An efficient route is described to an unusual exocyclic 4-β-d-ribofuranosyl-aminoimidazole nucleoside, related 4-N-benzylaminoimidazoles and imidazole analogues of precursors in the de novo biosynthesis of purines, via a regiospecific and stereoselective base-catalysed Dimroth-type rearrangement of 1-ribofuranosyl and 1-benzyl-5-aminoimidazoles. Use of a 15N labelled precursor showed the unequivocal endo- to exocyclic translocation of the nitrogen atom during the rearrangement.

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A complete family of acyclic nucleoside analogues has been obtained by combining the (2-hydroxy-1-phenylethoxy) methyl glycone with the nucleoside bases adenine, guanine, cytosine, thymine and uracil. In each case both optical antipodes have been prepared in enantiomerically pure form from styrene via asymmetric dihydroxylation. The conformation of the uracil and adenine derivatives has been compared by comprehensive calculations using the PM3 method with the conformation of 2',3'-didehydro-2',3'-dideoxyuridine (d4U) and the analogous 3-hydroxymethyl-1,3-dihydrobenzo[ c] furan nucleoside (bfU). Some antiviral activity has been observed.

Baseline separation of some new acyclic nucleosides which are potential antiviral agents was achieved using cyclodextrin capillary zone electrophoresis (CD-CZE). A method for the enantiomeric resolution of these compounds and determination of their enantiomeric purity was developed using anionic CDs (highly sulfated-CD or highly S-CD) as chiral selectors and capillaries, which were dynamically coated with polyethylene oxide (PEO). Operational parameters including (i) the nature and concentration of the chiral selectors, (ii) organic modifiers, (iii) temperature, and (iv) applied voltage were investigated. The use of charged CDs provides (i) a supplementary driving force for the compounds in a running buffer and (ii) enantiomeric resolution by inclusion of compounds in the CD cavity. The highly S-CD was found to be the most effective complexing agent and allowed good enantiomeric resolution. The complete resolution of five nucleoside analogs was obtained using 25 mM phosphate buffer, pH 2.5, containing either highly S-alpha-CD, S-beta-CD or S-gamma-CD at 30 degrees C with an applied field of 0.30 kV/cm. The apparent association constants of the inclusion complexes were calculated. The enantiomer migration order for the molecules investigated was determined and the detection limit of enantiomeric impurities was found to vary between 0.34 to 3.56 ng.mL(-1) for the first enantiomer.

Electrospray mass spectrometry and tandem mass spectrometry have aided the structural characterization of the diastereoisomeric cis- and trans-1-(3-benzoyloxymethyl-1,3-dihydrobenzo[c]furan-1-yl)thymines and the four enantiomerically pure stereoisomers of uracil analogues. Low-energy collision-induced dissociation MS/MS analysis of the various precursor molecular and cluster ions confirmed the characteristic fingerprint pattern obtained in the conventional electrospray spectra and allowed a convenient method for the characterization of novel 1,3-dihydrobenzo[c]furan nucleosides.

Unsaturated acyclic pyrimidine analogues, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}uracil, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}thymine and 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}cytosine having two asymmetric carbon atoms have been prepared in good yield starting from uridine and 5-methyluridine. The bis-vinyl thymine derivative underwent ring closure metathesis to give d4T, thus providing a novel synthesis of this compound.

Novel unsaturated acyclic nucleoside analogues, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}uracil, 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}thymine and 1-{1-[1-(hydroxymethyl)prop-2-enyloxy]prop-2-enyl}cytosine have been prepared in good yield from uridine and 5-methyluridine by periodate cleavage followed by a double Wittig reaction which introduces two vinyl groups. The thymine derivative underwent ring closure metathesis to give a novel synthesis of d4T.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

We reported a method of determination of enantiomeric purity of the new potential antiviral agents by direct analytical HPLC. Those agents are nucleoside analogs, having one chiral center. They are synthesized as a single enantiomer (R or S) by an asymmetric pathway. The chiral stationary phases chosen are silica-based cellulose tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H), or tris-methylbenzoate (Chiralcel OJ). Resolution was achieved using normal-phase chromatography with a mobile phase consisting of n-hexane-alcohol (ethanol or 2-propanol) in various percentages. Furthermore the effects of structural features on retention, selectivity and resolution, as well as on the elution order were thoroughly studied. Differences in the lipophilicity of the compounds were also examined.

The enantiomers of 1-{[(2-hydroxy-1-phenyl)ethoxy]methyl}thymine and 9-{[(2-hydroxy-1-phenyl)ethoxy]methyl}guanine have been obtained in high yield in five steps from (R)- and (S)-1-phenylethan-1,2-diol. These chiral compounds are acyclic nucleoside analogues of d4T and acyclovir, respectively.

Novel enantiomerically pure acyclic nucleoside analogues, 1-{[(2-hydroxy-1-phenyl)ethoxy]methyl}thymine (1) and 9-{[(2-hydroxy-1-phenyl)ethoxy]methyl} guanine (9), have been prepared in good yield from styrene via asymmetric dihydroxylation. The conformation of these species has been studied by theoretical methods.

In this article we examine the effect of molecular shape on the formation of thermotropic phases of alkyl-substituted poly-ols. The relationship between the cross-sectional area of the hydrophilic head group with respect to the that of the hydrophilic tails determines the type of mesophase formed. The results obtained are similar to those found for the formation of lyotropic phases.

A new efficient route is described to uracil, thymidine and cytosine derivatives of 1,3-dihydrobenzo[c]furan which are aromatic analogues of the well known antiviral 2',3'-dideoxy-2',3'-didehydronucleosides. These systems contain two chiral centres (corresponding to alpha/beta and D/L centres in a furanose sugar) and a route involving application of the Sharpless asymmetric oxidation methodology allowed access to each of the four stereoisomers of the uracil derivative in enantiomerically pure form.

2',3'-Dideoxy-2',3'-didehydronucleosides and azasaccharides are known to possess antiviral activity. The synthesized 1-methoxyisoindoline system (10), which is related to the above nucleosides, is potentially stable in-vivo. The 1-methoxyisoindoline was synthesized from the achiral phthalaldehyde in 10 steps via an enantiomerically pure diol obtained by Sharpless asymmetric dihydroxylation. The new heterocyclic compound is an azosaccharide mimic which provides an access to a new series of nucleoside analogues with potential as antiretroviral agents (anti-HIV) and as glycosidase inhibitors.

The results of our synthetic efforts and the investigation of the liquid-crystalline phase behaviour of a series of bis-mannosyl-amides are presented. In this investigation the structure of the polar carbohydrate groups was kept constant and the length of the terminal alkyl chain was varied between seven and twelve methylene groups. The results obtained from the DSC measurements, optical polarising microscopy and X-ray diffraction experiments will be reported and a structural model will be discussed.

1,2-O-Isopropylidene-α-d-xylofuranose has been used to protect one aldehyde group of o-phthalaldehyde. This chiral protecting group acts as a resolving agent and this leads to separable diastereoisomers when a new stereogenic centre is created by the conversion of the second aldehyde group to a benzyloxyhydroxyethyl chain. These separated diastereoisomers were cyclised to 1,3-dihydrobenzo[c]furans with retention of chiral integrity at the C3 site thus allowing further elaboration to enantiomerically pure nucleoside analogues.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The copper complex [Cu(ATICAR)2(H2O)]·2H2O (ATICAR=5-amino-1-tolylimidazole-4-carboxylate) has been prepared and characterized by its crystal structure determination. The ligand geometry around the copper(II) center is best described as predominantly square pyramidal (2/3) with a trigonal bipyramidal component (1/3). The ATICAR ligands act as bidentates to form the distorted square pyramid base of N2O2 donor atoms and a coordinated water molecule at the apex is held with a Cu–O bond that is unusually short (2.148 Å) for square pyramidal copper(II). Compound exhibits a dose-dependent antiproliferative effect on the growth of the B16F10 melanoma cell line while its lower IC50 value establish advantage by copper complexation.