Metal-Coordination-Assisted Folding and Guest Binding in Helical Aromatic Oligoamide Molecular Capsules.

The development of foldamer-based receptors is driven by the design of monomers with specific properties. Herein, we introduce a pyridazine-pyridine-pyridazine diacid monomer and its incorporation into helical aromatic oligoamide foldamer containers. This monomer codes for a wide helix diameter and can sequester metal ions on the inner wall of the helix cavity. Crystallographic studies and NMR titrations show that part of the metal coordination sphere remains available and may then promote the binding of a guest within the cavity. In addition to metal coordination, binding of the guest is assisted by cooperative interactions with the helix host, thereby resulting in significant enhancements depending on the foldamer sequence, and in slow guest capture and release on the NMR time scale. In the absence of metal ions, the pyridazine-pyridine-pyridazine monomer promotes an extended conformation of the foldamer that results in aggregation, including the formation of an intertwined duplex.

Tuning the guest-binding ability of a helically folded capsule by in situ modification of the aromatic oligoamide backbone.

Starting from a previously described aromatic oligoamide helically folded capsule that binds tartaric acid with high affinity and diastereoselectivity, we demonstrate the feasibility of the direct in situ modification of the helix backbone, which results in a conformational change that reduces its affinity for guests by two orders of magnitude. Specifically, ring contraction of the central pyridazine unit into a pyrrole in the full helical sequence was investigated by using electrochemical and chemical processes. The sequence containing the pyrrole was synthesized independently in a convergent manner to ascertain its structure. The conformation of the pyrrolic folded capsule was elucidated in the solid state by X-ray crystallography and in solution by using (1)H and (13)C NMR spectroscopy. Solution studies revealed an unanticipated solvent-dependent equilibrium between the anti-anti and syn-syn conformations of the pyrrole ring with respect to its two adjacent pyridine units. Titrations of the pyrrole-containing sequence monitored by (1)H NMR spectroscopy confirmed the expected drop in affinity for tartaric acid and malic acid that arises from the conformation change in the backbone that follows the replacement of the pyridazine by a pyrrole. The reduction of the pyridazine to a pyrrole was characterized by cyclic voltammetry both on the entire sequence and on a shorter precursor. The lower cathodic potential of the precursor made its preparative-scale electroreduction possible. Direct in situ modification of the pyridazine within the entire capsule sequence was achieved chemically by using zinc in acetic acid.

1,10-Phenanthroline and non-symmetrical 1,3,5-triazine dipicolinamide-based ligands for group actinide extraction.

The synthesis and evaluation of new extractants for spent nuclear fuel reprocessing are described. New bitopic ligands constituted of phenanthroline and 1,3,5-triazine cores functionalized by picolinamide groups were designed. Synthetic routes were investigated and optimized to obtain twelve new polyaza-heterocyclic ligands. In particular, an efficient and versatile methodology was developed to access non-symmetric 2-substituted-4,6-di(6-picolin-2-yl)-1,3,5-triazines from the 1,3,5-triazapentadiene precursor in the presence of anhydride reagents. Extraction studies showed the ability of both ligand series to extract and separate actinides selectively at different oxidation states (U(VI), Np(V,VI), Am(III), Cm(III), and Pu(IV)) from an acidic solution (3 M HNO3). Phenanthroline-based ligands show the most promising efficiency for use in the group actinide extraction (GANEX) process due to a higher number of donor nitrogen atoms and a suitable pre-organization of the dipicolinamide-1,10-phenanthroline architecture.

1-Oxo-1H-phenalene-2,3-dicarbonitrile heteroaromatic scaffold: revised structure and mechanistic studies.

Synthesis of the originally proposed 8-oxo-8H-acenaphtho[1,2-b]pyrrol-9-carbonitrile led to a structural revision, and the product has now been identified as unknown compound 1-oxo-1H-phenalene-2,3-dicarbonitrile. The structural assignment was corroborated by detailed NMR studies and unambiguously confirmed by X-ray diffraction. A mechanism is proposed to explain the formation of this original heterocyclic scaffold. In addition, some new chemical transformations involving this compound are presented.

Synthesis and Biological Evaluation of 4'-C,3'-O-Propylene-Linked Bicyclic Nucleosides.

A set of pyrimidine nucleosides fused with a 4'-C,3'-O-propylene bridge was successfully synthesised in 12 steps from 1,2:5,6-di-O-isopropylidene-α-d-glucofuranose, an inexpensive starting material, based on a ring-closing metathesis (RCM) reaction followed by Vorbrüggen-type nucleobase coupling. Antiviral and cytotoxicity activities of the targeted modified nucleosides, as well as their phosphoramidate prodrugs, are described.

Diastereoselective encapsulation of tartaric acid by a helical aromatic oligoamide.

A helical aromatic oligoamide foldamer encapsulates tartaric acid with exceptional affinity, selectivity, and diastereoselectivity. The structure of the complex has been elucidated both in solution by NMR spectroscopy and in the solid state by X-ray crystallography, making it possible to rationalize the strong effects observed, particularly the role of hydrogen bonds between the hydroxyl and carboxylic acid groups of tartaric acid and the inner wall of the helically folded capsule, which completely surrounds the guest and insulates it from the solvent.

Electrochemical synthesis and characterisation of alternating tripyridyl-dipyrrole molecular strands with multiple nitrogen-based donor-acceptor binding sites.

Synthesis of alternating pyridine-pyrrole molecular strands composed of two electron-rich pyrrole units (donors) sandwiched between three pyridinic cores (acceptors) is described. The envisioned strategy was a smooth electrosynthesis process involving ring contraction of corresponding tripyridyl-dipyridazine precursors. 2,6-Bis[6-(pyridazin-3-yl)]pyridine ligands 2a-c bearing pyridine residues at the terminal positions were prepared in suitable quantities by a Negishi metal cross-coupling procedure. The yields of heterocyclic coupling between 2-pyridyl zinc bromide reagents 12a-c and 2,6-bis(6-trifluoromethanesulfonylpyridazin-3-yl)pyridine increased from 68 to 95% following introduction of electron-donating methyl groups on the metallated halogenopyridine units. Favorable conditions for preparative electrochemical reduction of tripyridyl-dipyridazines 2b,c were established in THF/acetate buffer (pH 4.6)/acetonitrile to give the targeted 2,6-bis[5-(pyridin-2-yl)pyrrol-2-yl]pyridines 1b and 1c in good yields. The absorption behavior of the donor-acceptor tripyridyl-dipyrrole ligands was evaluated and compared to theoretical calculations. Highly fluorescent properties of these chromophores were found (ν(em)≈2 × 10(4) cm(-1) in MeOH and CH(2)Cl(2)), and both pyrrolic ligands exhibit a remarkable quantum yield in CH(2)Cl(2) (φ(f)=0.10). Structural studies in the solid state established the preferred cis conformation of the dipyrrolic ligands, which adopting a planar arrangement with an embedded molecule of water having a complexation energy exceeding 10 kcal mol(-1). The ability of the tripyridyl-dipyrrole to complex two copper(II) ions in a pentacoordinate square was investigated.

Theoretical study of the structures and hydrogen-bond properties of new alternated heterocyclic compounds.

The conformational preferences of a new bis-pyrrole derivative and its bis-pyridazine precursor have been investigated through quantum chemistry calculations (HF, DFT(MPWB1K), LMP2) and observations in the solid state. The global energetic minima are planar for both structures, with the conformational preferences being explained by pi-electronic conjugation between the aromatic systems and the occurrence of intramolecular hydrogen bonds (HB). For the bis-pyridazine derivative, the all-anti preferred conformation results from CH...Nsp(2) HB whereas the all-syn conformation of the bis-pyrrole is partly due to NH...Nsp(2) HB. For both systems, the validity of the theoretical conformational features is confirmed through the excellent agreement with the experimental data available. Calculations of electrostatic potential computed on the molecular surface of the various structures and their building blocks allow the variations to be rationalized in terms of molecular structure and are used to analyze the HB donor and acceptor sites of the compounds. The HB interaction sites predicted from the quantum chemical calculations are confirmed through the HB interactions observed in relevant crystal structures.

3,4-Dideoxy-3,3,4,4-tetrafluoro- and 4-OH epimeric 3-deoxy-3,3-difluoro-α-GalCer analogues: Synthesis and biological evaluation on human iNKT cells stimulation.

iNKT cells recognize CD1d/α-galactosylceramide (α-GalCer) complexes via their invariant TCR receptor and stimulate the immune response. Many α-GalCer analogues have been investigated to interrogate this interaction. Following our previous work related to the modification of the hydrogen bond network between α-GalCer and CD1d, we have now focused our attention on the synthesis of 3-deoxy-3,3-difluoro- and 3,4-dideoxy-3,3,4,4-tetrafluoro-α-GalCer analogues, and studied their ability to stimulate human iNKT cells. In each case, deoxygenation at the indicated positions was accompanied by difluoro introduction in order to evaluate the resulting electronic effect on the stability of the ternary CD1d/Galcer/TCR complex which has been rationalized by modeling study. With deoxy-difluorination at the 3-position, the two epimeric 4-OH analogues were investigated to establish their capacity to compensate for the lack of the hydrogen bond donating group at the 3-position. The 3,4-dideoxytetrafluoro analogue was of interest to highlight the amide NH-bond hydrogen bond properties.

3-fluoro- and 3,3-difluoro-3,4-dideoxy-KRN7000 analogues as new potent immunostimulator agents: total synthesis and biological evaluation in human invariant natural killer T cells and mice.

We propose here the synthesis and biological evaluation of 3,4-dideoxy-GalCer derivatives. The absence of the 3- and 4-hydroxyls on the sphingoid base is combined with the introduction of mono or difluoro substituent at C3 (analogues 8 and 9, respectively) to evaluate their effect on the stability of the ternary CD1d/GalCer/TCR complex which strongly modulate the immune responses. Biological evaluations were performed in vitro on human cells and in vivo in mice and results discussed with support of modeling studies. The fluoro 3,4-dideoxy-GalCer analogues appears as partial agonists compared to KRN7000 for iNKT cell activation, inducing T(H)1 or T(H)2 biases that strongly depend of the mode of antigen presentation, including human vs mouse differences. We evidenced that if a sole fluorine atom is not able to balance the loss of the 3-OH, the presence of a difluorine group at C3 of the sphingosine can significantly restore human iNKT activation.

Focus on the controversial activation of human iNKT cells by 4-deoxy analogue of KRN7000.

4-Deoxy-alpha-GalCer analogues are considered weaker agonists than KRN7000 for the stimulation of human iNKT cells, but this remains strongly debated. In this work, we described a strategy toward 4-deoxy-alpha-GalCers with, as a key step, a metathesis reaction allowing sphingosine modifications from a single ethylenic alpha-galactoside precursor. The 4-deoxy-KRN7000 derivative 2, described here, induced potent cytokinic responses, comparable to those of KRN7000, both from human iNKT cells in vitro and from their murine counterpart in vivo.

Asymmetric induction of the iodolactonization reaction of alpha-sulfurated gamma-unsaturated amides.

The 1,3-asymmetric iodolactonization reaction of enantiopure alpha-sulfurated gamma-unsaturated amides has been investigated. With sulfinyl and sulfonyl groups, a poorly stereoselective reaction was observed, whereas with a sulfanyl moiety, the diastereoselectivity can be high as 96:4. The role of the oxygen atom on the sulfur moiety is discussed.