Jean-Yves Mérour

A mild and selective method for N-Boc deprotection

Abstract A new mild method to remove N - tert -butyloxycarbonyl groups using TBAF in refluxing THF is reported. In all cases, the corresponding N -free products are obtained in good yields. The reactions are selective for acid- and base-sensitive groups, such as tert -butyl and alkyl esters, aldehydes.

The Azaindole Framework in the Design of Kinase Inhibitors

This review article illustrates the growing use of azaindole derivatives as kinase inhibitors and their contribution to drug discovery and innovation. The different protein kinases which have served as targets and the known molecules which have emerged from medicinal chemistry and Fragment-Based Drug Discovery (FBDD) programs are presented. The various synthetic routes used to access these compounds and the chemical pathways leading to their synthesis are also discussed. An analysis of their mode of binding based on X-ray crystallography data gives structural insights for the design of more potent and selective inhibitors.

Synthesis of 3,5-bis(2-indolyl)pyridine and 3-((2-indolyl)-5-phenyl)- pyridine derivatives as CDK inhibitors and cytotoxic agents

We here report the synthesis and biological evaluation of new 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine designed as potential CDK inhibitors. Indole, 5-hydroxyindole, and phenol derivatives were used to generate three substitutions of the pyridine. The resulting skeletons were successively exploited to introduce various dimethylaminoalkyl side chains by Williamson type reactions. The synthesis includes Stille or Suzuki type reactions, which were realized on the 3,5-dibromopyridine. The preparation and the use of stannylindoles in mono or bis cross-coupling reactions were also described and each step was optimized and detailed. Kinase assays were realized and shown that nude compounds 7, 18, and 25 inhibited CDK1 in the 0.3-0.7 micromolar range with a good selectivity over GSK-3. Cytotoxicity against CEM human leukemia cells was evaluated with IC(50) values in the 5-15 micromolar range. Precise structure-activity relationships were delineated. Molecular modeling and docking solutions were proposed to complete the studies and to explain the observed SAR in the CDK assays.

Synthesis of chromeno[3,4-b]indoles as Lamellarin D analogues : A novel DYRK1A inhibitor class

A library of substituted chromeno[3,4-b]indoles was developed as Lamellarin isosters. Synthesis was achieved from indoles after a four-step pathway sequence involving C-3 iodination, a Suzuki cross-coupling reaction, and a one pot deprotection/lactonisation step. Twenty final compounds were tested in order to determine their activity against topoisomerase I and kinases, the two major biological activities of Lamellarins. One newly synthesized derivative exhibited a strong topoisomerase activity comparable to reference compounds such as campthotecin and Lamellarin with only a weak kinase inhibition. Two other lead compounds were identified as new nanomolar DYRK1A inhibitors and several other drugs affected the kinases in the sub-micromolar range. These results will enable us to use the chromeno[3,4-b]indole as a pharmacophore to develop potent treatments for neurological or oncological disorders in which DYRK1A is fully involved.

Palladium heteroannulation process for synthesis of substituted pyrrolo[2,3-b]pyridin-3-ones

Abstract Substituted-3 H -pyrrolo[2,3- b ]pyridin-3-ones 7b-d were prepared from 2-amino-3-iodopyridine derivatives 3b-d by palladium carboannulation process with allenic compounds and then oxidative cleavage of the exocyclic carbon-carbon double bond.

Synthesis of 2-Substituted-1H-pyrrolo[2,3-b]pyridines: Preparation of 7-azaolivacine analogue and 7-azaindolopyridopyrimidine derivatives

Abstract 2-Substituted-1 H -pyrrolo[2,3- b ]pyridines have been prepared from 7-azaindole by lithiation followed by addition of various electrophiles. A 7-azaolivacine analogue and a pyrido[3′2′:4,5]pyrrolo[1,2- c ]pyrido[3,2- d ]pyrimidine have also been prepared.

Synthesis and biological activities of new furo[3,4-b]carbazoles: Potential topoisomerase II inhibitors

New 1,5-dihydro-4-(substituted phenyl)-3H-furo[3,4-b]carbazol-3-ones were synthesised via a key step Diels-Alder reaction under microwave irradiation. 3-Formylindole was successfully used in a 6-step synthesis to obtain those complex heterocycles. The Diels-Alder reaction generating the carbazole ring was optimised under thermal conditions or microwave irradiation. After cleavage of functional groups, DNA binding, topoisomerase inhibition and cytotoxic properties of the new-formed furocarbazoles were investigated. These carbazoles do not present a strong interaction with the DNA, and do not modify the relaxation of the DNA in the presence of topoisomerase I or II except for one promising compound. This compound is a potent topoisomerase II inhibitor, and its cellular activity is not moderated compared to etoposide. The synthesis of these molecules allowed the generalisation of the method using indole and 5-OBn indole and several benzaldehydes. The synthesis of these molecules produced chemical structures endowed with promising cytotoxic and topoisomerase II inhibition activities.

Stereoselective addition reactions to chiral N-benzylidene-p-toluenesulfinamides. Application to the synthesis of optically active 1,2-diphenylethylamines

Abstract An efficient and enantiospecific synthesis of substituted 1,2-diphenylethylamines 5 from benzaldehydes is described using a recyclable chiral auxiliary.

Synthesis of Pyrido[2,3-b]indole Derivatives via Diels–Alder Reactions of 2- and 3-Vinylpyrrolo[2,3-b]pyridines

Abstract Diels–Alder reactions between 2- or 3-vinylpyrrolo[2,3-b]pyridine with various dienophiles were investigated. The pyrido[2,3-b]indole adducts 9 and 13 obtained led us to the preparation of potential cytotoxic agents 19 and 20.

Synthesis and biological evaluation of new 3-(6-hydroxyindol-2-yl)-5-(Phenyl) pyridine or pyrazine V-Shaped molecules as kinase inhibitors and cytotoxic agents

We here report the synthesis and biological evaluation of new 3-[(2-indolyl)]-5-phenyl-3,5-pyridine, 3-[(2-indolyl)]-5-phenyl-2,4-pyridine and 3-[(2-indolyl)]-5-phenyl-2,6-pyrazine derivatives designed as potential CDK inhibitors. Indoles and phenyls were used to generate several substitutions of the pyridine and pyrazine rings. The synthesis included Stille or Suzuki type reactions, which were carried out on the 3,5-dibromopyridine, 2,4-dichloropyridine and 2,6-dichloro-1-4-pyrazine moieties. Cell effects of the V-shaped family were in the micromolar range. Kinase assays were conducted and showed that compound 11 inhibited CDK5 with an inhibitory concentration of 160 nM with a moderate selectivity over GSK3 compared to the reference C which exhibited a slightly lower activity on CDK5 (1.5 μM). Compound 11 was also found to be the most potent compound in the series and was identified as a new lead for DYRK1A inhibitor discovery (IC(50) = 60 nM). Docking studies were carried out in order to investigate the inhibition of DYRK1A.