Synthesis of new 6-substituted purinyl-5′-nor-1′-homocarbanucleosides based on indanol

A series of new 6-substituted purinyl-5′-nor-1′-homocarbanucleosides based on indanol were synthesized from (±)-cis-3-hydroxymethyl-1-indanol, an appropriately functionalized derivative of which was reacted with 6-chloropurine in the presence of NaH and 18-crown-6 ether to prepare a key intermediate that gave access to the target molecules, purinylcarbanucleosides in which position 6 is occupied by a chloro, hydroxy, methoxy, amino or substituted phenyl group.     

Optimisation of high performance liquid chromatography separation of neuroprotective peptides. Fractional experimental designs combined with artificial neural networks

The study of experimental design conjunction with artificial neural networks for optimisation of isocratic ion-pair reverse phase HPLC separation of neuroprotective peptides is reported. Different types of experimental designs (full-factorial, fractional) were studied as suitable input and output data sources for ANN training and examined on mixtures of humanin derivatives. The independent input variables were: composition of mobile phase, including its pH, and column temperature. In case of a simple mixture of two peptides, the retention time of the most retentive component and resolution were used as the dependent variables (outputs). In case of a complex mixture with unknown number of components, number of peaks, sum of resolutions and retention time of ultimate peak were considered as output variables. Fractional factorial experimental design has been proved to produce sufficient input data for ANN approximation and thus further allowed decreasing the number of experiments necessary for optimisation. After the optimal separation conditions were found, fractions with peptides were collected and their analysis using off-line matrix assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF-MS) was performed.     

Isotopic scrambling in Di-13C-labeled 2-butyl cation: evidence for a protonated cyclopropane intermediate

The (13)C NMR spectrum of 2-butyl-1,2-(13)C(2) cation (1) is unchanged on heating the sample to -78 degrees C, indicating no isomerization to another isotopomer. In contrast, the spectrum of 2-butyl-2,3-(13)C(2) cation (2) shows rapid formation of all of the other isotopomers except 1. These results are consistent with a protonated cyclopropane intermediate in the rearrangement process. In this mechanism, either C(1) and C(2) or C(3) and C(4) interchange. Only the bond between C(2) and C(3) breaks.     

Acylaminoacetyl derivatives of active methylene compounds. 2. The cyclization of the acetylaminoacetyl derivatives to α-substituted tetramic acids and the formation of N-acetyl-α-substituted tetramic acids

The reaction of aceturic acid p-nitrophenyl ester with active methylene compounds Y-CH₂-CO₂R has been found to give either the normally expected C-acylation compounds 2 (Y = -CN, -CO₂R, -COCH₃) or N-acetyl-α-Y-substituted tetramic acids 3 (Y = -CO₂R,-COCH₃), depending on the reaction conditions. Moreover, the intramolecular condensation of the C-acylation compounds 2 derived from malonic and acetoacetic esters (Y = -CO₂R, -COCH₃) to α-Y-substituted tetramic acids is shown to proceed through initial cyclization to the corresponding N-acetyl-α-Y-substituted tetramic acids 3 (Y = -CO₂R, -COCH₃).     

Electrostatics of PEGylated micelles and liposomes containing charged and neutral lipopolymers

The electrostatics of large unilamellar vesicles (LUVs) of various lipid compositions were determined and correlated with steric stabilization. The compositional variables studied include (a) degree of saturation, comparing the unsaturated egg phosphatidylcholine (EPC) and the fully hydrogenated soy phosphatidylcholine (HSPC) as liposome-forming lipids; (b) the effect of 40 mol % cholesterol; (c) the effect of mole % of three methyl poly(ethylene glycol) (mPEG)-lipids (the negatively charged mPEG-distearoyl phosphoethanolamine (DSPE) and two uncharged lipopolymers, mPEG-distearoyl glycerol (DSG) and mPEG-oxycarbonyl-3-amino-1,2-propanediol distearoyl ester (DS)); and (d) the negatively charged phosphatidyl glycerol (PG). The lipid phases were as follows: liquid disordered (LD) for the EPC-containing LUV, solid ordered (SO) for the HSPC-containing LUV, and liquid ordered (LO) for either of those LUV with the addition of 40 mol % cholesterol. The LUV zeta potential and electrical surface potential (psi(0)) were determined. It was found that progressive addition of mPEG(2k)-DSPE to liposomes increases negative surface potential and reduces surface pH to a similar extent as the addition of PG. However, due to the "hidden charge effect", zeta potential was more negative for liposomes containing PG than for those containing mPEG(2k)-DSPE. Replacing mPEG-DSPE with mPEG(2k)-DS or mPEG-DSG had no effect on surface pH and surface potential, and zeta potential was approximately zero. Addition of low concentrations of cationic peptides (protamine sulfate and melittin) to PG- or mPEG-DSPE-containing liposomes neutralized the liposome negative surface potential to a similar extent. However, only in liposomes containing PG, did liposome aggregation occur. Replacing the negatively charged lipopolymer mPEG-DSPE with the neutral lipopolymers mPEG-DS or mPEG-DSG eliminates or reduces such interactions. The relevance of this effect to the liposome performance in vivo is discussed.     

Computation in kinetics, III. A new method for kinetic model search based on simultaneous regression estimation of rate constants, stoichiometry and/or reaction order

Modified samples of natural mordenites have been found to catalyze the oxidative condensation of methane to yield ethane and ethylene. The selectivity towards C₂ hydrocarbons increases, whereas the acidity of zeolites falls.

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A very large diversity space of synthetically accessible compounds for use with drug design programs

We have constructed a very large virtual diversity space containing more than 10¹³ chemical compounds. The diversity space is built from about 400 combinatorial libraries, which have been expanded by choosing sizeable collections of suitable R-groups that can be attached to each link point of their scaffolds. These R-group collections have been created by selecting reagents that have drug-like properties from catalogs of available chemicals. As members of known combinatorial libraries, the compounds in the diversity space are in general synthetically accessible and useful as potential drug leads. Hence, the diversity space can be used as a vast source of compounds by a de novo drug design program. For example, we have used such a program to generate inhibitors of HIV integrase enzyme that exhibited activity in the micromolar range.     

The study of complex equilibria of uranium(VI) with selenate

Uranyl (M)-selenate (L) complex equilibria in solution were investigated by spectrophotometry in visible range and potentiometry by means of uranyl ion selective electrode. The formation ML and ML(2) species was proved and the corresponding stability constants calculated were: log beta(1) = 1.57(6) +/- 0.01(6), log beta(2) = 2.42(3) +/- 0.01(3) (I = 3.0 mol 1(-1) Na(ClO(4), SeO(4)) (spectrophotometry) at 298.2 K. Using potentiometry the values for infinite dilution (I --> 0 mol 1(-1)) were: log beta(1) = 2.64 +/- 0.01, log beta(2) 3.4 at 298.2 K. Absorption spectra of the complexes were calculated and analysed by deconvolution technique. Derivative spectrophotometry for the chemical model determination has also been successfully applied.     

Understanding the conformational dependence of spin-spin coupling constants: through-bond and through-space J(31P,31P) coupling in tetraphosphane-1,4-diides [M(L)x]2[P4R4

The characteristic dependence of J(31P,31P) spin-spin coupling constants of alkali metal tetraphosphane-1,4-diides on structure and composition has been analyzed by density functional methods. The computations confirm that the structure of the contact ion pairs is conserved in solution. Calculations on model systems M2P4H4, on naked P4H4(2-) anions, and on models including point charges, show that the role of the cations is mainly structural and to a smaller extent electrostatic. Three of the four J(P,P) coupling constants depend characteristically on the conformation of the anion, which in turn is determined by the substituents R and by cation-anion interactions. Several couplings exhibit a large through-space component and are thus strongly dependent on the relative orientation of nonbonding electron pairs on the phosphorus atoms involved. This is shown by visualization of coupling pathways using the recently introduced coupling energy density (CED), in combination with the electron localization function (ELF).     

Separation and identification of organic acid-coenzyme A thioesters using liquid chromatography/electrospray ionization-mass spectrometry

A method has been developed for the direct determination of coenzyme A (CoA) and organic acid-CoA thioesters in mixtures using directly combined liquid chromatography/electrospray ionization-mass spectrometry (LC/ESI-MS). Mixtures of CoA and organic acid-CoA thioesters were analyzed by LC/ESI-MS with detection of protonated molecular ions and characteristic fragment ions for each compound. The identities of the CoA-thioesters were established based on LC retention times and simultaneously recorded mass spectra. Monitoring of the CoA specific fragment ion at m/z 428 throughout the chromatogram provides a unique fingerprint for CoA content in the samples that corroborates the identification of organic acid-CoA thioesters in the mixtures. Furthermore, fragment ions arising from the ester linkage portion of the molecule allow unambiguous identification of the CoA esters in the samples. A second LC elution system was developed that allows the simultaneous separation and identification of 2-hydroxypropionyl-CoA (lactyl-CoA) and 3-hydroxypropionyl CoA (3HP-CoA), which have the same mass and identical MS fragmentation behavior. The utility of LC/ESI-MS employing this elution system is demonstrated by the determination of 3HP-CoA and lactyl-CoA (converted to CoA-thioesters from their corresponding free acids using CoA-transferase) in fermentation broths from Escherichia coli strains engineered for the production of 3-hydroxypropionic acid (3HP). External calibration employing a purified 3HP-CoA standard allowed indirect quantification of 3HP content in the broth with a precision of 1% (RSD). The feasibility of extending the method described above to perform LC/selected reaction monitoring-tandem mass spectrometry for direct determination of organic acid-CoA thioesters in cells was also demonstrated.