Reprogramming the chemical reactivity of iron in cancer stem cells

Cancer stem cells (CSCs) have been shown to be refractory to conventional therapeutic agents, can promote metastasis, and have been linked to cancer relapse. Salinomycin can selectively kill CSCs. We have shown that salinomycin derivatives accumulate in lysosomes and sequester iron in this organelle. As a result, accumulation of iron leads to the production of reactive oxygen species and lysosomal membrane permeabilization, which in turn promotes cell death by ferroptosis. These findings have revealed the prevalence of iron homeostasis in CSCs and paved the way toward the development of next-generation therapeutics.     

Structure of 1,2,3,4,9,9-hexachloro-6,7-tetrahydro-l,4-methano-naphthalene: a facially differentiated, annulated 1,3-cyclohexadiene

The X-ray crystal structure of the title compound is reported. Crystal data: T = 100 K, monoclinic, P2₁/n, a = 8.2990(17), b = 13.2300(26), c = 12.0350(24) Å, = 93.676(30)°, V = 1318.7 (5) ų, and R = 0.0368. The methylene carbon atoms in the cyclohexadiene ring are disordered over two positions above and below the ring plane. The chlorine substituted endocyclic double bond deviates from planarity with an angle of 8.10(13)° toward the endo-face. The facially differentiated 1,3-cyclohexadiene moiety is only slightly pyramidalized, deviating 1.75(20)° also toward the endo-face of the tricyclic system.     

Strained tridecane cage systems

Hexacyclo[6.5.0.0^2,7.0^4,12.0^5,10.0^9.13]tridecane (HCTD) contains two four-membered, two five-membered and two six-membered rings fused into a cage structure which contains about 77.0 kcal/mol of strain energy. Attempts to prepare the thioketal from the diketone of HCTD led to a skeletal rearrangement to produce a cage with one four-membered, four five-membered, and two six-membered rings fused into a cage (RHCTD). The corresponding RHCTD hydrocarbon has a strain energy 13.7 kcal/mol less than that of the starting tridecane (HCTD) which provides the driving force for the rearrangement. The X-ray structures of two HCTD derivatives and one RHCTD derivative are reported. The bond lengths in the three reported structures are normal for cages of this type. The structure of tetracyclo[6.3.0.0^3,7.0^4,11]undecane-5,10-dione mono(ketene 1,3-propanedithioacetal) is discussed also.     

Structure of a C2-symmetric bis(benzyloxy)trishomocubanone

The structure of a bis(benzyloxy)trishomocubanone with molecular C₂ symmetry reveals that substitution of benzyloxy groups has little effect on the trishomocubane cage.     

Synthesis and characterization of a novel pentacyclic C16 diketone and derivatives

The syntheses and crystal structures of pentacyclo[9.4.1.0^5,14.0^7,13.0^12,15]hexadecane-3,9-dione (2), a novel C₁₆ diketone with potential inclusion ability, and the products of the reaction of2 withn-butyllithium andmeso-erythritol (i.e.,meso-1,2,3,4-butanetetrol) are described. Crystal data:2·H₂O, orthorhombic,Pmmn,a=10.7385(8),b=9.0188(6),c=6.8411(4)Å,V=662.55(7)ų, andR=0.039 (379 reflections);3 (product from reaction withn-butyllithium), triclinic,P¯1,a=8.7192(7),b=10.9351(8),c=12.1842(8)Å,=68.933(5),=75.850(6), =80.309(6)°,V=1047.0(1)ų, andR=0.081 (1811 reflections);4 (product from reaction with erythritol), triclinic,P¯1,a=7.7224(8),b=10.1976(8),c=10.7021(9)Å,=85.405(7),=85.766(8), =76.056(7)°,V=814.0(1)ų, andR=0.052 (1471 reflections).     

New method to determine the total carbonyl functional group content in extractable particulate organic matter by tandem mass spectrometry

A functional group analysis method was developed to determine the quantitative content of carbonyl functional groups in atmospheric particulate organic matter (POM) using constant neutral loss scanning-tandem mass spectrometry (CNLS-MS/MS). The neutral loss method consists in monitoring the loss of a neutral fragment produced by the fragmentation of a precursor ion in a collision cell. The only ions detected are the daughter ions resulting from the loss of the neutral fragment under study. Then, scanning the loss of a neutral fragment characteristic of a functional group enables the selective detection of the compounds bearing the chemical function under study within a complex mixture. The selective detection of carbonyl functional groups was achieved after derivatization with pentafluorophenylhydrazine (PFPH) by monitoring the neutral loss of C(6)F(5)N (181 amu), which was characteristic of a large panel of derivatized carbonyl compounds. The method was tested on 25 reference mixtures of different composition, all containing 24 carbonyl compounds at randomly determined concentrations. The repeatability and calibration tests were satisfying as they resulted in a relative standard deviation below 5% and a linear range between 0.01 and 0.65 mM with a calculated detection limit of 0.0035 mM. Also, the relative deviation induced by changing the composition of the mixture while keeping the total concentration of carbonyl functional groups constant was less than 20%. These reliability experiments demonstrate the high robustness of the developed procedure for accurate carbonyl functional group measurement, which was applied to atmospheric POM samples.     

Anchoring of histidine-tagged proteins to molecular printboards: self-assembly, thermodynamic modeling, and patterning

In this paper the multivalent binding of hexahistidine (His6)-tagged proteins to beta-cyclodextrin (beta-CD) self-assembled monolayers (SAMs) by using the nickel(II) complex of a hetero-divalent orthogonal adamantyl nitrilotriacetate linker (4) is described. Nonspecific interactions were suppressed by using monovalent adamantyl-hexa(ethylene glycol) derivative 3. With the mono-His6-tagged maltose binding protein (His6-MBP), thermodynamic modeling based on surface plasmon resonance (SPR) titration data showed that the MBP molecules in solution were linked, on average, to Ni.4 in 1:1 stoichiometry. On the surface, however, the majority of His(6)-MBP was complexed to surface-immobilized beta-CDs through three Ni.4 complexes. This difference is explained by the high effective beta-CD concentration at the surface and is a new example of supramolecular interfacial expression. In a similar adsorption scheme, SPR proved that the alpha-proteasome could be attached to beta-CD SAMs in a specific manner. Patterning through microcontact printing of (His6)4-DsRed-fluorescent timer (DsRed-FT), which is a tetrameric, visible autofluorescent protein, was carried out in the presence of Ni.4 Fluorescence measurements showed that the (His6)4-DsRed-FT is bound strongly through Ni.4 to the molecular printboard.     

Spectral signatures and molecular origin of acid dissociation intermediates

The existence of a broad, mid-infrared absorption ranging from 1000 to 3000 cm(-1) is usually interpreted as a signature for the existence of protonated water networks. Herein, we use cryogenic mixtures of water and hydrogen fluoride (HF) and show experimental and computational evidence that similarly wide absorptions can be generated by a broad distribution of proton-shared and ion pair complexes. In the present case, we demonstrate that the broadening is mainly inhomogeneous, reflecting the fact that the topology of the first solvation shell determines the local degree of ionization and the shared-proton asymmetric stretching frequency within H2O x HF complexes. The extreme sensitivity of the proton transfer potential energy hypersurface to local hydrogen bonding topologies modulates its vibrational frequency from 2800 down to approximately 1300 cm(-1), the latter value being characteristic of solvation geometries that yield similar condensed-phase proton affinities for H2O and fluoride. By linking the local degree of ionization to the solvation pattern, we are able to propose a mechanism of ionization for HF in aqueous solutions and to explain some of their unusual properties at large concentrations. However, an important conclusion of broad scientific interest is our prediction that spectral signatures that are normally attributed to protonated water networks could also reveal the presence of strong hydrogen bonds between un-ionized acids and water molecules, with important consequences to spectroscopic investigations of biologically relevant proton channels and pumps.     

Reaction rates as a function of scale within ionic liquids: microscale in droplet microreactors versus macroscale reactions in the case of the Grieco three-component condensation reaction

Task-specific ionic liquids (TSILs) and more specifically binary task-specific ionic liquids (BTSILs), a unique subclass, have been shown to be excellent supports for solution-phase chemistry. The negligible volatility of ionic liquids enables their use as stable droplet microreactors in atmospheric environments without oil protection or confinement. These droplets can be moved, merged and mixed by electrowetting on a chip. Solution-phase synthesis can be performed on these open digital microfluidic labs-on-a-chip as illustrated by a study of the Grieco three-component reaction in [tmba][NTf(2)]-droplet (tmba=N-trimethyl-N-butylammonium NTf(2)=bis(trifluoromethylsulfonyl)imide) microreactors. A detailed study of matrices and scale effects on conversion and kinetic rates of this three-component condensation is presented in this paper. Reactions have been shown to be slower in droplets than in batches in the absence of additional mixing. Also, a significant influence of the ionic-liquid matrix has been observed. Finally, an increase of droplet's temperature resulted in a kinetics enhancement so as to reach macroscale reaction rates, probably because of a much better mixing of reaction's components involving a Marangoni's effect.