Chemical biology of salinomycin

Cancer stem cells (CSC) have been shown to be refractory to conventional therapeutic agents, can promote metastasis, and have been linked to cancer relapse. The natural product Salinomycin has been identified by means of high throughput phenotypic screening as a selective killer of CSC in vitro and in vivo. In this article we comprehensively review the chemistry of Salinomycin, documenting early total syntheses, along with strategies that have been developed over the years to effectively modify this natural product at key positions with the view to establish a robust structure-activity-relationship and to delineate the complex mechanism of action of this fascinating molecule in the context of cancer research. Then, we document the biology of Salinomycin, putting forward phenotypic alterations that have been observed in the relevant biological models and highlighting how chemistry has been instrumental in discovering unprecedented physiological features of cancer stem cells that can be exploited for therapeutic benefits.     

Reversible Silylene Insertion Reactions into Si−H and P−H σ‐Bonds at Room Temperature

Phosphine‐stabilized silylenes react with silanes and a phosphine by silylene insertion into E?H σ‐bonds (E=Si,P) at room temperature to give the corresponding silanes. Of special interest, the process occurs reversibly at room temperature. These results demonstrate that both the oxidative addition (typical reaction for transient silylenes) and the reductive elimination processes can proceed at the silicon center under mild reaction conditions. DFT calculations provide insight into the importance of the coordination of the silicon center to achieve the reductive elimination step.     

Modeling of Anionic Polymerization of Isoprene in an Industrial Reactor

One of the most important reasons for modeling polymerization processes is to provide a tool for estimating the risks of runaway reactions in polymer industry. This is especially important for batch processes, such as anionic polymerization of isoprene or butadiene. This work presents a theoretical and experimental research of the anionic polymerization of isoprene using cyclohexane as solvent and n‐butyllithium as initiator. In the first part, a phenomenological kinetic expression is obtained that describes the anionic polymerization of isoprene initiated by n‐butyllithium in cyclohexane. In the second, the mass and energy balance equations are solved to model the anionic polymerization of isoprene in a quasi‐adiabatic batch reactor. Adjustment of reactor parameters is made using the data obtained from a laboratory reactor. The proposed model predicts adequately the obtained temperature, pressure, and conversion profiles from this set of experiments. Finally, a mathematical model is developed to predict the behavior for the anionic polymerization of isoprene in an industrial reactor.     

Gas‐phase functionalized carbon‐carbon coupling reactions catalyzed by Ni (II) complexes

Gas‐phase C―C coupling reactions mediated by Ni (II) complexes were studied using a linear quadrupole ion trap mass spectrometer. Ternary nickel cationic carboxylate complexes, [(phen)Ni (OOCR¹)]⁺ (where phen = 1,10‐phenanthroline), were formed by electrospray ionization. Upon collision‐induced dissociation (CID), they extrude CO₂ forming the organometallic cation [(phen)Ni(R¹)]⁺, which undergoes gas‐phase ion‐molecule reactions (IMR) with acetate esters CH₃COOR² to yield the acetate complex [(phen)Ni (OOCCH₃)]⁺ and a C―C coupling product R¹‐R². These Ni(II)/phenanthroline‐mediated coupling reactions can be performed with a variety of carbon substituents R¹ and R² (sp³, sp², or aromatic), some of them functionalized. Reaction rates do not seem to be strongly dependent on the nature of the substituents, as sp³‐sp³ or sp²‐sp² coupling reactions proceed rapidly. Experimental results are supported by density functional theory calculations, which provide insights into the energetics associated with the C―C bond coupling step.     

Understanding the Deactivation Pathways of Iridium(III) Pyridine-Carboxiamide Catalysts for Formic Acid Dehydrogenation

The degradation pathways of highly active [Cp*Ir(κ²-N,N-R-pica)Cl] catalysts (pica=picolinamidate; 1 R=H, 2 R=Me) for formic acid (FA) dehydrogenation were investigated by NMR spectroscopy and DFT calculations. Under acidic conditions (1 equiv. of HNO₃), 2 undergoes partial protonation of the amide moiety, inducing rapid κ²-N,N to κ²-N,O ligand isomerization. Consistently, DFT modeling on the simpler complex 1 showed that the κ²-N,N key intermediate of FA dehydrogenation ( I_NH ), bearing a N-protonated pica, can easily transform into the κ²-N,O analogue ( I_NH2 ; ΔG^≠≈11 kcal mol⁻¹, ΔG ≈−5 kcal mol⁻¹). Intramolecular hydrogen liberation from I_NH2 is predicted to be rather prohibitive (ΔG^≠≈26 kcal mol⁻¹, ΔG≈23 kcal mol⁻¹), indicating that FA dehydrogenation should involve mostly κ²-N,N intermediates, at least at relatively high pH. Under FA dehydrogenation conditions, 2 was progressively consumed, and the vast majority of the Ir centers (58 %) were eventually found in the form of Cp*-complexes with a pyridine-amine ligand. This likely derived from hydrogenation of the pyridine-carboxiamide via a hemiaminal intermediate, which could also be detected. Clear evidence for ligand hydrogenation being the main degradation pathway also for 1 was obtained, as further confirmed by spectroscopic and catalytic tests on the independently synthesized degradation product 1 c . DFT calculations confirmed that this side reaction is kinetically and thermodynamically accessible.     

Standardization of multi-nuclide mixtures by a new spectrum unfolding method

A new spectrum unfolding method has been applied to double-labeled mixtures with excellent results, while the CIEMAT/NIST method has been used for gels. The convenience of applying both methods has been demonstrated with mixtures containing more than three components.⁹⁰Sr+⁹⁰Y,⁸⁹Sr,²⁰⁴TI,⁴⁵Ca and³⁵S nuclides were combined as three, four and five components, and the different quench values and activity ratios were assayed. The discrepancies between computed and experimental activities were also obtained. Mixtures with some of their components below background have been prepared in order to test low-level activities.     

Dissociation constants of carboxymethyloxysuccinic acid

The dissociation constants of carboxymethyloxysuccinic acid (CMOS) have been measured at 25° and an ionic strength of 0·1M in sodium perchlorate. The values found were: pK₁ = 2·52, pK₂ = 3·77 and pK₃ = 5·00. CMOS is thus seen to be rather stronger than its isomer citric acid.     

Determination of the micelle-solute association constants of some benzene and naphthalene derivatives by micellar high performance liquid chromatograph

Summary The interaction of some benzene and naphthalene derivatives with sodium dodecyl sulphate, hexadecyltrimethylmmonium bromide and polyoxyethylene [23] dodecanol micelles has been evaluated by high operformance liquid chromatography using micellar mobile phases. The micelle-solute association constants have been obtained for the compounds investigated. Good correlation between free energy of transfer for water-micelles and for octanol-water has been observed.     

Miniemulsion copolymerization of styrene–methyl methacrylate

Miniemulsion copolymerization of 50 : 50 weight fraction of styrene–methyl methacrylate monomer, using hexadecane as the cosurfactant, was carried out in both unseeded and seeded polymerizations. Effects of the hexadecane concentration and the ultrasonification time on the conversion–time curves and particle size of the final latex were investigated for unseeded polymerization. The kinetic and particle size distribution results showed that an increase in hexadecane concentration and ultrasonification time cause faster polymerization rate and smaller particle size. The mechanism of mass transport from miniemulsion droplets to polymer particles was also investigated for seeded polymerization. For this purpose a monomer miniemulsion was mixed with a fraction of a previously prepared miniemulsion latex particles prior to initiation of polymerization, using residual oil-soluble initiator in the seed latex. The concentration of hexadecane and a water-insoluble inhibitor (2,5 di-tert-butyl hydroquinone) in the miniemulsions were the main variables. Seeded polymerizations were also carried out in the presence of miniemulsion droplets containing a water-insoluble inhibitor and water-soluble initiator. The inhibitor concentration and the agitation speed during the course of polymerization were the experimental variables. The kinetic and particle size results from these seeded experiments suggested that collision between miniemulsion droplets and polymer particles may play a major role in the transport of highly water-insoluble compounds.