Aurélien Lebrun

Stereoselective synthesis of original spirolactams displaying promising folded structures

Access to diastereoisomeric forms of original spirolactam frameworks and investigation of their folded potentials are depicted here. Taking advantage of a stereoselective ring-contraction reaction, the Transannular Rearrangement of Activated Lactams (TRAL), followed by two unprecedented tandem reactions, we describe here an efficient access to elegant spirocyclic scaffolds. After dimerization, NMR analyses, circular dichroism, SEM and molecular modelling indicated the existence of an attractive edifice able to fold and behave as a PPII helix, a common yet neglected peptidic secondary structure.

Porphyrins Conjugated with Peripheral Thiolato Gold(I) Complexes for Enhanced Photodynamic Therapy

Porphyrins fused to imidazolium salts across two neighboring β-pyrrolic positions were used as N-heterocyclic carbene (NHC) precursors to anchor AuI -Cl complexes at their periphery. Synthesis of several thiolato-AuI complexes was then achieved by substituting chloride for thiolates. Photodynamic properties of these complexes were investigated: the data obtained show that the Au-S bonds could be cleaved upon irradiation. The proposed mechanism to explain the release of thiolate moiety involves the S atom oxidation by singlet oxygen generated in the course of irradiation. In view of photodynamic therapy (PDT) applications, these porphyrins fused to NHC-AuI complexes were tested as photosensitizers to kill MCF-7 breast cancer cells. Results show the important role played by the ancillary ligands (chloride versus thiolates) on the photodynamic effect.

Selective homodimerization of unprotected peptides using hybrid hydroxydimethylsilane derivatives

We developed a simple and straightforward way to dimerize unprotected peptide sequences that relies on a chemoselective condensation of hybrid peptides bearing a hydroxydimethylsilyl group at a chosen position (either C-ter, N-ter or side-chain linked) to generate siloxane bonds upon freeze-drying. Interestingly, the siloxane bond sensitivity to hydrolysis is strongly pH-dependent. Thus, we investigated the stability of siloxane dimers in different experimental conditions. For that purpose, 29Si, 13C and 1H NMR spectra were recorded to accurately quantify the ratio of dimer/monomer. More interestingly, we showed that 1H resonances of the methylene and methyl groups connected to the Si can be used as sensitive probes to monitor siloxane hydrolysis and to determine the half-lives of the dimers. Importantly, we showed that the dimers were rather stable at pH 7.4 (t1/2 ≈ 400 h) and we applied the dimerization strategy to bioactive sequences. Once optimized, three dimers of the growth hormone releasing hexapeptide (GHRP-6) were prepared. Interestingly, their pharmacological evaluation revealed that the activity of the dimeric ligands could be switched from agonist to inverse agonist depending on the position of dimerization.

Hydrophobic α,α-Disubstituted Disilylated TESDpg Induces Incipient 310-Helix in Short Tripeptide Sequence

To evaluate the contribution of triethylsilyl α,α-di-n-propylglycine, namely TESDpg, to induce a defined secondary structure, we have prepared model tripeptides in which TESDpg was inserted in three different positions. Studies in solid state and in solution with adapted techniques showed that TESDpg was able to induce a nascent 310 helix in both crystal and solution states.

A multinuclear NMR perspective on the complexation between bisboronic acids and bisbenzoxaboroles with cis-diols

The interaction between boronic acids and cis-diols is an intense area of research, with numerous applications in sensing, separation, drug delivery, and materials science. Several analytical tools have been proposed over the past 20 years to probe these interactions, but most of them are limited by shortcomings such as high concentration requirements and/or the lack of clear evidence of the nature of the species present in solution. These drawbacks are all the more problematic in the case of compounds bearing multiple binding sites. In this work, a multinuclear (1H, 11B, 19F) NMR spectroscopy approach has been used to investigate for the first time the equilibria between bisboronic acids and bisbenzoxaboroles (as well as their monofunctional counterparts) with representative cis-diols, including catechol derivatives. The developed method is shown to provide valuable and straightforward insight into the nature of the species in solution, and the way in which the equilibria can be affected by the complexation media. In particular, the interest of using a 19F-tag on the cis-diol is emphasized.