Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA.

Biofilm formation is one of main causes of bacterial antimicrobial resistance infections. It is known that the soluble lectins LecA and LecB, produced by Pseudomonas aeruginosa, play a key role in biofilm formation and lung infection. Bacterial lectins are therefore attractive targets for the development of new antibiotic-sparing anti-infective drugs. Building synthetic glycoconjugates for the inhibition and modulation of bacterial lectins have shown promising results. Light-sensitive lectin ligands could allow the modulation of lectins activity with precise spatiotemporal control. Despite the potential of photoswitchable tools, few photochromic lectin ligands have been developed. We have designed and synthesized several O- and S-galactosyl azobenzenes as photoswitchable ligands of LecA and evaluated their binding affinity with isothermal titration calorimetry. We show that the synthesized monovalent glycoligands possess excellent photophysical properties and strong affinity for targeted LecA with K d values in the micromolar range. Analysis of the thermodynamic contribution indicates that the Z-azobenzene isomers have a systematically stronger favorable enthalpy contribution than the corresponding E-isomers, but due to stronger unfavorable entropy, they are in general of lower affinity. The validation of this proof-of-concept and the dissection of thermodynamics of binding will help for the further development of lectin ligands that can be controlled by light.

Hoogsteen triplexes stabilized through ethynyl-linked pyrene-indole synthesized by high-temperature Sonogashira coupling.

The low binding affinity of unmodified triplex-forming oligonucleotides (TFO) is the main drawback to their promising utilization in gene therapy. In the present study, we have synthesized DNA intercalator 5-(pyren-1-ylethynyl)indole Y, known as twisted intercalating nucleic acid (TINA), by a Cu-mediated Sonogashira palladium-catalyzed coupling reaction of 1-ethynylpyrene with 5-iodoindole at a high temperature under anaerobic conditions. Coupling with indole C-5 was far more preferable in obtaining stable TINA-indole than enamine site C-3, as neither hydration of the triple bond to ketones nor competitive Glaser-type homocoupling of acetylenes was observed. The insertion of the new TINA monomer Y as a bulge in the middle or at the 5'-end of the oligodeoxynucleotide sequence via a flexible butane-1,2-diol linker showed extraordinary binding potential, resulting in excellent thermal stabilization of Hoogsteen-type triplex- and duplex-deoxyribonucleic acid (DNA) structures which was detected by thermal denaturation studies and supported by circular dichroism (CD). Molecular dynamics AMBER* revealed the lowest energy conformation in which a pyrenyl residue of the TINA monomer Y stacks in the dsDNA part, while an indolyl unit intercalates between the nucleobases of the TFO pattern. Overall the torsionally rigid conjugated TINA system with a decent twisting of 15.1° around acetylene is confirmed here as a requirement for the best fit inside the intercalation site of the triplex, resulting in high TFO-dsDNA affinity.

Reversing Reactivity: Stereoselective Desulfurative 1,2-trans-O-Glycosylation of Anomeric Thiosugars with Carboxylic Acids under Copper or Cobalt Catalysis.

We have discovered a new mode of reactivity of 1-thiosugars in the presence of Cu(II) or Co(II) for a stereoselective O-glycosylation reaction. The process involves the use of a catalytic amount of Cu(acac)2 or Co(acac)2 and Ag2CO3 as an oxidant in α,α,α-trifluorotoluene. Moreover, this protocol turned out to have a broad scope, allowing the preparation of a wide range of complex substituted O-glycoside esters in good to excellent yields with an exclusive 1,2-trans-selectivity. The late-stage modification of pharmaceuticals by this method was also demonstrated. To obtain a closer insight into the reaction mechanism, cyclic voltammetry was performed.

Conjugation of a 3-(1H-phenanthro[9,10-d]imidazol-2-yl)-1H-indole intercalator to a triplex oligonucleotide and to a three-way junction.

A new intercalating nucleic acid monomer M comprising a 4-(1-indole)-butane-1,2-diol moiety was synthesized via a classical alkylation reaction of indole-3-carboxaldehyde followed by a condensation reaction with phenanthrene-9,10-dione in the presence of ammonium acetate to form a phenanthroimidazole moiety linked to the indole ring. Insertion of the new intercalator as a bulge into a Triplex Forming Oligonucleotide resulted in good thermal stability of the corresponding Hoogsteen-type triplexes. Molecular modeling supports the possible intercalating ability of M. Hybridisation properties of DNA/DNA and RNA/DNA three-way junctions (TWJ) with M in the branching point were also evaluated by their thermal stability at pH 7. DNA/DNA TWJ showed increase in thermal stability compared to wild type oligonucleotides whereas this was not the case for RNA/DNA TWJ.

Synthesis of axially chiral biaryl thioglycosides through thiosugar-directed Pd-catalyzed asymmetric C-H activation.

Herein we report for the first time that the thiosugar moiety can be used both as a directing group enabling the regioselective activation of a C-H bond of biaryl scaffolds and as a chiral source inducing axial chirality. Our approach enables the easy generation of complex thioglycoside atropoisomers, thus paving the way to new products of potential biological interest.