Stéphane Massip

(Thio)Amidoindoles and (Thio)Amidobenzimidazoles: An Investigation of Their Hydrogen-Bonding and Organocatalytic Properties in the Ring-Opening Polymerization of Lactide

The mechanism of the ring-opening polymerization (ROP) of lactide catalyzed by two partner hydrogen-bonding organocatalysts was explored. New amidoindoles 4 a,c, thioamidoindoles 4 b,d, amidobenzimidazoles 5 a,c, and thioamidobenzimidazoles 5 b,c were synthesized and used as activators of the monomer. In the solid state and in solution, compounds 4 and 5 showed a propensity for self-association, which was evaluated. (Thio)Amides 4 and 5 do catalyze the ROP of lactide in the presence of a cocatalyst, tertiary amine 3 a or 3 b, which activates the growing polymer chain through hydrogen-bonding. Reactions were conducted in 2-24 h at 20 degrees C; conversion yields ranged between 22 and 100 %. A detailed study of the intermolecular interactions undertaken between the participating species showed that, as expected, simultaneous weak hydrogen bonds do exist to activate the reagents. Moreover, interactions have been revealed between the partner catalysts 4/5+3. ROP catalyzed by these partner activators is thus governed by multiple dynamic equilibria. The latter should be judiciously adjusted to fine-tune the catalytic properties of (thio)amides and organocatalysts, more generally.

Ring-Opening Polymerization of L-Lactide Efficiently Triggered by an Amido-Indole. X-ray Structure of a Complex between L-Lactide and the Hydrogen-Bonding Organocatalyst

N-(3,5-Bis(trifluoromethyl)phenyl)-1H-indole-2-carboxamide 1e is an efficient hydrogen-bonding organocatalyst for the ring-opening polymerization of l-lactide. This new catalytic species does control the dispersity (1.08) and molecular weight (3460 g/mol vs 3064 in theory) of the poly(l-lactides) prepared in 2 h. (1)H NMR analysis showed that compound 1e complexes l-lactide in CDCl(3) through the two available NH groups (amide and indole). In particular, the catalytic species appeared to be mainly the H-bonding donor amide (1e in extended conformation, alone or dimer (1e)(2)) and, to a lesser extend, the dual H-bonding amido-indole (1e in its the pinched conformation). The first X-ray structure of the complex between a H-bonding organocatalyst and l-lactide also revealed a tight H-bonded network between the dimer (1e)(2) and l-lactide.

Relative Helix—Helix Conformations in Branched Aromatic Oligoamide Foldamers

The de novo design and synthesis of large and well-organized, tertiary-like, α-peptidic folded architectures is difficult because it relies on multiple cooperative interactions within and between secondary folded motifs of relatively weak intrinsic stability. The very stable helical structures of oligoamides of 8-amino-2-quinoline carboxylic acid offer a way to circumvent this difficulty thanks to their ability to fold into predictable and stable secondary motifs. Branched architectures comprised of two pairs of tetrameric (1), pentameric (2), or octameric (3) oligomers connected via an ethylene glycol spacer were designed and synthesized. The short spacer holds two helices in close proximity, thus enabling interactions between them. Degrees of freedom allowed in the system are well-defined: the relative P or M handedness of the two helices; the relative orientation of the helix axes; and the gauche or anti conformation of the ethylene spacer. Investigating the structures of 1-3 in the solid state and in solution allowed a detailed picture to be drawn of their conformational preferences and dynamics. The high variability of the solid state structures provides many snapshots of possible solution conformations. Helix-helix handedness communication was evidenced and shown to depend both on solvent and on a defined set of side chains at the helix-helix interface. Interdigitation of the side chains was found to restrict free rotation about the ethylene spacer. One solid state structure shows a high level of symmetry and provides a firm basis to further design specific side chain/side chain directional interactions.

Synthesis and evaluation of the antiproliferative activity of novel pyrrolo[1,2-a]quinoxaline derivatives, potential inhibitors of Akt kinase. Part II.

Attenuation of protein kinases by selective inhibitors is an extremely active field of activity in anticancer drug development. Therefore, Akt, a serine/threonine protein kinase, also known as protein kinase B (PKB), represents an attractive potential target for therapeutic intervention. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel inhibitors with various heterocycle scaffolds. Based on previous results obtained on the antiproliferative activities of new pyrrolo[1,2-a]quinoxalines, a novel series was designed and synthesized from various substituted phenyl-1H-pyrrole-2-carboxylic acid alkyl esters via a multistep heterocyclization process. These new compounds were tested for their in vitro ability to inhibit the proliferation of the human leukemic cell lines K562, U937, and HL60, and the breast cancer cell line MCF7. The first biological evaluation of our new substituted pyrrolo[1,2-a]quinoxalines showed antiproliferative activity against the tested cell lines. From a general SAR point of view, these preliminary biological results highlight the importance of substitution at the C-4 position of the pyrroloquinoxaline scaffold by a benzylpiperidinyl fluorobenzimidazole group, and also the need for a functionalization on the pyrrole ring.

Synthesis of New Pyrrolo[1,2-a]quinoxaline Derivatives as Potential Inhibitors of Akt Kinase

Akt kinases are attractive targets for small molecule drug discovery because of their key role in tumor cell survival/proliferation and their overexpression/activation in many human cancers. Recent efforts in the development and biological evaluation of small molecule inhibitors of Akt have led to the identification of novel Akt kinase inhibitors, based on a quinoxaline or pyrazinone scaffold. A series of new substituted pyrrolo[1,2-a]quinoxaline derivatives, structural analogues of these active quinoxaline or pyrazinone pharmacophores, was synthesized from various substituted 2-nitroanilines or 1,2-phenylenediamine via multistep heterocyclization process. These new compounds were tested for their in vitro ability to inhibit the proliferation of the human leukemic cell lines K562, U937 and HL60, and the breast cancer cell line MCF7. Three of these human cell lines (K562, U937 and MCF7) exhibited an active phosphorylated Akt form. The most promising active pyrroloquinoxalines were found to be 1a that inhibited K562 cell line proliferation with an IC50 of 4.5 μM, and 1h that inhibited U937 and MCF7 cell lines with IC50 of 5 and 8 μM, respectively. These two candidates exhibited more potent activities than the reference inhibitor A6730.

Efficient Synthesis and First Regioselective C‐3 Direct Arylation of Imidazo[1,2‐b]pyrazoles

Highly regioselective: An efficient synthesis of the imidazo[1,2-b]pyrazole core has been developed, and the first regioselective palladium-catalyzed direct arylation of the C-3 position is described (see scheme). Good to excellent yields were obtained for a wide range of aryl partners with electron-rich and electron-poor substituents. This methodology allows rapid access to a large variety of imidazo[1,2-b]pyrazole products and could open the way to the design of new biologically active compounds.

Synthesis and Cesium Binding Affinity of New 25,27-Bis(alkyloxy)calix[4]arene-crown-6 Conformers in Relation to the Alkyl Pendent Moiety

The preparation of new 25,27-bis(alkyloxy)calix[4]arenes-crown-6 in the cone, partial-cone and 1,3-alternate conformation is reported. We have also investigated the alkylation of the cone monoalkylated calix[4]arene-crown-6 achieved using Cs 2 CO 3 . This reaction afforded a mixture of cone and partial-cone calix[4]arenes-crown-6 having an alkyl chain anti or syn to the polyether ring. Conformations have been probed using 1 H, 13 C, 2D-NMR and NOESY analysis, and using X-ray crystallography. Extraction experiments using a two-phase solvent method involving cesium picrate were performed for these newly synthesized conformers. They reveal and confirm the strong preference for the 1,3-alternate conformers. The affinity of 1,3-alternate calixarenes for Cs + has been assessed by complexation measurements (log g ) using a spectrophotometric technique. No significant Cs + extraction difference was observed in relation to the nature of the alkyl chains on the aromatic rings. 1 H NMR studies of the 1,3-alternate calixarene Cs + complexes confirms the cations spacial position between the two aromatic rings, due to cation- ~ interactions.

Lidocaine/L-menthol binary system: cocrystallization versus solid-state immiscibility.

We present the synthesis, structure determination, and thermodynamic properties of a never reported cocrystal prepared with lidocaine and L-menthol. The temperature-composition phase diagram of the lidocaine/L-menthol binary system was achieved using differential scanning calorimetry and X-ray diffraction experiments. The present study demonstrates that the only way to perform a phase equilibrium survey of the lidocaine/L-menthol system is to prepare the binary mixtures from the cocrystal, an equimolar stoichiometric compound of L-menthol and lidocaine. We describe a process that is crucial to elaborate pharmaceutical agents that remain in their thermodynamical stable state throughout their preparation, manufacture, and storage for effective use.

Synthesis of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxalines as antileishmanial agents by Suzuki-Miyaura cross-coupling reactions

A series of new 4-(E)-alkenylpyrrolo[1,2-a]quinoxaline derivatives, structural analogues of alkaloid chimanine B, was synthesized in good yields using efficient palladium(0)-catalyzed Suzuki-Miyaura cross-coupling reactions. These new compounds were tested for in vitro antiparasitic activity upon Leishmania amazonensis and Leishmania infantum strains. Biological results showed activity against the promastigote forms of L. amazonensis and L. infantum with IC50 ranging from 0.5 to 7 μM. From a Structure-Activity Relationships point of view, these pharmacological results mainly enlightened the importance of the 4-lateral C6, C7 or C8 α-unsaturated trans-alkenyl chain of unsubstituted pyrrolo[1,2-a]quinoxaline moiety.

Synthesis and PreliminaryIn Vitro Evaluation of Antimycobacterial Activity of New Pyrrolo[1,2-a]quinoxaline-carboxylic Acid Hydrazide Derivatives

New pyrrolo[1,2-a]quinoxaline-2- or -4-carboxylic acid hydrazide derivatives were synthesized from nitroaniline or 1,2-phenylenediamine, and evaluated in vitro for their antimycobacterial activity as part of a TAACF TB screening program. Two compounds 7c and 13 showed an interesting activity at 6.25 μg/mL against Mycobacterium tuberculosis H37Rv, with a 94 and 100 percentage inhibition, respectively.