Conformational Properties of Aryl -Glucosides in Solution.

The conformational study of saccharides and glycomimetics in solution is critical for a comprehensive understanding of their interactions with biological receptors and enabling the design of optimized glycomimetics. Here, we report a nuclear magnetic resonance (NMR) study centered on the conformational properties of the hydroxymethyl group and glycosidic bond of four series of aryl -glucosides. We found that in acetyl-protected and free aryl -β-glucosides, the rotational equilibrium around the C5-C6 bond (hydroxymethyl group) exhibits a linear dependence on the electronic properties of the aglycone, namely, as the aryl's substituent electron-withdrawing character increases, the dominance of the rotamer declines and the contribution rises.

Influence of the / configuration on the supramolecular aggregation of aryltriazoles.

The ability of - and -1,2-glucopyranosyl and cyclohexyl ditriazoles, synthesized by CuAAC "click" chemistry, to form gels was studied, their physical properties determined, and the self-aggregation behavior investigated by SEM, X-ray, and EDC studies. The results revealed that self-assembly was driven mainly by π-π stacking interactions, in addition to hydrogen bonding, with the aromatic rings adopting a high degree of parallelism, as seen in crystal packings and ECD data. Furthermore, π-bromine interactions between the bromine atom of the aryl substituents and the triazole units might also contribute to an overall stabilization of the supramolecular aggregation of bis(4-bromophenyl)triazoles.

Absolute Configuration of Dihydro-β-agarofuran Sesquiterpenes from Maytenus jelskii and Their Potential Antitumor-Promoting Effects.

Chemoprevention of human cancer appears to be a feasible strategy for cancer control, especially when chemopreventive intervention is involved during early stages of the carcinogenesis process. As a part of our ongoing research program into new chemopreventive agents, herein are reported the isolation, structural elucidation, and biological evaluation of 10 new (1-10) and three known (11-13) sesquiterpenes with a dihydro-β-agarofuran skeleton from the leaves of Maytenus jelskii Zahlbr. Their stereostructures have been elucidated by means of spectroscopic analysis, including 1D and 2D NMR techniques, ECD studies, and biogenetic considerations.

Synthetic menthyl α/β-(1→6)-diglucopyranosides-induced cell death in human leukemia cells is dependent on caspases.

A series of alkyl α/β-(1→6)-diglucopyranosides 1-12 were synthesized and assessed for cytotoxicity against HL-60, U937, Molt-3 and MCF-7 cancer cell lines. The menthyl derivatives displayed strong cytotoxic properties showing IC(50) values between 6 and 16 μM. Furthermore, we demonstrated that the selected synthetic (+)-menthyl β-(1→6)-diglucopyranoside 5 induces apoptotic cell death in human leukemia cells through a mechanism that involves activation of multiple caspases.

Comparison of the conformational properties of carbasugars and glycosides: the role of the endocyclic oxygen.

A series of carbasugars were prepared and their conformational properties studied by means of NMR spectroscopy. The results were compared to those previously found for O-, S-, and C-β-glycoside analogs. While the rotational populations of the hydroxymethyl group in O-, S-, and C-glycosides are known to depend on the structural nature of their aglycon, in carbasugars it proved to be independent of the pseudo-aglycon.

Stereochemical properties of glucosyl sulfoxides in solution.

A series of alkyl β-glucosyl sulfoxides were synthesized and characterized in order to study their stereochemical properties. The dependence of the aglycon, solvent and absolute configuration of the sulfinyl group on the conformational properties around the glucosidic and C5-C6 (hydroxymethyl group) bonds were studied. The results for R(S) sulfoxides show linear correlations between the rotamer populations of the hydroxymethyl group and the corresponding Taft's steric parameter (E(S)) of the alkyl group attached to the sulfinyl group in polar and apolar solvents, an increase in the absolute value of E(S) leading to an increase in the gt population.

Synthesis, biological evaluation and structural characterization of novel glycopeptide analogues of nociceptin N/OFQ.

To examine if the biological activity of the N/OFQ peptide, which is the native ligand of the pain-related and viable drug target NOP receptor, could be modulated by glycosylation and if such effects could be conformationally related, we have synthesized three N/OFQ glycopeptide analogues, namely: [Thr(5)-O-α-D-GalNAc-N/OFQ] (glycopeptide 1), [Ser(10)-O-α-D-GalNAc]-N/OFQ (glycopeptide 2) and [Ser(10)-O-β-D-GlcNAc]-N/OFQ] (glycopeptide 3). They were tested for biological activity in competition binding assays using the zebrafish animal model in which glycopeptide 2 exhibited a slightly improved binding affinity, whereas glycopeptide 1 showed a remarkably reduced binding affinity compared to the parent compound and glycopeptide 3. The structural analysis of these glycopeptides and the parent N/OFQ peptide by NMR and circular dichroism indicated that their aqueous solutions are mainly populated by random coil conformers.

Withanolides from Withania aristata and their cytotoxic activity.

Seven new withanolides (1-7), along with three known ones (8-10), were isolated from the leaves of Withania aristata. Their structures were elucidated on the basis of spectroscopic analysis, including 2D NMR experiments and spectrometric techniques, and the absolute configuration of 1 and 2 was established by CD analysis. In the search for new cytotoxic compounds from Withania species, the isolated compounds 1-9, along with two derivatives, were assayed for their cytotoxicity against HeLa, MCF-7 and A-549 human tumor cell lines.

Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors.

The thyroid hormone and retinol transporter protein known as transthyretin (TTR) is in the origin of one of the 20 or so known amyloid diseases. TTR self assembles as a homotetramer leaving a central hydrophobic channel with two symmetrical binding sites. The aggregation pathway of TTR into amiloid fibrils is not yet well characterized but in vitro binding of thyroid hormones and other small organic molecules to TTR binding channel results in tetramer stabilization which prevents amyloid formation in an extent which is proportional to the binding constant.

Conformational domino effect in saccharides. 2. Anomeric configuration control.

A series of alkyl beta-D-glucopyranosyl-(1-->6)-alpha-D-glucopyranosides were synthesized and analyzed by NMR and CD techniques. As in their beta-anomer series, the rotational populations of the hydroxymethyl group involved in the interglycosidic linkage (torsion angle omega) are shown to depend on the aglycon and the solvent. However, for this alpha-anomer series the rotational dependence arises directly from steric effects.

Conformational domino effect in saccharides: a prediction from alkyl beta-(1-->6)-diglucopyranosides.

A series of alkyl beta-D-glucopyranosyl-(1-->6)-beta-D-glucopyranosides, containing nonchiral and chiral aglycons, were synthesized and analyzed by NMR and CD. The results, collected from four sets of disaccharides, demonstrated that the rotational properties of the interglycosidic linkage depend on the structural natures of both the aglycon and the solvent. Stereoelectronic and steric factors explain this rotational dependence, the gauche- trans (gt) rotamer being the most stable.

Cytotoxic effects of C-glycosides in HOS and HeLa cell lines.

Fifty-two C-glycosides were synthesized and their in-vitro antiproliferative activity screened against human cervical carcinoma (HeLa) and osteosarcoma (HOS) cell lines. Nine of them had growth inhibitions (GI(50) values) below 10 microM, the C-glucopyranoside 38 being the most active against HeLa (5.4 microM) and the dichlorocyclopropyl derivative 42 against HOS (1.

Antiproliferation and apoptosis induced by C-glycosides in human leukemia cancer cells.

A large series of alkyl C-glycosides was synthesized from D-glucal or D-galactal. These compounds were screened against the human promyelocytic leukemia cell line (HL60), showing significant activity and apoptosis. Up to 13 C-glucopyranosides, but no C-galacto- or C-mannopyranosides, exhibited inhibitory concentrations (IC(50) values) below 20 microM, five of them in the range 4-8 microM.

Hydroxymethyl rotamer populations in disaccharides.

Sixteen methyl glucopyranosyl glucopyranoside disaccharides (methyl beta-d-Glcp(p-Br-Bz)-(1-->x)-beta/alpha-d-Glcp) containing beta-glycosidic linkages (1-->2, 1-->3, 1-->4, and 1-->6) were synthesized and analyzed by means of CD and NMR spectroscopy in three different solvents. For each of these four types of disaccharides, a correlation was observed between the hydroxymethyl rotational populations around the C5-C6 bond of the glucopyranosyl residue II with the substituents and the anomeric configuration of the methoxyl group in residue I, as well as with the solvent. Nonbonded interactions, the stereoelectronic exo-anomeric effect, and hydrogen bonding were found to be responsible for the observed rotameric differences.

Supramolecular helical stacking of metallomesogens derived from enantiopure and racemic polycatenar oxazolines.

The present report undertakes a challenge of general interest in supramolecular chemistry: the achievement of helical organizations with controlled structure. To achieve this target we considered the possibility of inducing supramolecular chirality using molecules that were designed to organize into columnar mesophases. The use of oxazoline-derived ligands and metal coordination served as tools to prepare molecules with a phasmidic-like structure, which show columnar organization in the liquid crystalline state.