Innovative Multipodal Ligands Derived from Tröger's Bases for the Sensitization of Lanthanide(III) Luminescence.

Herein, the synthesis and characterization of the first family of multipodal ligands with a Tröger's base framework designed for the preparation of luminescent lanthanide(III) complexes are reported. Eight ligands were designed and synthesized using different strategies, including alkylation reactions, amide couplings, and Ugi multicomponent reactions. All the ligands bear carboxylate groups for the coordination of the lanthanide(III) ions, with the lanthanide(III)-sensitizing units consisting of the Tröger's base framework itself or attached benzamides. Upon irradiation of the chromophoric ligands, green terbium(III) emission was efficiently generated, whereas europium(III) emission was negligible. The geometry and substitution pattern of the ligands allow control of the stoichiometry of the species formed and the TbIII luminescence sensitization efficiency, showing that para-substitution patterns are more efficient than meta substitution for the formation of coordination compounds with lower TbIII /ligand ratio. We propose that the species formed are self-assembled 2:2 or 2:4 metallosupramolecular structures.

A Six-Armed Phenhomazine Ligand with a Potential "Turn-Off" Copper(II) Sensing Capability through Terbium(III) Luminescence Quenching.

Herein, the design, synthesis, and characterization of a phenhomazine ligand are described. The ligand has six pendant acetate arms designed for the combined coordination of copper(II) and lanthanide(III) ions, with the perspective of developing a "turn-off" copper sensor. The key step for the ligand preparation was the one-step endomethylene bridge fission of a diamino Tröger's base with a concomitant alkylation. Fluorescence and absorption spectroscopies as well as nuclear magnetic resonance (NMR) experiments were performed to analyze and understand the coordination properties of the ligand. Transition metal coordination was driven by the synergistic effect of the free nitrogen atoms of the diazocinic core and the two central acetate arms attached to those nitrogen atoms, whereas lanthanide coordination is performed by the external acetate arms, presumably forming a self-assembled 2:2 metallosupramolecular structure. The terbium complex shows the typical green emission with narrow bands and long luminescence lifetimes. The luminescence quenching produced by the presence of copper(II) ions was analyzed. This work sets, therefore, a starting point for the development of a phenhomazine-based "turn-off" copper(II) sensor.

In vitro antiviral activity of dehydroepiandrosterone, 17 synthetic analogs and ERK modulators against herpes simplex virus type 1.

In the present study the in vitro antiviral activity of dehydroepiandrosterone (DHEA) and 17 synthetic derivatives against herpes simplex type 1 (HSV-1) was determined. DHEA, epiandrosterone (EA), two synthetic DHEA analogs and three synthetic EA analogs showed a selective inhibitory effect on HSV in vitro multiplication. DHEA and E2, a synthetic derivative of EA, were not found to be virucidal to cell-free HSV-1 and did not impair virus adsorption or penetration. We determined that treatment with both compounds decreased viral protein synthesis. Moreover, inhibitory effect of DHEA and E2 on extracellular viral titer was stronger than the inhibition found on total viral infectivity, suggesting that the antiherpetic activity of these compounds may also be in part due to an inhibition in virus formation and release. Since DHEA is a known Raf/MEK/ERK signaling pathway activator, we studied the role of this pathway on HSV-1 infection. ERK1/2 phosphorylation was stimulated in HSV-1 infected cultures. UO126, a Raf/MEK/ERK signaling pathway inhibitor, impaired viral multiplication, while anisomycin, an activator of this pathway, enhanced it. Treatment with DHEA 6 h before infection enhanced HSV-1 multiplication. On the contrary, pre-treatment with E2, which does not modulate Raf/MEK/ERK signaling pathway, did not produce an increase of viral replication. Taking together these results, the antiviral activity of DHEA seems to occur via a mechanism independent of its ability to modulate ERK phosphorylation.

Anti-adenovirus activity of epiandrosterone and dehydroepiandrosterone derivatives.

BACKGROUND: Dehydroepiandrosterone (DHEA) exhibits a wide range of biological functions including antiviral activity. In this work, we present in vitro anti-adenovirus (AdV) activity of seven DHEA and twelve epiandrosterone (EA) analogues. METHODS: The cytotoxic effect of the compounds was determined by the MTT assay and the antiviral activity by a virus yield inhibition assay. The mode of antiviral activity was examined using time-of-addition experiments, adsorption and internalization assays and Western blot analysis. RESULTS: EA, DHEA, and two synthetic derivatives inhibit virus replication with selectivity indices ranging between 42 and 83. Virus adsorption and internalization are not the target of the inhibitory action; meanwhile, AdV protein synthesis was diminished in the presence of DHEA. CONCLUSIONS: DHEA and some synthetic derivatives present antiviral activity similar to cidofovir, which was used as reference drug. These steroidal compounds adversely affect virus protein synthesis and viral mature particle formation.

In vitro antiviral activity of dehydroepiandrosterone and its synthetic derivatives against vesicular stomatitis virus.

In this work the antiviral activity of 20 dehydroepiandrosterone (DHEA) analogs with different substituents at positions C-3, C-15, C-16 and C-17 were evaluated against vesicular stomatitis virus (VSV) in Vero cell cultures. The selectivity indexes (SI) obtained with DHEA and epiandrosterone (EA) were 50 and 72.6, respectively. The work showed that the compounds 21-norpregna-5,17(20)-dien-3beta,16alpha-diyl-diacetate, 17,17-ethylendioxyandrostan-5,15-dien-3beta-ol and 3beta-hydroxypregn-17(20)-en-16-one had higher SI values than ribavirin, which was used as a reference drug. The antiviral mode of action of DHEA was also investigated against VSV replication in Vero cells, and time of addition experiments showed that DHEA mainly affected a late event in the virus growth cycle. Analysis of RNA and protein synthesis indicated that DHEA adversely affected positive strand RNA synthesis and viral mature particle formation.

Synthesis of 4-azasteroids by an intramolecular Ugi reaction.

In this paper we report the use of an intramolecular Ugi reaction to synthesize new 4-azacholestanes diversely substituted both at N-4 and C-5. Both the scope and the stereochemical outcome of this approach were studied by varying the nature of the components necessary for this multicomponent reaction. In sight of our results we concluded that this methodology can be applied to obtain 4-azasteroids targeted to find new biologically active compounds.

Dehydroepiandrosterone, epiandrosterone and synthetic derivatives inhibit Junin virus replication in vitro.

In the present paper the in vitro antiviral activity of dehydroepiandrosterone (DHEA), epiandrosterone (EA) and 16 synthetic derivatives against Junin virus (JUNV) replication in Vero cells was studied. DHEA and EA caused a selective inhibition of the replication of JUNV and other members of the Arenaviridae family such as Pichinde virus and Tacaribe virus. The compounds were not virucidal to cell-free JUNV. The impairment of viral replication was not due to an inhibitory effect of the steroids on virus adsorption or internalization. An inhibitory effect of the compounds on JUNV protein synthesis and both intracellular and extracellular virus production was demonstrated. A partial inhibitory action on cell surface expression of JUNV glycoprotein G1 was also detected on DHEA- and EA-treated cultures. Like DHEA and EA, three compounds obtained from EA by chemical synthesis showed selectivity indexes higher than ribavirin, the only antiviral compound that has shown partial efficacy against arenavirus infections.

Syntheses of immunomodulating androstanes and stigmastanes: comparison of their TNF-alpha inhibitory activity.

In a previous work our group showed that some synthetic stigmastanes may play a role in immune-mediated inflammation. In this paper we report the syntheses of a series of new steroidal compounds derived from dehydroepiandrosterone and stigmasterol, and the evaluation of their in vitro inhibitory activity of the TNF-alpha production by macrophages. A preliminary qualitative structure-activity relationship was established.