Sub-2 microm HPLC coupled with sub-ppm mass accuracy for analysis of pharmaceutical compound libraries

Recent advances in accurate mass analysis are poised to allow the high-throughput production of accurate mass data on many more compounds than was previously available. It is shown that sub-ppm mass accuracy (producing elemental compositions) can be obtained on a simple TOF mass spectrometer operating in the manufacturer's standard mode. Concomitantly, there have been important technological advances in LC with respect to speed of analysis using sub-2 microm particle columns. Much of the sub-2 microm work in the literature has been under the label ultra performance LC (UPLC), however, we show that very high-speed results can be obtained using other manufacturer's pumps by using elevated column temperatures. Using elevated temperatures, HPLC peak widths on the order of 1 s can be obtained. We report the coupling of these two technologies (sub-ppm mass accuracy MS with high-speed HPLC) for the rapid analysis of compounds entering pharmaceutical libraries.     

Luminescence properties of C-diazaborolyl-ortho-carboranes as donor-acceptor systems

Seven derivatives of 1,2-dicarbadodecaborane (ortho-carborane, 1,2-C(2)B(10)H(12)) with a 1,3-diethyl- or 1,3-diphenyl-1,3,2-benzodiazaborolyl group on one cage carbon atom were synthesized and structurally characterized. Six of these compounds showed remarkable low-energy fluorescence emissions with large Stokes shifts of 15100-20260 cm(-1) and quantum yields (Φ(F)) of up to 65% in the solid state. The low-energy fluorescence emission, which was assigned to a charge-transfer (CT) transition between the cage and the heterocyclic unit, depended on the orientation (torsion angle, ψ) of the diazaborolyl group with respect to the cage C-C bond. In cyclohexane, two compounds exhibited very weak dual fluorescence emissions with Stokes shifts of 15660-18090 cm(-1) for the CT bands and 1960-5540 cm(-1) for the high-energy bands, which were assigned to local transitions within the benzodiazaborole units (local excitation, LE), whereas four compounds showed only CT bands with Φ(F) values between 8-32%. Two distinct excited singlet-state (S(1)) geometries, denoted S(1)(LE) and S(1)(CT), were observed computationally for the benzodiazaborolyl-ortho-carboranes, the population of which depended on their orientation (ψ). TD-DFT calculations on these excited state geometries were in accord with their CT and LE emissions. These C-diazaborolyl-ortho-carboranes were viewed as donor-acceptor systems with the diazaborolyl group as the donor and the ortho-carboranyl group as the acceptor.     

Folic Acid‐Decorated Nanocomposites Prepared by a Simple Solvent Displacement Method

A biodegradable nanocarrier system based on PLGA applicable for FR targeting is described. PEI‐based conjugates with covalently coupled folic acid are synthesized, characterized with regard to their composition and used for DNA complexation. The preparation of composites is performed by a solvent displacement technique, assuming an electrostatic interaction of PEI‐based polyplexes with PLGA. The synthesis of a folic acid‐PEG3kDa‐PEI25kDa conjugate is achieved. Blending of PLGA with polyplexes results in spherical nanoparticles with sizes ≤ 250 nm. Incorporation of polyplexes and the localization of folic acid on the particle surface, performed by antibody binding, is confirmed. The method is suitable for the preparation of nanosized, folic‐acid‐decorated nanoparticles.

     

Exploring the intrinsic polar [4 + 2+] cycloaddition reactivity of gaseous carbosulfonium and carboxonium ions

Gas‐phase reactions of model carbosulfonium ions (CH₃‐S⁺ = CH_2; CH₃CH₂‐S⁺ = CH₂ and Ph‐S⁺ = CH₂) and an O‐analogue carboxonium ion (CH₃‐O⁺ = CH₂) with acyclic (isoprene, 1,3‐butadiene, methyl vinyl ketone) and cyclic (1,3‐cyclohexadiene, thiophene, furan) conjugated dienes were systematically investigated by pentaquadrupole mass spectrometry. As corroborated by B3LYP/6‐311 G(d,p) calculations, the carbosulfonium ions first react at large extents with the dienes forming adducts via simple addition. The nascent adducts, depending on their stability and internal energy, react further via two competitive channels: (1) in reactions with acyclic dienes via cyclization that yields formally [4 + 2⁺] cycloadducts, or (2) in reactions with the cyclic dienes via dissociation by HSR loss that yields methylenation (net CH⁺ transfer) products. In great contrast to its S‐analogues, CH₃‐O⁺ = CH₂ (as well as C₂H₅‐O⁺ = CH₂ and Ph‐O⁺ = CH₂ in reactions with isoprene) forms little or no adduct and proton transfer is the dominant reaction channel. Isomerization to more acidic protonated aldehydes in the course of reaction seems to be the most plausible cause of the contrasting reactivity of carboxonium ions. The CH₂ = CH‐O⁺ = CH₂ ion forms an abundant [4 + 2⁺] cycloadduct with isoprene, but similar to the behavior of such α,β‐unsaturated carboxonium ions in solution, seems to occur across the C = C bond. Copyright © 2012 John Wiley & Sons, Ltd.     

Essential oil from the leaves of Annona vepretorum: chemical composition and bioactivity

The essential oil from the leaves of Annona vepretorun was obtained by hydrodistillation using a Clevenger-type apparatus and analyzed by GC-MS and GC-FID. Eighteen compounds representing 98.1% of the crude essential oil were identified. The major compounds identified were bicyclogermacrene (43.7%), spathulenol (11.4%), alpha-felandrene (10.0%), alpha-pinene (7.1%), (E)-beta-ocimene (6.8%), germacrene D (5.8%), and p-cymene (4.2%). The trypanocidal activity against Trypanosoma cruzi epimastigote forms, as well as, the antimicrobial and antioxidant proprieties was investigated. The essential oil showed a potent trypanocidal activity with IC50 value of 31.9 +/-1.3 microg x mL(-1). For antimicrobial activity, the best result was observed against Candida tropicalis with a MIC value of 100 microg x mL(-1). For antioxidant capacity the essential oil showed weak activity.     

Microbiological assay for lomefloxacin in coated tablets

The validation of a microbiological assay, applying cylinder plate method for determination of the activity of lomefloxacin in coated tablets is described. Using a strain of Bacillus subtilis ATCC 9372 as the test organism, lomefloxacin was measured in concentrations ranging from 2.0 to 8.0 microg/mL. The method validation showed that it is linear (r = 0.9999), precise (relative standard deviation = 1.15%), and accurate (it measured the added quantities). The excipients did not interfere in the determination. It was concluded that the microbiological assay is satisfactory for quantitation of lomeflox tablets.     

X-ray crystallographic and Mössbauer spectroscopic applications in dependence of partial quadrupole splitting, [R], on the C-Sn-C angle in seven-coordinated diorganotin(IV) complexes

The synthesis and the IR, NMR (1H, 13C, and 119Sn), and M?ssbauer spectroscopies and single-crystal X-ray diffraction studies of seven-coordinated diorganotin(IV) complexes, namely, [Ph2Sn(Hdapsc)]Cl.H2O.DMF [7; H(2)dapsc = 2,6-diacetylpyridine bis(semicarbazone)], [Me(2)Sn(H2,6Achexim)]Br.H2O [8; H(2)2,6Achexim = 2,6-diacetylpyridine bis(3-hexamethyleneiminylthiosemicarbazone)], [Me(2)Sn(dapmts)] [9; H(2)dapmts = 2,6-diacetylpyridine bis(4-methythiosemicarbazone)], and [nBu2Sn(dapmdtc)] [10; H(2)dapmdtc = 2,6-diacetylpyridine bis(S-methydithiocarbazate)], were done. The determination of the structures of [Ph(2)Sn(Hdapsc)]+, [Me2Sn(H2,6Achexim)]+ and [Me2Sn(dapmts)], [nBu2Sn(dapmdtc)] revealed the presence of monocationic and neutral complexes, respectively. The structures consist of monomeric units in which the Sn(IV) ions exhibit distorted pentagonal-bipyramidal geometries, with the X,N,N,N,X-donor (X = O, S) systems of the ligands lying in the equatorial plane and the organic groups in the apical positions. The C-Sn-C angle in the seven-coordinated diorganotin(IV) complexes was estimated using a correlation between M?ssbauer and X-ray data based on the point-charge model and using new values obtained in this work for [alkyl] = -1.00 mm s(-1) and [aryl] = -0.80 mm s(-1) for complexes containing O,N,N,N,O-pentadentate ligands and new values for [alkyl] = -0.87 mm s(-1) and [aryl] = -0.75 mm s(-1) for complexes containing S,N,N,N,S-pentadentate ligands.     

Desorption sonic spray ionization for (high) voltage-free ambient mass spectrometry

Sonic spray ionization is shown to create a supersonic cloud of charged droplets able to promote efficient desorption and ionization of drugs directly from the surfaces of commercial drug tablets at ambient conditions. Compared with desorption electrospray ionization (DESI), desorption sonic spray ionization (DeSSI) is advantageous since it uses neither heating nor high voltages at the spray capillary. DeSSI therefore provides a more friendly environment in which to perform ambient mass spectrometry (MS). DeSSI-MS is herein evaluated for the analysis of drug tablets, and found to be, in general, as sensitive as DESI-MS. The (high) voltage-free DeSSI method provides, however, cleaner mass spectra with less abundant solvent cluster ions and with enough abundant analyte signal for tandem mass spectrometry (MS/MS). These features may therefore facilitate the DeSSI-MS detection of low molar mass components or impurities, or both. The higher-velocity supersonic DeSSI spray also facilitates matrix penetration thus providing more homogenous sampling and longer lasting ion signals.     

First enantioselective total synthesis of neocarazostatin B, determination of its absolute configuration and transformation into carquinostatin A

The first enantioselective total synthesis of neocarazostatin B, the determination of its absolute configuration and transformation into carquinostatin A are described.