Jesus Trujillo Vazquez

The conformational properties of ester-protected alkyl glucosyl sulfones were studied by means of nuclear magnetic resonance (NMR) and circular dichroism (CD). The equilibrium about the C5–C6 rotational axis (hydroxymethyl group) in polar and apolar media is distributed between the gg and gt rotamers, and the equilibrium contributions of each rotamer are modulated by the steric properties of the aglycone, where an increment in the alkyl substituent's bulkiness leads to progressive increments in gt contributions at the expense of gg. The equilibrium about the glycosidic bond is also dependent on the aglycone's bulkiness and appears more sensitive to the media polarity. Glucosyl sulfones carrying small aglycones, e.g, those substituted with methyl and ethyl groups, show a ϕ torsion predominated by the g+ conformer in apolar media (C₆D₆) and distributed between g− and g+ conformers in a polar solvent (CD₃CN). Compounds substituted with larger alkyl groups, such as iso-propyl and tert-butyl groups, show glycosidic bond conformations predominated by the g− conformer.

The ability of trans- and cis-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. The trans or cis spatial disposition of the triazole rings is highly important for gelation, with the cis configuration having higher propensity.

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. The isolated metabolites and eight previously reported sesquiterpenes (14–21) were screened for their antitumor-promoting activity using a short-term in vitro assay for Epstein–Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Six compounds from this series (4, 5, 11, and 13–15) were found to exhibit higher efficacies than β-carotene, used as reference inhibitor for EBV-EA activation. In particular, promising antitumor activity was observed for compound 5, exhibiting inhibition even at the lowest concentration assayed (10 mol ratio/TPA). Preliminary structure–activity relationship analysis revealed that the acetate, benzoate, and hydroxy groups are the most desirable substituents on the sesquiterpene scaffold for activity in the EBV-EA activation assay.

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. In addition, NOE experiments reveal that as the bulkiness of the alkyl group increases the population of the g– rotamer increases, the latter stabilized by the exo-anomeric effect. These results are in complete agreement with the participation of the exo-anomeric effect in both conformational properties of R_S sulfoxides. Sulfoxides with the S_S configuration show different behavior to their R_S epimers; thus, an increase in the E_S value of the alkyl group leads to similar or lower gt populations in apolar solvents and to increases in gt in polar solvents. Their NOE studies reveal a conformational equilibrium (in polar and apolar solvents) between g– and g+, dependent on the size of the alkyl group R attached to the sulfinyl group. All these results for both epimers support the general hypothesis that the exo-anomeric effect modifies the conformation of the hydroxymethyl group, fulfills the stereoelectronic requirements, and shows dependence on the solvent.

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: [Thr⁵-O-α-D-GalNAc-N/OFQ] (glycopeptide 1), [Ser¹⁰-O-α-D-GalNAc]-N/OFQ (glycopeptide 2) and [Ser¹⁰-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. However, in membrane mimic environments a certain proportion of the molecules of all these peptides exist as α-helix structures. Interestingly, under these experimental conditions, glycopeptide 1 (glycosylated at Thr-5) exhibited a population of folded hairpin-like geometries. From these facts it is tempting to speculate that nociceptin analogues showing linear helical structures are more complementary and thus interact more efficiently with the native NOP receptor than folded structures, since glycopeptide 1 showed a significantly reduced binding affinity for the NOP receptor.