Iron Trichloride-Mediated Cascade Reaction of Aminosugar Derivatives for the Synthesis of Fused Tetrahydroisoquinoline-Tetrahydrofuran Systems.

A method to obtain tetrahydroisoquinolines (THIQs) fused to tetrahydrofuran rings from aminosugar derivatives has been developed. The procedure relies on a key deprotection of benzyl ethers followed by a double-cyclization sequence, using FeCl3 as the sole reagent. This tandem reaction affords the construction of novel fused polycyclic heterocycles with total stereochemical control.

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

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.

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

A series of alkyl α/ß-(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 ß-(1→6)-diglucopyranoside 5 induces apoptotic cell death in human leukemia cells through a mechanism that involves activation of multiple caspases. Cell death was completely prevented by the non-specific caspase inhibitor z-VAD-fmk and found to be associated with the release of cytochrome c, an increase in the expression of Bax levels and a decrease in the generation of reactive oxygen species.

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-ß-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. This result confirms that endocyclic oxygen is necessary for the observed relationship between the structure of the aglycon and the rotational populations of the hydroxymethyl group, and indicates that the stereoelectronic exo-anomeric effect is mainly responsible for such conformational dependence.

Stereochemical properties of glucosyl sulfoxides in solution.

A series of alkyl ß-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.

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-ß-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.

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 (1.6 microM). Some preliminary structure-activity relationships were established.

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. Preliminary structure-activity relationships were established.

Stereospecific Synthesis of 1,6-Dioxadecalins and 2,2'-Linked Ditetrahydrofurans by Rearrangement of Steroidal Spiroacetals.

The reduction of steroidal spiroacetal methanesulfonate derivatives, containing the 1,6-dioxaspiro[4.5]decan-10-yl ring system, with DIBALH promotes a new rearrangement to give steroidal 1,6-dioxadecalin (octahydropyrano[3,2-b]pyran) or 2,2'-linked ditetrahydrofuran (octahydro[2,2']bifuranyl) derivatives. To study the scope and selectivity of the reaction, several steroidal spiroacetals such as (23R,25R)-3beta-methoxy-5alpha-spirostan-23-yl methanesulfonate (2) and its 23S-isomer (5) and (22R,23R,25R)-3beta-acetoxy-16beta,23:23,26-diepoxycholest-5-en-22-yl methanesulfonate (15) and its 22S-isomer (19) have been synthesized. Compound 2 was rearranged with absolute regio- and stereoselectivity to give (22S,23S,25R)-3beta-methoxy-16beta,23:22,26-diepoxy-5alpha-cholestane (3) which possesses a cis-fused 1,6-dioxadecalin ring system. The reaction of compound 5 gave exclusively (22S,23R,25R)-3beta-methoxy-23,26-epoxy-5alpha-furostane (6) in which the spiroacetal was converted into a ditetrahydrofuran subunit. The two other isomeric spiroacetals 15 and 19 were also mainly transformed into (22S,23S,25R)-3beta-acetoxy-16beta,23:22,26-diepoxycholest-5-ene (16) and (22R,23R,25R)-3beta-acetoxy-23,26-epoxyfurost-5-ene (20), respectively. A mechanism is proposed to explain the regio- and sterospecificity observed in the rearrangement.