Synthesis of an iminosugar based peptidomimetic analogue

The synthesis of an 1-deoxymannojirimycin based analogue of a known HIV-protease inhibitor is described. The strategies employed for introduction of the pharmacophore groups onto the azasugar scaffold were based on regioselective reactions of the hydroxyl groups of the natural product and of d-fructopyranoside derivatives.     

Miniaturised enzymatic conductometric biosensor with Nafion membrane for the direct determination of formaldehyde in water samples

A new conductometric enzyme-based biosensor was developed for the determination of formaldehyde (FA) in aqueous solutions. The biosensor was prepared by cross-linking formaldehyde dehydrogenase from Pseudomonas putida with bovine serum albumin in saturated glutaraldehyde vapours (GA) at the surface of interdigitated gold microelectrodes. Nicotinamide adenine dinucleotide cofactor (NAD⁺) was added in solution at each measurement to maintain enzyme activity. Addition of a Nafion layer over the enzyme modified electrode resulted in a significant increase of biosensor signal due to enhanced accumulation of protons generated by enzymatic reaction at the electrode surface. Different parameters affecting enzyme activity or playing a role in ionic transfer through the Nafion membrane were optimised. In optimal conditions (0.045 mg enzyme, 30 min exposure to GA, 0.3 μL of a 1 % (v/v) Nafion solution deposit, measurement in 5 mM phosphate buffer pH 7 containing 20 μM NAD⁺), the biosensor signal was linear up to 10 mM FA, and the detection limit was 18 μM. Relative standard deviations calculated from five consecutive replicates of FA solutions were lower than 5 % in the 1–10 mM range. The biosensor was successfully applied to the determination of FA in spiked water samples (tap water and Rhone river water), with recoveries in the 95–110 % range.

Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging

Glycogen synthase kinase‐3 (GSK‐3) regulates multiple cellular processes in diabetes, oncology, and neurology. N‐(3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(3‐chloro‐4‐methoxyphenyl)oxazole‐4‐carboxamide (PF‐04802367 or PF‐367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK‐3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF‐367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF‐367 is ideal for discovery of radiopharmaceuticals for GSK‐3 in the central nervous system. A ¹¹C‐isotopologue of PF‐367 was synthesized and preliminary PET imaging studies in non‐human primates confirmed that we have overcome the two major obstacles for imaging GSK‐3, namely, reasonable brain permeability and displaceable binding.     

Synthesis and deprotonation of 2-(pyridyl)phenols and 2-(pyridyl)anilines

2-(2- and 3-Pyridyl)anilines (1, 2), 2,2-dimethyl-N-[2-(2- and 3-pyridyl)phenyl]propanamides (3, 4), and 2-, 3- and 4-(2-methoxyphenyl)pyridines (7-9) are readily synthesized using cross-coupling reactions. Whereas the amines 1, 2 undergo side reactions, the corresponding amides 3, 4 are deprotonated with lithium 2,2,6,6-tetramethylpiperidide (LTMP): the compound 3 at C6' under in situ quenching, and the compound 4 at C4'. When the ether 7 is subjected to the same reagent, lithiation occurs at C6'.     

Synthesis of sugar-based ethenyl ethers through a vinyl bis-sulfone methodology

The recently devised route to ethenyl ethers—i.e. 1,2-bis(phenylsulfonyl)ethylene (BPSE)-mediated conversion of alcohols into β-alkoxyvinyl sulfones followed by reductive desulfonylation—has been applied in the carbohydrate field to the synthesis of a number of vinyl-functionalised monosaccharides, a number of which had not been prepared via alternative routes.     

A study of the removal of heavy metals from aqueous solutions by Moringa oleifera seeds and amine-based ligand 1,4-bis[N,N-bis(2-picoyl)amino]butane

Uptake for lead, copper, cadmium, nickel and manganese from aqueous solution using the Moringa oleifera seeds biomass (MOSB) and amine-based ligand (ABL) was investigated. Experiments on two synthetic multi-solute systems revealed that MOSB performed well in the biosorption and followed the decreasing orders Pb(II) > Cu(II) > Cd(II) > Ni(II) > Mn(II) and Zn(II) > Cu(II) > Ni(II). The general trend of the heavy metal ions uptake by the amine-based ligand followed decreased in the order Mn > Cd > Cu > Ni > Pb, which is the reverse trend for what was observed for MOSB. Comparing the single- and multi-metal solutions, there was no clear effect in the biosorption capacity of MOSB suggesting the presence of sufficient active binding sites for all metal ions studied. The MOSB performance is also not affected by pH in the range 3.5–8.     

Pyridylmagnesiates: generation by bromine–metal exchange and enantioselective addition to aldehydes

Butyl and dibutylmagnesiates incorporating chiral ligands have been prepared and their reactivity studied. The reagents were efficient to promote the clean bromine–magnesium exchange of azinyl bromides at room temperature and subsequent reaction with aldehydes affording pyridylcarbinols. (R,R)-TADDOL-based dibutylmagnesiate was the best reagent leading to acceptable to good enantioselectivities, depending on the substrate and on the aldehyde substitution. This is the first example of enantioselective addition of in situ generated pyridylmagnesiate to carbonyl electrophiles.     

Straightforward Conversion of Alcohols into Nitriles

The reaction of various alcohols with cyanogen bromide, triphenylphosphine, and a base afforded the corresponding nitrile in satisfactory yields.     

Enantioselective straightforward access to benzo[b]thiophene analogs of Azatoxin

Horner-Wadsworth Emmons olefination followed by asymmetric hydrogenation allowed the first synthetic access to the chiral thiotryptophan with good enantiomeric excess. Oxazolidinone formation followed by a Pictet–Spengler condensation provided the benzothiophenic analog of Azatoxin.