ß-Peptides incorporating polyhydroxylated cyclohexane ß-amino acid: synthesis and conformational study.

We describe the synthesis of trihydroxylated cyclohexane ß-amino acids from (-)-shikimic acid, in their cis and trans configuration, and the incorporation of the trans isomer into a trans-2-aminocyclohexanecarboxylic acid peptide chain. Subsequently, the hydroxyl groups were partially or totally deprotected. The structural study of the new peptides by FTIR, CD, solution NMR and DFT calculations revealed that they all fold into a 14-helix secondary structure, similarly to the homooligomer of trans-2-aminocyclohexanecarboxylic acid. This means that the high degree of substitution of the cyclohexane ring of the new residue is compatible with the adoption of a stable helical secondary structure and opens opportunities for the design of more elaborate peptidic foldamers with oriented polar substituents at selected positions of the cycloalkane residues.

Polyhydroxylated Cyclopentane ß-Amino Acids Derived from d-Mannose and d-Galactose: Synthesis and Protocol for Incorporation into Peptides.

A stereoselective synthesis of polyhydroxylated cyclopentane ß-amino acids from hexoses is reported. The reaction sequence comprises, as key steps, ring-closing metathesis of a polysubstituted diene intermediate followed by the stereoselective aza-Michael functionalization of the resulting cyclopent-1-ene-1-carboxylic acid ester. Examples of synthesis of polysubstituted 2-aminocyclopentanecarboxylic acid derivatives starting from protected d-mannose and d-galactose are presented. A general protocol for the incorporation of these highly functionalized alicyclic ß-amino acids into peptides is also reported.

NMR spectral fingerprint patterns as diagnostics for the unambiguous configurational analysis of the classic organo-gelator 1,3:2,4-dibenzylidene-d-sorbitol (DBS) and its derivatives.

On the basis of experimental data and density functional theory (DFT) chemical shift and scalar coupling predictions, simple spectral nuclear magnetic resonance (NMR) fingerprint patterns have been established for the determination of the configuration in 1,3:2,4-dibenzylidene-d-sorbitol (DBS), a classic low molecular weight gelator, and its derivatives. The results rigorously prove the orientation of the phenyl rings in DBS that had been previously assumed in the literature on the basis of thermodynamic arguments.

New Morphiceptin Peptidomimetic Incorporating (1S,2R,3S,4S,5R)-2-Amino-3,4,5-trihydroxycyclopen-tane-1-carboxylic acid: Synthesis and Structural Study.

We present the synthesis and structural study of a new peptidomimetic of morphiceptin, which can formally be considered as the result of the replacement of the central proline residue of this natural analgesic drug with a subunit of (1S,2R,3S,4S,5R)-2-amino-3,4,5-trihydroxycyclopentane-1-carboxylic acid, previously obtained from L-idose. An optimized synthesis of this trihydroxylated cispentacin derivative is also reported. Molecular docking calculations on the target receptor support a favorable role of the hydroxy substituents of the non-natural ß-amino acid incorporated into the peptidomimetic.

Environmental Effects Determine the Structure of Potential ß-Amino Acid Based Foldamers.

This work shows that hybrid peptides formed by alternating trans-2-aminocyclopentanecarboxylic acid (trans-ACPC) and trans-2-aminocyclohexanecarboxylic acid (trans-ACHC) do not fold in the solvents typically used in the study of their homo-oligomers. Only when the peptides are assayed in SDS micelles are the predicted helical structures obtained. This indicates that the environment could play an equally important role (as the backbone stereochemistry) in determining their fold, possibly by providing a sequestered environment.

The folding of a metallopeptide.

We have applied solid-phase synthesis methods for the construction of tris(bipyridyl) peptidic ligands that coordinate Fe(ii) ions with high affinity and fold into stable mononuclear metallopeptides. The main factors influencing the folding pathway and chiral control of the peptidic ligands around the metal ions have been studied both by experimental techniques (CD, UV-vis and NMR) and molecular modeling tools. Amongst the numerous molecular variables that have been studied, this study clearly illustrates how the chirality of a given set of aminoacids (proline in this case) of the peptide dictates the chirality of the metal center of the resulting metallopeptide. Moreover, the relatively hydrophobic peptidic models used in this work show that the most stable structures present reduced solvent contacts and, in counterpart, stabilize the cis configuration of the proline residues.

Integrated Ugi-based assembly of functionally, skeletally, and stereochemically diverse 1,4-benzodiazepin-2-ones.

A practical, integrated and versatile U-4CR-based assembly of 1,4-benzodiazepin-2-ones exhibiting functionally, skeletally, and stereochemically diverse substitution patterns is described. By virtue of its convergence, atom economy, and bond-forming efficiency, the methodology documented herein exemplifies the reconciliation of structural complexity and experimental simplicity in the context of medicinal chemistry projects.

Conformational analysis of the anti-obesity drug lorcaserin in water: how to take advantage of long-range residual dipolar couplings.

The conformational state of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (lorcaserin) in water has been determined on the basis of one-bond and long-range C-H residual dipolar coupling (RDC) data along with DFT computations and (3)J(HH) coupling-constant analysis. According to this analysis, lorcaserin exists as a conformational equilibrium of two crown-chair forms, of which the preferred conformation has the methyl group in an equatorial orientation.

Custom-fit ruthenium(II) metallopeptides: a new twist to DNA binding with coordination compounds.

A new bipyridine building block has been used for the solid-phase synthesis of dinuclear DNA-binding ruthenium(II) metallopeptides. Detailed spectroscopic studies suggest that these compounds bind to the DNA by insertion into the DNA minor groove. Moreover, the potential of the solid-phase peptide synthesis approach is demonstrated by the straightforward synthesis of an octaarginine derivative that shows effective cellular internalization and cytotoxicity linked with strong DNA interaction, as evidenced by steady-state fluorescence spectroscopy and AFM studies.

Influence of solvent and salt concentration on the alignment properties of acrylamide copolymer gels for the measurement of RDC.

The dependence of molecular alignment with solvent nature and salt concentration has been investigated for mechanically stretched polyacrylamide copolymer gels. Residual dipolar couplings (RDCs) were recorded for D(2)O, DMSO-d(6), and DMSO-d(6)/D(2)O solutions containing different proportions of the solvents and different sodium chloride concentrations. Alignment tensors were determined by fitting the experimental RDCs to the DFT-computed structure of N-methylcodeinium ion. Analysis of the tensors shows that the degree of alignment decreases with the proportion of DMSO-d(6) as well as with the concentration of sodium chloride, most likely due to enhanced ion-pair aggregation. Furthermore, rotation of the alignment tensor is observed when increasing the salt concentration.

Conformational analysis of an isoquinolinium hydrochloride in water using residual dipolar couplings.

The use of the cetylpyridinium chloride (CPCL)/NaCl/hexanol liquid crystal allowed the measurement of (1)D(CH) residual dipolar couplings of the isoquinoline alkaloid salsolidine in its protonated state. Populations of its two half-chair forms were determined by using the single alignment tensor approximation combined with global superposition of conformers. These populations were in good agreement with the DFT-computed energies for both conformers.

Residual dipolar couplings of freely rotating groups in small molecules. Stereochemical assignment and side-chain conformation of 8-phenylmenthol.

A procedure for the direct use of (1)D(CH) residual dipolar couplings (RDCs) from freely rotating groups in the structural analysis of small molecules was implemented. (1)D(CH) RDCs were used to determine both the preferred conformation and the stereochemical assignment of the diastereotopic geminal methyls of 8-phenylmenthol. Furthermore, a method was also set up to fit RDC data to a set of conformations in solution on the assumption that they all have the same alignment tensor.

The Tubulin Binding Mode of MT Stabilizing and Destabilizing Agents Studied by NMR.

Tubulin is a fascinating molecule that forms the cytoskeleton of the cells and plays an important role in cell division and trafficking of molecules. It polymerizes and depolymerizes in order to fulfill this biological function. This function can be modulated by small molecules that interfere with the polymerization or the depolymerization. In this article, the structural basis of this behavior is reviewed with special attention to the contribution of NMR spectroscopy. Complex structures of small molecules that bind to tubulin and microtubules will be discussed. Many of them have been determined using NMR spectroscopy, which proves to be an important method in tubulin research.

TAR-RNA recognition by a novel cyclic aminoglycoside analogue.

The formation of the Tat-protein/TAR-RNA complex is a crucial step in the regulation of human immunodeficiency virus (HIV)-gene expression. To obtain full-length viral transcripts the Tat/TAR complex has to recruit the positive transcription elongation factor complex (P-EFTb), which interacts with TAR through its cyclin T1 (CycT1) component. Mutational studies identified the TAR hexanucleotide loop as a crucial region for contacting CycT1. Interfering with the interaction between the Tat/CycT1 complex and the TAR-RNA is an attractive strategy for the design of anti-HIV drugs. Positively charged molecules, like aminoglycosides or peptidomimetics, bind the TAR-RNA, disrupting the Tat/TAR complex. Here, we investigate the complex between the HIV-2 TAR-RNA and a neooligoaminodeoxysaccharide by NMR spectroscopy. In contrast to other aminoglycosides, this novel aminoglycoside analogue contacts simultaneously the bulge residues required for Tat binding and the A35 residue of the hexanucleotide loop. Upon complex formation, the loop region undergoes profound conformational changes. The novel binding mode, together with the easy accessibility of derivatives for the neooligoaminodeoxysaccharide, could open the way to the design of a new class of TAR-RNA binders, which simultaneously inhibit the formation of both the Tat/TAR binary complex and the Tat/TAR/CycT1 ternary complex by obstructing both the bulge and loop regions of the RNA.