Eric Bacque

Synthesis of 3-Amino 3-Phenyl Azetidine

Abstract We report a convenient preparation of 3-amino 3-phenyl azetidine from N-benzhydryl 3-azetidinone. Our strategy involves a modified Strecker reaction using dibenzylamine as an amino equivalent followed by the displacement of the cyano group by phenyl magnesium bromide and a final catalytic hydrogenation.

Electrochemical reduction of pristinamycin IA and related streptogramins in aqueous acidic medium.

Abstract The electrochemical reduction of the picolinoyl residue of pristinamycin I A and related streptogramins was performed at a mercury cathode, in aqueo

Reactivity of 1-(des-3-hydroxy-picolinoyl) pristinamycin IA

Abstract 1-(Des-3-hydroxy-picolinoyl) pristinamycin IA (PI-NH2) was shown to undergo a variety of reactions, including two unexpected transformations, to afford new pristinamycin IA derivatives.

NEW DERIVATIVES OF 4,4-DIPHENYL-2-CYCLOHEXEN-ONE

Abstract The syntheses of some new derivatives of 4, 4-diphenyl-2-cyclohexen-one are reported. In particular, we described a palladium-based strategy for the preparation of dienes (1) and (2).

Preparation of des-3-hydroxy-picolinoyl pristinamycins I

Abstract The cleavage of the 3-hydroxy-picolinoyl residue of pristinamycin I A and related compounds is reported to occur by a simple zinc reduction in aqueous acidic solution.

Incidence of the peptidic lactone opening on the electrochemical reduction of pristinamycin IA

Abstract Comparison of the cathodic behaviour of pristinamycin IA with an open ring derivative corroborates the role of the steric crowding exerted by the peptidic lactone.

A Convenient Synthesis of 2,2-Diphenyl-Cyclohexanone and 6,6-Diphenyl-2-Cyclohexen-One

Abstract A short, convenient and large scale synthesis of 2,2-diphenyl-cyclohexanone and 6,6-diphenyl-2-cyclohexen-one using respectively the regioselective hydrogenolysis of 1,3-diketone (3) and the radical reduction of 3-bromo-enone (4) is reported.

Abstract 2911: SAR125844: a potent and selective ATP-competitive inhibitor of MET kinase

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The tyrosine kinase MET is a membrane receptor that is essential for embryonic development and wound healing in normal cells. Stimulation of MET by its natural ligand, the hepatocyte growth factor (HGF), induces cell proliferation, migration, and invasion. Abnormal MET activation (over-expression of MET protein, amplification or mutations of the MET gene) has been observed in multiple human cancer types. We report herein the discovery of a potent and selective small molecule inhibitor (SAR125844) with potential therapeutic application in cancer patients with deregulated MET-dependent malignancies. Our initial hit identification approach was based on the biochemical screen of an in-house kinase inhibitor biased library where a series of benzimidazole sulfonate derivatives were identified with sub-micromolar MET inhibition. In particular, the initial hit exhibited an IC50 of 140 nM vs MET but it also had strong affinity for CDK9 (IC50= 6 nM), a CDK isoform involved in gene transcription. Chemical modifications of the series to dial out CDK9 affinity and remove potential normal cell cytotoxicity led to a more selective derivative with IC50s of 80nM and 1355nM vs MET and CDK9 respectively. Further sub-structural exploration allowed us to identify a heteorocyclic moiety which was shown by X-ray data to specifically interact with Tyr1230 in a non active conformation of the protein. The resulting highly favourable U-shape mode of binding in MET of representative examples from these series (e.g. IC50= 1nM) was not tolerated in CDK9 (IC50 > 10µM). Final multi-parametric medicinal chemistry optimisation led to SAR125844 with single digit nanomolar antiproliferative activity on MET-amplified cell lines. SAR125844 is highly selective for MET kinase in a panel of 275 kinases tested, with only 5 other protein kinases inhibited at IC50 values below 300 nM. This compound exhibits also satisfactory eADMET in vitro properties and has shown moderate total plasma clearance, large volume of distribution and moderate to long terminal elimination half-life in rats. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2911. doi:1538-7445.AM2012-2911

Influence of steric crowding on the electrochemical reduction of substituted tertiary pyridylcarboxamides in aqueous acidic medium

In order to assess the influence of the steric crowding on the electrochemical reduction of pyridylcarboxamides, we have studied a series of tertiary aromatic or alicyclic pyridylcarboxamides. We have shown that increasing steric hindrance at the amide nitrogen led to the production of either tetrahydropyridine or aminomethylpyridine.