Nicolas Masurier

Novel imidazo[1,2-a]naphthyridinic systems (part 1) : Synthesis, antiproliferative and DNA-intercalating activities

Novel imidazo[1,2-a]naphthyridinic systems 6a-15a and 6b-15b were obtained from Friedländers reaction in imidazo[1,2-a]pyridine series. Most of the compounds were evaluated for their antitumor activity in the NCIs in vitro human tumor cell line screening panel. Among them, pentacyclic derivatives 13b and 14a exhibited in vitro activity comparable to anticancer agent such as amsacrine. Their mechanism of cytotoxicity action was unrelated to poisoning or inhibiting abilities against topo1. On the contrary, we highlighted a direct intercalation of the drugs into DNA by electrophoresis on agarose gel.

Helical Oligomers of Thiazole‐Based γ‐Amino Acids: Synthesis and Structural Studies

9-Helix: 4-Amino(methyl)-1,3-thiazole-5-carboxylic acids (ATCs) were synthesized as new γ-amino acid building blocks. The structures of various ATC oligomers were analyzed in solution by CD and NMR spectroscopy and in the solid state by X-ray crystallography. The ATC sequences adopted a well-defined 9-helix structure in the solid state and in aprotic and protic organic solvents as well as in aqueous solution.

Thiazole-Based γ-Building Blocks as Reverse-Turn Mimetic to Design a Gramicidin S Analogue: Conformational and Biological Evaluation

This paper describes the ability of a new class of heterocyclic γ-amino acids named ATCs (4-amino(methyl)-1,3-thiazole-5-carboxylic acids) to induce turns when included in a tetrapeptide template. Both hybrid Ac-Val-(R or S)-ATC-Ile-Ala-NH2 sequences were synthesized and their conformations were studied by circular dichroism, NMR spectroscopy, MD simulations, and DFT calculations. It was demonstrated that the ATCs induced highly stable C9 pseudocycles in both compounds promoting a twist turn and a reverse turn conformation depending on their absolute configurations. As a proof of concept, a bioactive analogue of gramicidin S was successfully designed using an ATC building block as a turn inducer. The NMR solution structure of the analogue adopted an antiparallel β-pleated sheet conformation similar to that of the natural compound. The hybrid α,γ-cyclopeptide exhibited significant reduced haemotoxicity compared to gramicidin S, while maintaining strong antibacterial activity.

Synthesis and anti-Candida activity of novel 2-hydrazino-1,3-thiazole derivatives

Eighteen new hydrazino-1,3-thiazole derivatives were evaluated against 8 strains of multi-resistant Candida spp. Introduction of an indolyl moiety linked to the hydrazone function enhanced the in vitro anti-Candida activity, with an activity spectrum towards Candida albicans strains. Introduction of a (S)-2-aminoethyl chain on the thiazole nucleus largely enhanced the in vitro antifungal activity, with a selectivity oriented towards non-C. albicans species.

Imidazopyridine-fused [1,3]-diazepinones: synthesis and antiproliferative activity.

A series of 15 pyrido-imidazo-1,3-diazepin-5-ones and pyrido-1,3-diazepine-2,5-diones were synthesized and their anticancer activities were evaluated. Among tested compounds on a cell lines panel, compound 6a presents the best growth inhibition activity on 21 cell lines with a cytotoxic effect on MDA-MB-435 melanoma cells. This compound led to deep cell morphological changes and revealed to be an inhibitor of the Hepatocyte progenitor kinase-like kinase (HGK), which is known to be implicated in the migration, adhesion and invasion of various tumor cells.

A New Highly Versatile Handle for Chemistry on a Solid Support: The Pipecolic Linker

The versatility of the pipecolic linker (Pip-linker) is illustrated by the synthesis of modified amino acids, C-terminal-modified pseudopeptides, and cyclic peptides, through side-chain anchoring of a lysine residue (see figure). Introduction of the first residue was easily accomplished and the Pip-linker revealed to be robust enough to support various chemical modifications.

Optimized strategies to synthesize β-cyclodextrin-oxime conjugates as a new generation of organophosphate scavengers.

A new generation of organophosphate (OP) scavengers was obtained by synthesis of β-cyclodextrin-oxime derivatives 8-12. Selective monosubstitution of β-cyclodextrin was the main difficulty in order to access these compounds, because reaction onto the oligosaccharide was closely related to the nature of the incoming group. For this purpose, non-conventional activation conditions were also evaluated. Intermediates 5 and 7 were then obtained with the better yields under ultrasounds irradiation. Finally, the desired compounds 8-10 were obtained from 5-7 in high purity by desilylation using potassium fluoride. Quaternarisation of compounds 8 and 9 was carried out. OP hydrolytic activity of compounds 8-12 was evaluated against cyclosarin (GF) and VX. None of the tested compounds was active against VX, but these five cyclodextrin derivatives detoxified GF, and the most active scavengers 10 and 11 allowed an almost complete hydrolysis of GF within 10 min. Even more fascinating is the fact that compounds 9 and 10 were able to hydrolyze enantioselectively GF.

Recycling the versatile Pipecolic linker.

The Pipecolic linker is a new highly versatile handle which immobilizes on solid support through a carboxylic acid function a wide range of amines, alcohols, and hydrazines. The anchoring step on pipecolic resin is very easy and efficient, and compounds are released with high purities upon acidic treatment. During this treatment, an oxazolonium intermediate is hydrolyzed, yielding the cleavage of ester or amide bond and the release of free carboxylic acid of the starting linker. In this study, we report the possibility of recycling the pipecolic resin after the use of several trifluoroacetic acid (TFA) cleavage cocktails. We demonstrate that it can be reused up to five times without significant loading decrease.

Solid-Supported Synthesis and 5-HT7/5-HT1A Receptor Affinity of Arylpiperazinylbutyl Derivatives of 4,5-dihydro-1,2,4-triazine-6-(1H)-one

A series of arylpiperazinylbutyl derivatives of 4,5‐dihydro‐1,2,4‐triazine‐6(1H)‐ones was designed and synthesized according to the new solid‐supported methodology. In this approach, triazinone scaffold was constructed from the Fmoc‐protected glycine. The library representatives showed different levels of affinity for 5‐HT7 and 5‐HT1A receptors; compounds 13, 14 and 18–20 were classified as dual 5‐HT7/5‐HT1A receptors ligands. The structure–affinity relationship analysis revealed that the receptor affinity and selectivity of the tested compounds depended on the kind of substituent in position 3 of triazinone fragment as well as substitution pattern of the phenylpiperazine moiety.

C9/12 Ribbon-Like Structures in Hybrid Peptides Alternating α- and Thiazole-Based γ-Amino Acids

According to their restricted conformational freedom, heterocyclic γ-amino acids are usually considered to be related to Z-vinylogous γ-amino acids. In this context, oligomers alternating α-amino acids and thiazole-based γ-amino acids (ATCs) were expected to fold into a canonical 12-helical shape as described for α/γ-hybrid peptides composed of cis-α/β-unsaturated γ-amino acids. However, through a combination of X-ray crystallography, NMR spectroscopy, FTIR experiments, and DFT calculations, it was determined that the folding behavior of ATC-containing hybrid peptides is much more complex. The homochiral α/(S)-ATC sequences were unable to adopt a stable conformation, whereas the heterochiral α/(R)-ATC peptides displayed novel ribbon structures stabilized by unusual C9/12 -bifurcated hydrogen bonds. These ribbon structures could be considered as a succession of pre-organized γ/α dipeptides and may provide the basis for designing original α-helix mimics.