Jean-Yves Laronze

Improved gelatinase a selectivity by novel zinc binding groups containing galardin derivatives.

The synthesis of several analogues of galardin, a MMP inhibitor, are presented with their in vitro inhibitory activity against MMP-1 and MMP-2. These compounds contain a distinct Zinc Binding Group (ZBG). Those having a 2-acylated-heterocycle as well as a 2-arylamide function do not exhibit a good inhibition/selectivity against the enzymes tested. On the contrary, those that are based on a hydrazide scaffold present potent selectivity for MMP-2 versus MMP-1.

A Convenient Synthesis of Conformationally Constrained β-Substituted Tryptophans

Abstract A short and general synthesis for the preparation of various conformationally constrained β-substituted tryptophans has been elaborated starting from indole, aldehydes and Meldrums acid by using trimolecular condensation and Curtius rearrangement mediated functional group transformations followed by deprotections, as key-steps. The relative configurations of the two diastereomeric series have been determined indirectly by the measurement of 3 J coupling constants in the corresponding tetrahydro-β-carbolines, and further supported by means of molecular modelizations.

Introduction of the 4-(4 bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity

Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC(50)=3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br-C6H4)-C6H4-SO(2)-). Interaction with the S2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation.

Synthesis and biological evaluation of novel 4,5-bis(dialkylaminoalkyl)-substituted acridines as potent telomeric G-quadruplex ligands

Several 4,5-bis(dialkylaminoalkyl)-substituted acridines have been prepared starting from acridine and their telomeric G-quadruplex stabilizing properties were evaluated using FRET melting and TRAP (Telomerase Repeat Amplification Protocol Assay) experiments.

Synthesis of chiral 2′,3′-pyranone(pyrrolidinone)-fused tryptamines

Chiral pyrano- and pyrrolidino-fused tryptamines were prepared by a diasteroselective trimolecular condensation between indole, Garners aldehyde and Meldrums acid, followed by selective functional group transformations.

A general preparation of β-substituted tryptophan esters

Abstract The title compounds 6 have been synthesized in 4 steps from indoles, aldehydes and Meldrums acid.

The Hofmann-like fragmentation induced by N-acylation of 1-methyl-1-aza-4-cyclanones and its use in the synthesis of 2-aza-hydrindanones and 2-aza-decalones

Abstract The N-methyl-piperidone 4a was fragmented to the vinylketonic acrylamide 9a by successive treatment with acryloyl chloride and Hunigs base. The 2-azahydrindandione 13a resulted from the cyclization of 9a in the form of its enol dimethylterbutyl ether. N-methyl-azepinone 4b was transformed in a similar way to the two epimeric 2-azadecalindiones 13b + 14b in four steps only.

Synthesis of Substituted 1,2,3,4-Tetrahydro-1-thiacarbazole and Spiro[pyrrolidinone-3,3′-indolinones] through a Common Intermediate Obtained by Condensation of Indolin-2-one, (Aryl)aldehydes, and Meldrum's Acid

Trimolecular adducts resulting from condensation between indolin-2-one (or indoline-2-thione), (aryl)aldehydes, and Meldrum’s acid are useful intermediates for the synthesis of either 1,2,3,4-tetrahydro-1-thiacarbazoles or spiro[pyrrolidino-3,3′-oxindoles] related to the natural product horsfiline. These latter compounds were obtained in a three-step procedure characterized by acyl azide formation, Curtius rearrangement, and subsequent thermal spiro cyclization. The relative stereochemistry of the spiro derivatives was determined by comparison of NOESY data and calculated conformational analyses. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

Stereochemically controlled syntheses of indole-substituted dihydrofuran-2-ones and a pyrrolidin-2-one

In order to obtain constrained analogues of tryptophane, five-membered lactams and lactones bearing 4-indolyl and 3-carboxylic groups were prepared in a completely diastereoselective manner, resulting in a trans relationship. Furthermore, the use of chiral precursors in the synthesis yielded enantiomerically pure compounds with three contiguous chiral centres.

A Convenient Synthesis of Indole‐Substituted 2‐Pyrrolidones and Their Cyclized Derivatives

Condensation between indole, Meldrum’s acid, and benzyloxycarbonylacetaldehyde or aminoacetaldehyde derivatives yielded trimolecular adducts 7a−c. The latter were cyclized to indole-substituted 2-pyrrolidones 15a−b or 3-aminopyrrolid-2-ones 18a−b, depending on the starting material. Derivative 18a was transformed into pyrrolo[3′,4′:5,6]pyrido[3,4-b]indol-3(2H)-ones 19a and 20a by a Pictet−Spengler condensation with benzaldehyde.