b) TURBOMOLE: R. Ahlrichs. M. Blr. M. Haser. H. Horn. C. Kolmel. Chem. P/7? 5 . Lcjtt. 1989. 162. 165-169. The ring foldingangle at the B--B diagoiial is 32.3'in 2u, and 31.3-in 2u,; the barriers LO ring inversion of the folded four-membered ring are calculated as 4.5 kcalinol-' for 2u, and 5.5 kcalmol-I for 2u, and thus are significantly smaller than for a homodiboriranide without strong C-B hyperconjugation (7.9 kc;ilinol-' [4]).
The dendritic cell-specific intercellular adhesion molecule (ICAM) 3-grabbing nonintegrin (DC-SIGN) is a C-type lectin that appears to perform several different functions. Besides mediating adhesion between dendritic cells and T lymphocytes, DC-SIGN recognizes several pathogens some of which, including HIV, appear to exploit it to invade host organisms. The intriguing diversity of the roles attributed to DC-SIGN and their therapeutic implications have stimulated the search for new ligands that could be used as biological probes and possibly as lead compounds for drug development. The natural ligands of DC-SIGN consist of mannose oligosaccharides or fucose-containing Lewis-type determinants. Using the known 3D structure of the Lewis-x trisaccharide, we have identified some monovalent alpha-fucosylamides that bind to DC-SIGN with inhibitory constants 0.4-0.5 mM, as determined by SPR, and have characterized their interaction with the protein by STD NMR spectroscopy. This work establishes for the first time alpha-fucosylamides as functional mimics of chemically and enzymatically unstable alpha-fucosides and describes interesting candidates for the preparation of multivalent systems able to block the receptor DC-SIGN with high affinity and with potential biomedical applications.
The solid‐phase synthesis and characterization of a series of peptides (3–9), containing reverse‐turn mimetic bicyclic lactams (1a, 1b), was reported in the preceding paper. The bicyclic lactams (1a, 1b) possess high structural similarity to the two central residues of a β‐turn. The conformational preferences of the constrained peptides have been investigated by NMR spectroscopy and IR spectroscopy. Our experimental results have been complemented by computer modelling studies and show that the constrained peptides (3–9) form an inverse γ‐turn or a type‐II′ β‐turn through intramolecular hydrogen bonding, depending on the nature of the reverse‐turn mimic. In N‐acetylated tetrapeptide mimics incorporating the two different bicyclic lactams (a series and b series), H5 is available for either a γ‐turn (7‐membered ring with the carbonyl group of the bicyclic lactam) or a β‐turn (10‐membered ring with the carbonyl group of residue 2), as shown in Figures 7 and 9. The a series incorporating the (5,7)‐bicyclic lactam predominantly induces the γ‐turn conformation, while the b series incorporating the (5,6)‐bicyclic lactam can promote either a γ‐turn or a β‐turn conformation, with the β‐turn usually being preferred and with varying degrees of β‐hairpin formation.
The synthesis of eight bifunctional diketopiperazine (DKP) scaffolds is described; these were formally derived from 2,3-diaminopropionic acid and aspartic acid (DKP-1-DKP-7) or glutamic acid (DKP-8) and feature an amine and a carboxylic acid functional group. The scaffolds differ in the configuration at the two stereocenters and the substitution at the diketopiperazinic nitrogen atoms. The bifunctional diketopiperazines were introduced into eight cyclic peptidomimetics containing the Arg-Gly-Asp (RGD) sequence. The resulting RGD peptidomimetics were screened for their ability to inhibit biotinylated vitronectin binding to the purified integrins α(v)β(3) and α(v)β(5), which are involved in tumor angiogenesis. Nanomolar IC(50) values were obtained for the RGD peptidomimetics derived from trans DKP scaffolds (DKP-2-DKP-8). Conformational studies of the cyclic RGD peptidomimetics by (1)H NMR spectroscopy experiments (VT-NMR and NOESY spectroscopy) in aqueous solution and Monte Carlo/Stochastic Dynamics (MC/SD) simulations revealed that the highest affinity ligands display well-defined preferred conformations featuring intramolecular hydrogen-bonded turn motifs and an extended arrangement of the RGD sequence [Cβ(Arg)-Cβ(Asp) average distance ≥8.8 Å]. Docking studies were performed, starting from the representative conformations obtained from the MC/SD simulations and taking as a reference model the crystal structure of the extracellular segment of integrin α(v)β(3) complexed with the cyclic pentapeptide, Cilengitide. The highest affinity ligands produced top-ranked poses conserving all the important interactions of the X-ray complex.
Cyclic RGD-containing functionalized azabicycloalkane peptides were synthesized with the aim of developing high-affinity selective integrin ligands as carriers for therapeutic and diagnostic purposes. Herein we describe the synthesis and in vitro screening of these RGD derivatives, as well as the determination of their conformational properties in solution by spectroscopic and computational methods. Docking studies with the X-ray crystal structure of the extracellular domain of integrin alpha(v)beta(3) were also performed to elucidate the structural binding requirements and to rationalize the biological results. One compound in particular was found to be the best alpha(v)beta(3) integrin binder (IC(50)=53.7 nM) among the new functionalized RGD cyclic peptides, thus emerging as a promising candidate for covalent bonding and selective homing of useful functional units.
A molecular scaffold was identified which enables the establishment of intramolecular interactions between a monosaccharide and a nearby phenyl ring. A group of molecules containing four different monosaccharides (glucose, galactose, N-acetyl-glucosamine, and N-acetyl-galactosamine) was synthesized and used to investigate the extent and nature of this carbohydrate-arene interaction, as well as the effect on the overall 3D structure of the molecules involved. The sugar-aromatic distance was evaluated by rigorous NMR studies supported by molecular modeling and found to be constant throughout the series, independent of the nature of the sugar and of the conformational behavior of the fragment connecting the two elements. Ab initio calculations at the B3LYP/DZV(2d,p) level of theory enable the analysis of the electronic nature of the interaction. The study shows that, given the opportunity, persistent intramolecular aromatic-sugar interactions can be established and can significantly influence overall molecular shape and energetics. These results have important implications in the design of structural mimics of oligosaccharides.
The design and synthesis of two GM1 glycomimetics, 6 and 7, and analysis of their conformation in the free state and when complexed to cholera toxin is described. These compounds, which include an (R)-cyclohexyllactic acid and an (R)-phenyllactic acid fragment, respectively, display significant affinity for cholera toxin. A detailed NMR spectroscopy study of the toxin/glycomimetic complexes, assisted by molecular modeling techniques, has allowed their interactions with the toxin to be explained at the atomic level. It is shown that intramolecular van der Waals and CH-pi carbohydrate-aromatic interactions define the conformational properties of 7, which adopts a three-dimensional structure significantly preorganized for proper interaction with the toxin. The exploitation of this kind of sugar-aromatic interaction, which is very well described in the context of carbohydrate/protein complexes, may open new avenues for the rational design of sugar mimics.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.