Anionic hyperconjugation

Although hyperconjugation involving alkyl groups to a carbocation is a well-established concept, the analogous charge delocalization generated in anions by electronegative substitution has long been a subject of controversy. We have investigated this phenomenon for the β-hydroxyethyl and β-trifluoroethyl anions using ab initio electronic structure calculations. Split valence basis sets augmented by diffuse functions were used with fully optimized geometries. Three dimensional molecular orbital plots clearly show an in-plane HOMO-LUMO mixing of a C-X σ antibonding orbital with the carbon lone pair which yields hyperconjugative π bonding in the anti conformation. Deformation density maps further demonstrate that this delocalization leads to the development of a π component as well as a previously unrecognized sigma enhancement. These results support and extend the work of Apeloig and that of Schleyer and Kos, but are in opposition to the induction hypothesis of Streitwieser and Holtz. The recent experimental determination of the acidity of (CF₃)₃CH by Tatlow $\text{et al}$ and their interpretation in terms of fluorine hyperconjugation are also in accord with this work.     

Phase separation of p53 precedes aggregation and is affected by oncogenic mutations and ligands

Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF). The mechanism of the formation of the aggregates in the nucleus remains uncertain. The present study demonstrated that the DNA-binding domain of p53 (p53C) underwent phase separation (PS) on the pathway to aggregation under various conditions. p53C phase separated in the presence of the crowding agent polyethylene glycol (PEG). Similarly, mutant p53C (M237I and R249S) underwent PS; however, the process evolved to a solid-like phase transition faster than that in the case of wild-type p53C. The data obtained by microscopy of live cells indicated that transfection of mutant full-length p53 into the cells tended to result in PS and phase transition (PT) in the nuclear compartments, which are likely the cause of the GoF effects. Fluorescence recovery after photobleaching (FRAP) experiments revealed liquid characteristics of the condensates in the nucleus. Mutant p53 tended to undergo gel- and solid-like phase transitions in the nucleus and in nuclear bodies demonstrated by slow and incomplete recovery of fluorescence after photobleaching. Polyanions, such as heparin and RNA, were able to modulate PS and PT in vitro. Heparin apparently stabilized the condensates in a gel-like state, and RNA apparently induced a solid-like state of the protein even in the absence of PEG. Conditions that destabilize p53C into a molten globule conformation also produced liquid droplets in the absence of crowding. The disordered transactivation domain (TAD) modulated both phase separation and amyloid aggregation. In summary, our data provide mechanistic insight into the formation of p53 condensates and conditions that may result in the formation of aggregated structures, such as mutant amyloid oligomers, in cancer. The pathway of mutant p53 from liquid droplets to gel-like and solid-like (amyloid) species may be a suitable target for anticancer therapy.

Mutant p53 tends to form aggregates with amyloid properties, especially amyloid oligomers inside the nucleus, which are believed to cause oncogenic gain-of-function (GoF).     

Matrix polyelectrolyte microcapsules: new system for macromolecule encapsulation

A new approach to fabricate polyelectrolyte microcapsules is based on exploiting porous inorganic microparticles of calcium carbonate. Porous CaCO3 microparticles (4.5-5.0 microns) were synthesized and characterized by scanning electron microscopy and the Brunauer-Emmett-Teller method of nitrogen adsorption/desorption to get a surface area of 8.8 m2/g and an average pore size of 35 nm. These particles were used as templates for polyelectrolyte layer-by-layer assembly of two oppositely charged polyelectrolytes, poly(styrene sulfonate) and poly(allylamine hydrochloride). Calcium carbonate core dissolution resulted in formation ofpolyelectrolyte microcapsules with an internal matrix consisting of a polyelectrolyte complex. Microcapsules with an internal matrix were analyzed by confocal Raman spectroscopy, scanning electron microscopy, force microscopy, and confocal laser-scanning fluorescence microscopy. The structure was found to be dependent on a number of polyelectrolyte adsorption treatments. Capsules have a very high loading capacity for macromolecules, which can be incorporated into the capsules by capturing them from the surrounding medium into the capsules. In this paper, we investigated the loading by dextran and bovine serum albumin as macromolecules. The amount of entrapped macromolecules was determined by two independent methods and found to be up to 15 pg per microcapsule.     

Electrophilic acetylation and bromination reactions of benzo[b]naphtho[2,3-e][1,4]dioxin

The reactivity of benzo[b]naphtho[2,3-e][1,4]dioxin in the electrophilic aromatic substitution reactions has been studied. Friedel-Crafts acetylation resulted in the formation of three out of the possible five monoacetylated products, with the acetyl group located in positions 8 (major), 7 and 6 (minor) of the heterocycle. In the bromination reaction a higher selectivity was observed with the 6-bromo derivative found as the only monobrominated product and the 6,11-dibromo derivative found as the only polybrominated product. A ratio of unreacted heterocycle:6-bromo:6,11-dibromo derivatives in the bromination reaction has been found to depend strongly on the reaction conditions and on the heterocycle:bromine ratio.     

Two-Photon Excitation of 4'-Hydroxymethyl-4,5',8-Trimethylpsoralen

Abstract— Psoralens are a class of pharmaceutical agents commonly used to treat several cutaneous disorders. When irradiated with a mode-locked titanium: sapphire (Ti: sapphire) laser tuned to 730 nm, an aqueous solution of 4'-hydroxymethyl-4,5',8-trimethylpsoralen (HMT) emits blue light. The emission spectrum is centered at 452 nm and is identical to that obtained by one-photon excitation with UVA excitation, and its magnitude depends quad-ratically on the intensity of laser excitation. These results suggest that two-photon excitation occurs to a potentially photochemically active state. To estimate the two-photon absorption cross section, it was first necessary to measure the emission quantum yield of HMT using 365 nm excitation at room temperature that resulted in a value of 0.045 ± 0.007. The two-photon absorption cross section of HMT at 730 nm is therefore estimated to be 20 ± 10⁻⁵⁰ cm⁴ s (20 Göppert-Mayer). The excited-state photophysics and photochemistry of psoralens suggest potential applications to cutaneous phototherapy in diseases such as psoriasis and dystrophic epidermolysis bullosa.     

Identification of inhibitors for UDP-galactopyranose mutase

The flavoenzyme uridine 5'-diphosphate (UDP)-galactopyranose mutase (UGM) plays a key role in the cell wall biosynthesis of many pathogens, including Mycobacterium tuberculosis. Using a synthetic fluorescent ligand, we screened 16 000 compounds in a fluorescence polarization assay. Effective inhibitors of UGM were identified.     

Stabilised phosphorus(I) and arsenic(I) iodide: readily-synthesised reagents for low oxidation state main group chemistry

Herein we report a surprisingly facile and clean synthesis of base-stabilised phosphorus(I) and arsenic(I) iodide salts, which are reagents that provide convenient access to new low oxidation state main group compounds.     

Reactions of dicobalt octacarbonyl and related compounds with gem-dihalides

Dicobalt octacarbonyl and some of its derivatives (NaCo(CO)₄, Co₄(CO)₁₂, Hg[Co(CO)₄]₂, [Co(CO)₃PPh₃]₂, NaCo(CO)₃PPh₃) react with activated gem-dihalides, R₂CX₂, such as dichlorodiphenylmethane, 9,9-dihalofluorenes and dimethyl dibromomalonate, to give the ‘dimer’ olefin, R₂CCR₂. The course of this conversion involves formation of the coupling product, R₂XCCXR₂, followed by dehalogenation of the latter. These separate steps have been confirmed for activated monohalides (bromodiphenylmethane, 9-bromofluorene, dimethyl bromomalonate) which were readily coupled by cobalt carbonyls, and for activated vicinal dihalides (D,L and meso-dibromostilbene, 9,9′-dichlorobisfluorenyl) which cobalt carbonyls readily dehalogenated. A radical mechanism is favored for these processes, and indirect evidence in its favor is presented.     

205Tl NMR methods for the characterization of monovalent cation binding to nucleic acids

Monovalent cations play an important role in many biological functions. The guanine rich sequence, d(G4T4G4), requires monovalent cations for formation of the G-quadruplex, d(G4T4G4)2. This requirement can be satisfied by thallium (Tl+), a potassium (K+) surrogate. To verify that the structure of d(G4T4G4)2 in the presence of Tl+ is similar to the K+-form of the G-quadruplex, the solution structure of the Tl+-form of d(G4T4G4)2 was determined. The 10 lowest energy structures have an all atom RMSD of 0.76 +/- 0.16 A. Comparison of this structure to the identical G-quadruplex formed in the presence of K+ validates the isomorphous nature of Tl+ and K+. Using a 1H-205Tl spin-echo difference experiment we show that, in the Tl+-form of d(G4T4G4)2, small scalar couplings (<1 Hz) exist between 205Tl and protons in the G-quadruplex. These data comprise the first 1H-205Tl scalar couplings observed in a biological system and have the potential to provide important constraints for structure determination. These experiments can be applied to any system in which the substituted Tl+ cations are in slow exchange with the bulk ions in solution.     

Conformational and stereoelectronic investigation in 1,2-difluoropropane: The gauche effect

The effect of attaching an additional fluorine atom at C-2 in 1-fluoropropane (FP), giving 1,2-difluoropropane (DFP), on its conformational equilibrium, is theoretically evaluated. This substitution causes critical implications on the conformer stabilities of DFP (TG, GT and GG conformations) and the steric and electrostatic interactions should favor the conformer with fluorine atoms trans. However, the gauche effect plays a major role in describing the energies balance in DFP, shifting the equilibrium towards the conformation in which the two fluorine atoms are gauche. The origin of this effect is discussed through an NBO analysis, which allows the evaluation of both classical and non-classical (hyperconjugation and bent bonds) interactions as the prevailing factors governing the conformational equilibrium of molecules containing the 1,2-difluoroethane fragment.