Total Synthesis of Five Lipoteichoic acids of Clostridium difficile

The emergence of hypervirulent resistant strains have made Clostridium difficile a notorious nosocomial pathogen and has resulted in a renewed interest in preventive strategies, such as vaccines based on (synthetic) cell wall antigens. Recently, the structure of the lipoteichoic acid (LTA) of this species has been elucidated. Additionally, this LTA was found to induce the formation of protective antibodies against C. difficile in rabbits and mice. The LTA from C. difficile is isolated as a microheterogenous mixture, differing in size and composition, impeding any structure–activity relationship studies. To ensure reliable biological results, pure and well‐defined synthetic samples are required. In this work the total synthesis of LTAs from C. difficile with defined chain length is described and the initial biological results are presented.     

Automated solid phase synthesis of teichoic acids

This communication describes the first automated solid phase synthesis of teichoic acids (TAs) and the preparation by this method of a number of well-defined TA structures, which were probed for their antigenicity. An opsonophagocytic killing assay revealed a clear TA-length-activity relationship and indicated a promising candidate for future vaccine development.     

The synthesis of a menthol derivative of 2-aminopurine as a fluorescent DNA lesion

An efficient synthetic route to the phosphoramidite of a menthol functionalized guanosine analog is presented. Two procedures were executed for the key introduction of the 6′-allyl menthyl moiety. Stille vinylation on 6-O-tosylguanosine followed by cross-metathesis using an excess of allyl menthyl ether proved to be less efficient than a Stille coupling on the same tosylate using an advanced menthyl-allyl stannane derivative. Incorporation of the modified nucleoside using the phosphoramidite method into a DNA 50-mer proceeded uneventfully.     

Fluorous linker facilitated synthesis of teichoic acid fragments

The use of perfluorooctylpropylsulfonylethanol as a new phosphate protecting group and fluorous linker is evaluated in the stepwise solution phase synthesis of a number of biologically relevant (carbohydrate substituted) glycerol teichoic acid fragments. Teichoic acid fragments, up to the dodecamer level, were assembled by means of phosphoramidite chemistry, using a relatively small excess of the building blocks and a repetitive efficient purification procedure of the protected intermediates by fluorous solid phase extraction (F-SPE).     

Infrared and Raman spectroscopy at high pressures

Pressure is accepted theoretically as a useful variable. However in a studies on liquid or solid samples, it is still relatively unusual for pressure to be used as an experimental variable. The reluctance of experimentalists to use this theoretically attractive variable is caused mainly by the technical difficulties associated with the use of sufficiently high pressures. In this talk I will try to show that in many cases the experimental limitations are no longer those introduced by the use of high pressures. High pressure spectroscopic studies clearly imply the use of high pressure spectroscopic cells. A brief account will therefore be given of the various types of high pressure optical cells which are currently being used for spectroscopic studies. Each individual high pressure spectroscopic study has its own special justification. However there are a few quite general observations that can be made which cover many of the specific objectives of individual high pressure spectroscopic studies. For example:(i) pressure induced frequency shifts carry unambiguous information about anharmonic terms in the relevant potential function (i.e. the potential V is a function of distance d. therefore pressure can be used to change d and study V.)(ii) all known materials undergo structural phase transitions if the form which is thermodynamically stable under ambient conditions is compressed to high enough pressures: these high pressure phases should be studied.(iii) as the application of pressure forces a material towards a phase transition, the spectroscopic study can be used to gain information about the approaching structural instability.(iv) virtually all infrared and Raman spectra contain examples of Fermi resonance which confuse the interpretation of the spectra and the effects of pressure are valuable aids to the correct assignment of the resonating levels.(v) pressure induced frequency shifts can often give extra information to help with the more reliable assignment of features within a spectrum.The above points will be discussed and illustrated by examples chosen mainly from recent work by members of the spectroscopy group at King's College London.     

Lattice dynamics of InAs under hydrostatic pressures

The lattice dynamics of InAs under variable hydrostatic pressures is investigated on the basis of an ‘11-parameter’ rigid-ion model (RIM). The calculated phonon dispersion curves are in satisfactory agreement with the neutron scattering data (available for the TA modes only) measured at room temperature and atmospheric pressure. The one- and two-phonon densities of states functions and mode Gruneisen parameters have been computed at two arbitrary hydrostatic pressures. The effect of high pressure on the phonon dispersion curves is shown to lead to a typical ‘softening’ in the transverse acoustic modes and eventually to a phase trnasformation of the compound.     

Raman and resonance-Raman spectra of CsI/I−3

Raman and resonance-Raman spectra of the I^?₃ ion isolated within CsI crystals have been studied using 647 nm and 488 nm exciting radiation. Sample temperatures between 300 and 20 K have been used. Eleven overtones of the symmetric stretching mode (nν₁) have been observed in the resonance-Raman spectrum excited by the 488 nm Ar⁺ laser line. Bands centred at 153, 170, 264 and 304 cm^?1 have been assigned as ν₃, 2ν₂, ν₁+ν₃ and 2ν₃(Σ⁺) respectively. The remaining structure between the nν₁ lines has been assigned as due to combinations of these lines with the lattice vibrations of the CsI crystal.     

Stereoselective synthesis of L-guluronic acid alginates

The glycosylation properties of gulopyranosides have been mapped out, and it is shown that gulose has an intrinsic preference for the formation of 1,2-cis-glycosidic bonds. It is postulated that this glycosylation behaviour originates from nucleophilic attack at the oxacarbenium ion, which adopts the most favourable 3H4 conformation. Building on the stereoselectivity of gulose, a guluronic acid alginate trisaccharide was assembled for the first time by using gulopyranosyl building blocks.     

N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT_1A, 5-HT_2A, 5-HT₆, and D₂ receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D₂ receptor antagonists with additional 5-HT₆R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT₆R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT₆R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D₂R antagonist function combined with 5-HT₆R agonism, and mixed D₂/5-HT₆R antagonists in murine models of psychosis.