Development of a pharmaceutical cocrystal of a monophosphate salt with phosphoric acid

We report the first case of a pharmaceutical cocrystal formed between an inorganic acid and an active pharmaceutical ingredient (API), which enabled us to develop a stable crystalline and bioavailable solid dosage form for pharmaceutical development where otherwise only unstable amorphous free form or salts could have been used.     

Sequential bond energies and barrier heights for the water loss and charge separation dissociation pathways of Cd(2+)(H2O)n, n = 3-11

The bond dissociation energies for losing one water from Cd(2+)(H(2)O)(n) complexes, n = 3-11, are measured using threshold collision-induced dissociation in a guided ion beam tandem mass spectrometer coupled with a thermal electrospray ionization source. Kinetic energy dependent cross sections are obtained for n = 4-11 complexes and analyzed to yield 0 K threshold measurements for loss of one, two, and three water ligands after accounting for multiple collisions, kinetic shifts, and energy distributions. The threshold measurements are converted from 0 to 298 K values to give the hydration enthalpies and free energies for sequentially losing one water from each complex. Theoretical geometry optimizations and single point energy calculations are performed on reactant and product complexes using several levels of theory and basis sets to obtain thermochemistry for comparison to experiment. The charge separation process, Cd(2+)(H(2)O)(n) → CdOH(+)(H(2)O)(m) + H(+)(H(2)O)(n-m-1), is also observed for n = 4 and 5 and the competition between this process and water loss is analyzed. Rate-limiting transition states for the charge separation process at n = 3-6 are calculated and compared to experimental threshold measurements resulting in the conclusion that the critical size for this dissociation pathway of hydrated cadmium is n(crit) = 4.     

Correlation of amine number and pDNA binding mechanism for trehalose-based polycations

Glycopolymers with repeat units comprised of the disaccharide trehalose and an oligoamine of increasing amine have been previously synthesized by our group and shown to efficiently deliver pDNA (plasmid DNA) to HeLa cells while remaining relatively nontoxic. Complexes formed between the most amine-dense of these polycations and pDNA were also found to be relatively stable in serum and have low aggregation, which is desirable for in vivo gene delivery. To lend insight into these interesting results, this study was aimed at investigating the binding strength and mechanism of interaction between these macromolecules, via isothermal titration calorimetry (ITC) and ethidium bromide exclusion assays. The size of these pDNA-polymer complexes, or polyplexes, at various states of formation was determined through light scattering and zeta-potential measurements. Varying degrees of pDNA secondary structure change occurred upon interaction with the polymers, as evidenced by circular dichroism spectra through increasing molar ratios of polymer amine to DNA phosphate, and Fourier transform infrared (FT-IR) results demonstrated stronger electrostatic binding with the phosphate backbone with the least amine-dense of the series. It was concluded that, depending on the number of secondary amines in the repeat unit, these polymers interact with pDNA via different mechanisms with varying extents of electrostatic interaction and hydrogen bonding. These differing mechanisms may affect the ability of trehalose to serve as a deterrent against aggregation in serum conditions and lend insight into the roles of polymer-pDNA binding during the complex transfection process.     

A structural transition in duplex DNA induced by ethylene glycol

The twist energy parameter ( E T) that governs the supercoiling free energy, and the linking difference (Delta l) are measured for p30delta DNA in solutions containing 0-40 w/v % ethylene glycol (EG). A plot of E T vs -ln a w, where a w is the water activity, displays the full (reverse) sigmoidal profile of a discrete structural transition. A general theory for the effect of added osmolyte on a cooperative structural transition between two duplex states, 1 right arrow over left arrow 2, is formulated in terms of parameters applicable to individual base-pair subunits. The resulting fraction of base pairs in the 2-state ( f 2 (0)) is incorporated into expressions for the effective torsion and bending elastic constants, the effective twist energy parameter ( E T (eff)), and the change in intrinsic twist (delta l 0). Fitting the expression for E T (eff) to the measured E T values yields reasonably unambiguous estimates of E T 1 and E T 2 , the midpoint value (ln a w) 1/2, and the midpoint slope ( partial differential E T/ partial differential ln a w) 1/2, but does not yield unambiguous estimates of the equilibrium constant ( K 0), the difference in DNA-water preferential interaction coefficient (DeltaGamma), or the inverse cooperativity parameter ( J). Fitting a noncooperative model (assumed J = 1.0) to the data yields K 0 = 0.067 and DeltaGamma = -30.0 per base pair (bp). Essentially equivalent fits are provided by models with a wide range of correlated J, DeltaGamma, and K 0 values. Other results favor DeltaGamma in the range -1.0 to 0, which then requires K 0 > or = 0.914, and a cooperativity parameter, 1/ J > or = 30.0 bp. The measured delta l 0 and circular dichroism (CD) at 272 nm are found to be compatible with curves predicted using the same f 2 (0) values that best-fit the E T data. At least 7-10% of the base pairs are inferred to exist in the 2-state in 0.1 M NaCl in the complete absence of added osmolyte. Compared with the 1-state, the 2-state has a approximately 2.0- to 2.1-fold greater torsion elastic constant, a approximately 0.70-fold smaller bending elastic constant, a approximately 0.91-fold smaller E T value, a approximately 0.2% lower intrinsic twist, a somewhat lower CD near both 272 and 245 nm, and less water and/or more EG in its neighborhood. However, the relative change in preferential interaction coefficient associated with the transition is likely rather slight.     

Identification of Marchfeld asparagus using Sr isotope ratio measurements by MC-ICP-MS

This work focuses on testing and application of Sr isotope signatures for the fast and reliable authentication and traceability of Asparagus officinalis originating from Marchfeld, Austria, using multicollector inductively coupled plasma mass spectrometry after optimised Rb/Sr separation. The major sample pool comprises freeze-dried and microwave-digested asparagus samples from Hungary and Slovakia which are compared with Austrian asparagus originating from the Marchfeld region, which is a protected geographical indication. Additional samples from Peru, the Netherlands and Germany were limited in number and allowed therefore only restricted statistical evaluation. Asparagus samples from Marchfeld were harvested within two subsequent years in order to investigate the annual variation. The results show that the Sr isotope ratio is consistent within these 2 years of investigation. Moreover, the Sr isotope ratio of total Sr in soil was found to be significantly higher than in an NH₄NO₃ extract, reflecting the mobile (bioavailable) phase. The isotope composition in the latter extract corresponds well to the range found in the asparagus samples in Marchfeld, even though the concentration of Sr in asparagus shows no direct correlation to the concentration of Sr in the mobile phase of the soil. The major question was whether the ‘Marchfelder Spargel’ can be distinguished from samples from the neighbouring countries of Hungary and Slovakia. According to our findings, they can be clearly (100%) singled out from the Hungarian samples and can be distinguished from the Slovakian asparagus samples with a probability of more than 80%.     

The inverse sandwich complex [(K(18-crown-6))2Cp][CpFe(CO)2]--unpredictable redox reactions of [CpFe(CO)2]I with the silanides Na[SiRtBu2] (R = Me, tBu) and the isoelectronic phosphanyl borohydride K[PtBu2BH3

The dimeric iron carbonyl [CpFe(CO)(2)](2) and the iodosilanes tBu(2)RSiI were obtained from the reaction of [CpFe(CO)(2)]I with the silanides Na[SiRtBu(2)] (R = Me, tBu) in THF. By the reactions of [CpFe(CO)(2)]I and Na[SiRtBu(2)] (R = Me, tBu) the disilanes tBu(2)RSiSiRtBu(2) (R = Me, tBu) were additionally formed using more than one equivalent of the silanide. In this context it should be noted that reduction of [CpFe(CO)(2)](2) with Na[SitBu(3)] gives the disilanes tBu(3)SiSitBu(3) along with the sodium ferrate [(Na(18-crown-6))(2)Cp][CpFe(CO)(2)]. The potassium analogue [(K(18-crown-6))(2)Cp][CpFe(CO)(2)] (orthorhombic, space group Pmc2(1)), however, could be isolated as a minor product from the reaction of [CpFe(CO)(2)]I with [K(18-crown-6)][PtBu(2)BH(3)]. The reaction of [CpFe(CO)(2)](2) with the potassium benzophenone ketyl radical and subsequent treatment with 18-crown-6 yielded the ferrate [K(18-crown-6)][CpFe(CO)(2)] in THF at room temperature. The crown ether complex [K(18-crown-6)][CpFe(CO)(2)] was analyzed using X-ray crystallography (orthorhombic, space group Pna2(1)) and its thermal behaviour was investigated.     

Balancing target flexibility and target denaturation in computational fragment‐based inhibitor discovery

Accounting for target flexibility and selecting “hot spots” most likely to be able to bind an inhibitor continue to be challenges in the field of structure‐based drug design, especially in the case of protein–protein interactions. Computational fragment‐based approaches using molecular dynamics (MD) simulations are a promising emerging technology having the potential to address both of these challenges. However, the optimal MD conditions permitting sufficient target flexibility while also avoiding fragment‐induced target denaturation remain ambiguous. Using one such technology (Site Identification by Ligand Competitive Saturation, SILCS), conditions were identified to either prevent denaturation or identify and exclude trajectories in which subtle but important denaturation was occurring. The target system used was the well‐characterized protein cytokine IL‐2, which is involved in a protein–protein interface and, in its unliganded crystallographic form, lacks surface pockets that can serve as small‐molecule binding sites. Nonetheless, small‐molecule inhibitors have previously been discovered that bind to two “cryptic” binding sites that emerge only in the presence of ligand binding, highlighting the important role of IL‐2 flexibility. Using the above conditions, SILCS with hydrophobic fragments was able to identify both sites based on favorable fragment binding while avoiding IL‐2 denaturation. An important additional finding was that acetonitrile, a water‐miscible fragment, fails to identify either site yet can induce target denaturation, highlighting the importance of fragment choice. © 2012 Wiley Periodicals, Inc.     

Substrate changes associated with the chemistry of self-assembled monolayers on silicon

Alkylsiloxane self-assembled monolayers (SAMs) are used in the semiconductor industry and, more recently, as proxies for organics adsorbed on airborne mineral dust and on buildings and construction materials. A number of methods have been used for removing the SAM from the substrate after reaction or use, particularly plasmas or piranha (H2SO4/H2O2) solution. However, when the substrates are reused to make new SAMs, the impact of the cleaning methods on the chemistry of subsequently formed SAMs on the surface is not known. Here we report atomic force microscopy, X-ray photoelectron spectroscopy, Auger electron spectroscopy, and Fourier transform infrared studies of changes in a silicon substrate upon repetitive deposition and removal of SAMs by these two methods. It is shown that a thicker layer of silicon oxide is formed, and the surface becomes irregular and roughened, particularly after the piranha treatment. This layer of silica impacts the structure of the SAMs attached to it and can serve as a reservoir for trace gases that adsorb on it, potentially contributing to the subsequent reactions of the SAM. The implications for the use of such surfaces as a proxy for reactions of organics on airborne dust particles and on structures in the boundary layer are discussed.     

High-precision catalysts: regioselective hydroformylation of internal alkenes by encapsulated rhodium complexes

We report the formation of high-precision catalysts using encapsulated rhodium complexes. In the current example, the encapsulated rhodium catalyst shows unprecedented high selectivity in the rhodium-catalyzed hydroformylation of internal alkenes, forming predominantly one of the branched aldehydes. This catalyst system is the first example that is able to discriminate between carbon atoms C3 and C4 in trans-3-octene.