Showing papers on "Aquation published in 2022"

A [ ¹ H, ¹⁵ N] Heteronuclear Single Quantum Coherence NMR Study of the Solution Reactivity of the Ruthenium‐Based Mitochondrial Calcium Uniporter Inhibitor Ru265

Abstract: The synthesis and characterization of the 15N-labeled analogue of the mitochondrial calcium uptake inhibitor [Cl(NH3)4Ru(μ-N)Ru(NH3)4Cl]3+ (Ru265) bearing [15N]NH3 ligands is reported. Using [1H,15N] HSQC NMR spectroscopy, the rate constants for the axial chlorido ligand aquation of [15N]Ru265 in pH 7.4 buffer at 25 °C were found to be k1=(3.43±0.03)×10−4 s−1 and k2=(4.03±0.09)×10−3 s−1. The reactivity of [15N]Ru265 towards biologically relevant small molecules was also assessed via this method, revealing that this complex can form coordination bonds to anionic oxygen and sulfur donors. Time-based studies on these ligand-binding reactions reveal this process to be slow relative to the time required for the complex to inhibit mitochondrial calcium uptake, suggesting that hydrogen-bonding interactions, rather than the formation of coordination bonds, may play a more significant role in mediating the inhibitory properties of this complex.

Cytotoxicity of Alizarine versus Tetrabromocathecol Cyclometalated Pt(II) Theranostic Agents: A Combined Experimental and Computational Investigation

Abstract: Platinum compounds cytotoxicity is strictly related to their ability to be converted into active mono- and di-aquated species and consequently to the replacement of labile ligands by water molecules. This activation process makes the platinum center prone to nucleophilic substitution by DNA purines. In the present work, quantum mechanical density functional theory (DFT) computations and experimental investigations were carried out in order to shed light on the relationship between the internalization, aquation, and DNA binding of two isostructural anionic theranostic complexes previously reported by our group, NBu4[(PhPy)Pt(Aliz)], 1 (IC50 1.9 ± 1.6 μM), and NBu4[(PhPy)Pt(BrCat)], 2 (IC50 52.8 ± 3.9 μM). Cisplatin and a neutral compound [(NH3)2Pt(Aliz)], 3, were also taken as reference compounds. The computed energy barriers and the endergonicity of the hydrolysis reactions showed that the aquation rates are comparable for 1 and 2, with a slightly higher reactivity of 1. The second hydrolysis process was proved to be the rate-determining step for both 1 and 2, unlike for compound 3. The nucleophilic attack by the N7 site of guanine to both mono- and di-aquated forms of the complexes was computationally investigated as well, allowing to rationalize the observed different cytotoxicity. Computational results were supported by photostability data and biological assays, demonstrating DNA as the main target for compound 1.

Cytotoxic properties of rhenium(I) tricarbonyl complexes of N-heterocyclic carbene ligands.

Abstract: A family of eight rhenium(I) tricarbonyl complexes bearing pyridyl-imidazolylidene or bis-imidazolylidene ligands in combination with a series of N-acetyl amino acids ligands (glycine, isoleucine, and proline) and an acetate have been synthesised and characterised. These complexes are of interest as potential anticancer agents, where the oxygen bound carboxylate ligand can exchange with water giving rise to cytotoxic cationic complexes. The pseudo-first-order aquation rate constants for the complexes were evaluated using 1H NMR time-course experiments and for the complexes of the bis-imidazolylidene ligand the average k1 value was 6.22 × 10-5 s-1 while for the pyridyl-imidazolylidene ligand the aquation rate was slower with the average k1 value being 3.00 × 10-5 s-1. Cytotoxicity studies in three cancer cell lines (MDA-MB-231, PC3 and HEPG2) showed that the Re(I) complexes of the bis-imidazolylidene ligand were significantly more toxic than those of the pyridyl-imidazolylidene ligand.

Potent Ruthenium-Ferrocene Bimetallic Antitumor Antiangiogenic Agent That Circumvents Platinum Resistance: From Synthesis and Mechanistic Studies to In Vivo Evaluation in Zebrafish.

Abstract: Emergence of resistance in cancer cells and dose-limiting side effects severely limit the widespread use of platinum (Pt) anticancer drugs. Multi-action hybrid anticancer agents that are constructed by merging two or more pharmacophores offer the prospect of circumventing issues of Pt drugs. Herein, we report the design, synthesis, and in-depth biological evaluation of a ruthenium-ferrocene (Ru-Fc) bimetallic agent [(η6-p-cymene)Ru(1,1,1-trifluoro-4-oxo-4-ferrocenyl-but-2-en-2-olate)Cl] and its five analogues. Along with aquation/anation chemistry, we evaluated the in vitro antitumor potency, Pt cross-resistance profile, and in vivo antiangiogenic properties. A structure activity analysis was performed to understand the impact of Fc, CF3, and p-cymene groups on the anticancer potency of the Ru-Fc hybrid. Finally, in addition to assessing cellular uptake and intracellular distribution, we demonstrated that the Ru-Fc hybrid binds to nucleophilic biomolecules and produces reactive oxygen species, which causes mitochondrial dysfunction and induces ER stress, leading to poly(ADP-ribose) polymerase-mediated necroptotic cell death.

Fast Hydrolysis and Strongly Basic Water Adducts Lead to Potent Os(II) Half-Sandwich Anticancer Complexes.

Abstract: Complexes of the formula [Os(η6-arene)(C,N-phenylpyridine)Z] (where Z is chlorido or a tethered oxygen) undergo very fast Os-Z hydrolysis (<5 min), and the high basicity of the coordinated water molecule of the aqua adducts (Os-OH2; pKa > 8) very much contrasts with previously reported Os-aqua adducts bearing NN- and NO-chelating ligands (pKa < 6). The Os-Cl bond is unreactive in pure DMSO, yet the complexes readily form DMSO adducts upon aquation when dimethyl sulfoxide is present. Such a peculiar aqueous behavior is directly related to the negatively charged CN ligand. Potent Os-CN compounds (but not their Os-NN analogues) are particularly reactive; they bind to cysteine in vitro and decrease the activity of thioredoxin reductase (TrxR) in living cancer cells. By revealing some interesting structure-activity relationship on Os-CN vs Os-NN complexes, we start uncovering the molecular rationale for the successful biological applications of osmium(II) half-sandwich compounds.

Kinetics and Mechanisms of Aryldiazonium Ions in Aqueous Solutions

Abstract: In aqueous acid solution and in mixed alcohol-water solvents ([H3O+] > 10–2 M), in the dark and in the absence of reductants, the spontaneous decomposition of aryldiazoniumAryldiazonium, ArN2+, salts proceeds throughSN1 (Dn + AN ) mechanism borderlineDn + AN (SN1) mechanism SN1 (DN + AN) -SN2 mechanismsSN2 mechanism. The rate constant values depend strongly on the nature of the substituents attached to the aromatic ring of ArN2+ and, for those with electron-withdrawing substituents, on solution composition. The product distribution is proportional to the composition of the solvation shellSolvation shell of the ipso carbon, which reflects the composition of the water/cosolvent mixture. However, upon decreasing moderately the acidity, reactions involving the formation of diazohydroxidesDiazohydroxides, ArN2OH, diazoethersDiazoethers, ArN2OR, and diazoatesDiazoates, ArN2O−, become competitive and may even be the main decomposition pathway. The stability of ArN2OH, ArN2OR, and ArN2O− species (which may coexist with ArN2+ in solution) is intimately related to the Z-E (syn-anti, cis-trans) isomerization of the O-adductsO-adducts, so that they may undergo further reactions when they are components of a Lewis acid-base equilibrium, or undergo homolytic scission to produce homolytic reductionHomolytic reduction products. In this book chapter, we aim to provide the reader with a practical and (hopefully) useful view of the complex chemistry of ArN2+ in aqueous and mixed alcohol-water solutions, mainly covering the kinetics and mechanisms of the reactions. In a last section, we introduce some analytical methods for the determination of diazonium salts and their degradation products.