more consistent and cleaner CH2/CH3 edited spectra. The new DEPTQ+ is expected to be attractive for fast 13C analysis of small‐to medium sized molecules, especially in high‐throughput laboratories. With concentrated samples and/or by exploiting the high sensitivity of cryogenically cooled 13C NMR probeheads, the efficacy of such investigations may be improved, as it is possible to unequivocally identify all carbon multiplicities, with only one scan, for each of the two independent DEPTQ+ experiments and without loss of quality

Luminescent blue emissive bis(alkynyl) borane compounds with a N,O-coordinated ligand

Five bis(alkynyl)boranes with a (imidazo[1,5-a]pyridin-3-yl)phenolate ligand have been synthesized and characterized both in solution (1H, 13C, 11B, 19F NMR) and in the solid state (X-ray). All derivatives, differing for the substituent R (H, Me, OMe, CF3, NMe2) in the para position of the phenylacetylene moieties, displayed blue fluorescence emission in solution, linearly correlated to the electronic properties of the substituent R (i.e., its σp Hammett constant). High Stokes shifts and good quantum yields were recorded. Time-Dependent Density Functional Theory (TD-DFT) calculations were performed to describe the percentage contribution of each fragment of the molecule to the frontier orbitals. Electron Density Difference Maps (EDDMs) calculated for all derivatives allowed to explain the emissive properties of the studied compounds

Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

Tethering known drugs to a metalorganic moiety is an efficient approach for modulating the anticancer, antibacterial, and antiparasitic activity of organometallic complexes. This study focused on the synthesis and evaluation of new dinuclear ruthenium(II)–arene compounds linked to several antimicrobial compounds such as dapsone, sulfamethoxazole, sulfadiazine, sulfadoxine, triclosan, metronidazole, ciprofloxacin, as well as menadione (a 1,4‐naphtoquinone derivative). In a primary screen, 30 compounds (17 hybrid molecules, diruthenium intermediates, and antimicrobials) were assessed for in vitro activity against transgenic T. gondii tachyzoites constitutively expressing β‐galactosidase (T. gondii β‐gal) at 0.1 and 1 μM. In parallel, the cytotoxicity in noninfected host cells (human foreskin fibroblasts, HFF) was determined by an alamarBlue assay. When assessed at 1 μM, five compounds strongly impaired parasite proliferation by >90%, and HFF viability was retained at 50% or more, and they were further subjected to T. gondii β‐gal dose‐response studies. Two compounds, notably 11 and 13, amide and ester conjugates with sulfadoxine and metronidazole, exhibited low IC50 (half‐maximal inhibitory concentration) values 0.063 and 0.152 μM, and low or intermediate impairment of HFF viability at 2.5 μM (83 and 64%). The nature of the anchored drug as well as that of the linking unit impacted the biological activity

New Nucleic Base-Tethered Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Compounds: Synthesis and Antiparasitic Activity

Aiming toward compounds with improved anti-Toxoplasma activity by exploiting the parasite auxotrophies, a library of nucleobase-tethered trithiolato-bridged dinuclear ruthenium(II)-arene conjugates was synthesized and evaluated. Structural features such as the type of nucleobase and linking unit were progressively modified. For comparison, diruthenium hybrids with other type of molecules were also synthesized and assessed. A total of 37 compounds (diruthenium conjugates and intermediates) were evaluated in a primary screening for in vitro activity against transgenic Toxoplasma gondii tachyzoites constitutively expressing β-galactosidase (T. gondii β-gal) at 0.1 and 1 µM. In parallel, the cytotoxicity in non-infected host cells (human foreskin fibroblasts, HFF) was determined by alamarBlue assay. Twenty compounds strongly impairing parasite proliferation with little effect on HFF viability were subjected to T. gondii β-gal half maximal inhibitory concentration determination (IC50) and their toxicity for HFF was assessed at 2.5 µM. Two promising compounds were identified: 14, ester conjugate with 9-(2-oxyethyl)adenine, and 36, a click conjugate bearing a 2-(4-(hydroxymethyl)-1H-1,2,3-triazol-1-yl)methyl substituent, with IC50 values of 0.059 and 0.111 µM respectively, significantly lower compared to pyrimethamine standard (IC50 = 0.326 µM). Both 14 and 36 exhibited low toxicity against HFF when applied at 2.5 µM and are candidates for potential treatment options in a suitable in vivo model