Santiago Vázquez

Exploring the Size Limit of Templates for Inhibitors of the M2 Ion Channel of Influenza A Virus

Amantadine inhibits the M2 proton channel of influenza A virus, yet its clinical use has been limited by the rapid emergence of amantadine-resistant virus strains. We have synthesized and characterized a series of polycyclic compounds designed as ring-contracted or ring-expanded analogues of amantadine. Inhibition of the wild-type (wt) M2 channel and the A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Several bisnoradamantane and noradamantane derivatives inhibited the wt ion channel. The compounds bind to a primary site delineated by Val27, Ala30, and Ser31, though ring expansion restricts the positioning in the binding site. Only the smallest analogue 8 was found to inhibit the S31N mutant ion channel. The structure-activity relationship obtained by TEV assay was confirmed by plaque reduction assays with A/H3N2 influenza virus carrying wt M2 protein.

Easily accessible polycyclic amines that inhibit the wild-type and amantadine-resistant mutants of the M2 channel of influenza A virus

Amantadine inhibits the M2 proton channel of influenza A virus, yet most of the currently circulating strains of the virus carry mutations in the M2 protein that render the virus amantadine-resistant. While most of the research on novel amantadine analogues has revolved around the synthesis of novel adamantane derivatives, we have recently found that other polycyclic scaffolds effectively block the M2 proton channel, including amantadine-resistant mutant channels. In this work, we have synthesized and characterized a series of pyrrolidine derivatives designed as analogues of amantadine. Inhibition of the wild-type M2 channel and the A/M2-S31N, A/M2-V27A, and A/M2-L26F mutant forms of the channel were measured in Xenopus oocytes using two-electrode voltage clamp assays. Most of the novel compounds inhibited the wild-type ion channel in the low micromolar range. Of note, two of the compounds inhibited the amantadine-resistant A/M2-V27A and A/M2-L26F mutant ion channels with submicromolar and low micromolar IC50, respectively. None of the compounds was found to inhibit the S31N mutant ion channel.

3-Azatetracyclo[5.2.1.15,8.01,5]undecane Derivatives: From Wild-Type Inhibitors of the M2 Ion Channel of Influenza A Virus to Derivatives with Potent Activity against the V27A Mutant

We have synthesized and characterized a series of compounds containing the 3-azatetracyclo[5.2.1.1(5,8).0(1,5)]undecane scaffold designed as analogues of amantadine, an inhibitor of the M2 proton channel of influenza A virus. Inhibition of the wild-type (WT) M2 channel and the amantadine-resistant A/M2-S31N and A/M2-V27A mutant ion channels were measured in Xenopus oocytes using two-electrode voltage clamp (TEV) assays. Most of the novel compounds inhibited the WT ion channel in the low micromolar range. Of note, several compounds inhibited the A/M2 V27A mutant ion channel, one of them with submicromolar IC50. None of the compounds was found to inhibit the S31N mutant ion channel. The antiviral activity of three novel dual WT and A/M2-V27A channels inhibitors was confirmed by influenza virus yield assays.

External validation of a prognostic model for predicting survival of cirrhotic patients with refractory ascites

OBJECTIVE:Cirrhotic patients with refractory ascites (RA) have a poor prognosis, although individual survival varies greatly. A model that could predict survival for patients with RA would be helpful in planning treatment. Moreover, in cases of potential liver transplantation, a model of these characteristics would provide the bases for establishing priorities of organ allocation and the selection of patients for a living donor graft. Recently, we developed a model to predict survival of patients with RA. The aim of this study was to establish its generalizability for predicting the survival of patients with RA.METHODS:The model was validated by assessing its performance in an external cohort of patients with RA included in a multicenter, randomized, controlled trial that compared large-volume paracentesis and peritoneovenous shunt. The values for actual and model-predicted survival of three risk groups of patients, established according to the model, were compared graphically and by means of the one-sample log-rank test.RESULTS:The model provided a very good fit to the survival data of the three risk groups in the validation cohort. We also found good agreement between the survival predicted from the model and the observed survival when patients treated with peritoneovenous shunt and with paracentesis were considered separately.CONCLUSION:Our survival model can be used to predict the survival of patients with RA and may be a useful tool in clinical decision making, especially in deciding priority for liver transplantation.

Synthesis, chemical trapping and dimerization of tricyclo[3.3.0.03,7]oct-1(5)-ene, the consummate member of a series of pyramidalized alkenes

The synthesis of tricyclo[3.3.0.03,7]oct-1(5)-ene, 5, the consummate member of a series of pyramidalized alkenes, has been carried out by deiodination of 4 in different ways. Reaction of 4 with sodium in boiling dioxane gave in good yield diene 8, whose formation can be easily explained through the intermediacy of 5 and its cyclobutane dimer 6. Reaction of 4 with t-butyllithium in THF at −78 °C in the presence of 1,3-diphenylisobenzofurane gave 10, a Diels-Alder adduct derived from 5.

Synthesis and pharmacological evaluation of several ring-contracted amantadine analogs

Abstract The synthesis of several (3-noradamantyl)amines, [(3-noradamantyl)methyl]amines, (3,7-dimethyl-1-bisnoradamantyl)amines, and [(3,7-dimethyl-1-bisnoradamantyl)methyl]amines is reported. They were evaluated against a wide range of viruses and one of them inhibited the cytopathicity of influenza A virus at a concentration similar to that of amantadine. Several of the new polycyclic amines show an interesting activity as NMDA receptor antagonists. A rimantadine analogue displayed significant trypanocidal activity. Moreover, to further characterize the pharmacology of these compounds, their effects on dopamine uptake were also assessed.

A concise approach to the preparation of 2-hydroxydiarylketones by an intramolecular acyl radical ipso substitution☆

Abstract Substituted 2-hydroxydiarylketones have been simply prepared using an intramolecular acyl radical [1,6] ipso substitution reaction.

Low temperature X-ray diffraction analysis of 4,5,10,11-tetramethyl-heptacyclo[8.2.1.12,5.14,7.18,11.01,8.02,7]hexadecane: DSC, MM2 and 1H NMR study of its [2 + 2]retrocycloaddition to an isomeric diene

Abstract The synthesis of pure 3 has been achieved by deiodination of 1 with NaK alloy at r.t. and by [2+2] photocyclization of diene 4 . X-ray diffraction analysis at −30°C of the thermally unstable 3 shows the cyclobutane ring to be highly rectangular with large central and short lateral bonds. Also, the C4C5 and C10C11 bonds in 3 and diene 4 are very large. A clear neat DSC conversion of 3 to 4 allowed us to obtain the ΔH and the Ea values for this transformation. ΔH is in good agreement with MM2 calculations, while Ea compares well with kinetic measurements in CDCl 3 solution.

Synthesis and Anti-influenza A Virus Activity of 2,2-Dialkylamantadines and Related Compounds.

The synthesis of several 2,2-dialkyladamantyl-1-amines through the combination of a Ritter reaction with a Wagner-Meerwein rearrangement from noradamantane alcohols is reported. Several of the novel amines displayed low micromolar activities against several H1N1 influenza virus strains, including the amantadine-resistant A/PuertoRico/8/34 strain. Most of the compounds did not show cytotoxicity for MDCK cells.

Role of the viral hemagglutinin in the anti-influenza virus activity of newly synthesized polycyclic amine compounds.

Abstract We here report on the synthesis of new series of polycyclic amines initially designed as ring-rearranged analogs of amantadine and featuring pentacyclo, hexacyclo, and octacyclo rings. A secondary amine, 3-azahexacyclo[7.6.0.01,5.05,12.06,10.011,15]pentadeca-7,13-diene, 3, effectively inhibited A/M2 proton channel function, and, moreover, possessed dual activity against an A/H3N2 virus carrying a wild-type A/M2 proton channel, as well as an amantadine-resistant A/H1N1 virus. Among the polycyclic amines that did not inhibit influenza A/M2 proton channel function, several showed low-micromolar activity against tested A/H1N1 strains (in particular, the A/PR/8/34 strain), but not A/H3N2 influenza viruses. A/PR/8/34 mutants selected for resistance to these compounds possessed mutations in the viral hemagglutinin that markedly increased the hemolysis pH. Our data suggest that A/H1N1 viruses such as the A/PR/8/34 strain are particularly sensitive to a subtle increase in the endosomal pH, as caused by the polycyclic amine compounds.