Elena Gómez

Pyrano(3,2-c)quinoline-6-Chlorotacrine Hybrids as a Novel Family of Acetylcholinesterase- and β-Amyloid-Directed Anti-Alzheimer Compounds

Two isomeric series of dual binding site acetylcholinesterase (AChE) inhibitors have been designed, synthesized, and tested for their ability to inhibit AChE, butyrylcholinesterase, AChE-induced and self-induced beta-amyloid (Abeta) aggregation, and beta-secretase (BACE-1) and to cross blood-brain barrier. The new hybrids consist of a unit of 6-chlorotacrine and a multicomponent reaction-derived pyrano[3,2-c]quinoline scaffold as the active-site and peripheral-site interacting moieties, respectively, connected through an oligomethylene linker containing an amido group at variable position. Indeed, molecular modeling and kinetic studies have confirmed the dual site binding of these compounds. The new hybrids, and particularly 27, retain the potent and selective human AChE inhibitory activity of the parent 6-chlorotacrine while exhibiting a significant in vitro inhibitory activity toward the AChE-induced and self-induced Abeta aggregation and toward BACE-1, as well as ability to enter the central nervous system, which makes them promising anti-Alzheimer lead compounds.

Tacrine-based dual binding site acetylcholinesterase inhibitors as potential disease-modifying anti-Alzheimer drug candidates.

Two novel families of dual binding site acetylcholinesterase (AChE) inhibitors have been developed, consisting of a tacrine or 6-chlorotacrine unit as the active site interacting moiety, either the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone fragment of donepezil (or the indane derivative thereof) or a 5-phenylpyrano[3,2-c]quinoline system, reminiscent to the tryciclic core of propidium, as the peripheral site interacting unit, and a linker of suitable length as to allow the simultaneous binding at both sites. These hybrid compounds are all potent and selective inhibitors of human AChE, and more interestingly, are able to interfere in vitro both formation and aggregation of the beta-amyloid peptide, the latter effects endowing these compounds with the potential to modify Alzheimers disease progression.

Homocysteine and other plasma amino acids in preeclampsia and in pregnancies without complications

OBJECTIVES To evaluate a). the plasma amino acid changes observed in pregnant women (n = 124) and b). the homocysteine and other amino acid changes in preeclampsic patients (n = 18), and to determine c) whether these changes were also evident in nonpregnant women with a prior history of preeclampsia (n = 18). DESIGN AND METHODS Case-control study. Plasma total homocysteine (tHcy): HPLC with fluorescence detection, and amino acids (AA): ion exchange chromatography. RESULTS a). Significantly lower absolute AA values were observed in the pregnant controls for homocysteine, total, essential, and nonessential AA compared with nonpregnant controls. b. In preeclampsia, significantly higher absolute values of tHcy, total, essential and nonessential AA were observed, but relative values referred to total AA were not different. These changes corrected after delivery. CONCLUSIONS Hyperhomocysteinemia and an increase in most AA levels were observed in preeclampsia. Relative AA values suggested that these changes might be explained by fluctuations in plasma volume. Abnormal AA levels corrected after delivery.

Benzimidazolium Salts as Small, Nonpeptidic and BBB-Permeable Human Prolyl Oligopeptidase Inhibitors

Prolyl oligopeptidase (POP) is a cytosolic serine peptidase that hydrolyzes proline‐containing peptides at the carboxy terminus of proline residues. This peptidase has gained importance as a target for the treatment of cognitive disturbances of patients with neuropsychiatric diseases. Our research addresses the identification of POP inhibitors from a small focused library of polar heterocyclic compounds arising from multicomponent reactions. Two selective POP‐specific inhibitors were identified on the basis of their inhibition of dipeptidyl peptidase IV. The most active compounds were evaluated for their in vitro transport through the blood–brain barrier (BBB) using a parallel artificial membrane permeability assay. Our results show for the first time that benzimidazolium salts are new POP‐inhibitory scaffolds with properties of solubility, specificity, and lipophilicity that may allow them to cross the BBB by passive diffusion. These findings constitute an excellent starting point to synthesize new POP inhibitors with enhanced properties.

Synthesis of diastereomeric 13-amido-substituted huprines as potential high affinity acetylcholinesterase inhibitors

Two diastereomeric huprines additionally functionalized at position 13 with a methanesulfonamido group have been synthesized in seven steps from the known 9,9-ethylenedioxybicyclo[3.3.1]nonane-3,7-dione (5). In a key-step, nickel boride non-stereoselective reduction of an oxime gave a mixture of amines which was separated as methanesulfonamido derivatives. The substitution pattern of these huprines could lead to an extended binding near the active site of acetylcholinesterase (AChE), and consequently to improved AChE inhibitors.

On the regioselectivity of the Friedländer reaction leading to huprines: stereospecific acid-promoted isomerization of syn-huprines to their anti-regioisomers

Abstract Racemic 12-amino-6,7,8,11-tetrahydro-7,11-methanocycloocta[ b ]quinoline derivatives ( syn -huprines) substituted at the 9-position with a methyl or ethyl group, and both enantioenriched forms of the 9-ethyl derivative, obtained by chiral MPLC resolution of the racemic mixture, were readily converted to the corresponding anti -isomers (huprines) by stereospecific acid-promoted (AlCl 3 or triflic acid) isomerization of the endocyclic CC double bond from the 9(10)- to the 8(9)-position. These results support the hypothesis that the hitherto unseen syn -huprines are also formed under the usual acidic Friedlander reaction conditions used to prepare the known huprines, but rearrange in situ to the more stable anti -regioisomers (B3LYP/6-31G*).

Eina per a l'elaboració del TFG en un entorn estadístic mitjançant Moodle ("book")

El objetivo del articulo es presentar un trabajo de innovacion docente, realizado por un grupo de profesores del Departamento de Econometria, Estadistica y Economia Aplicada de la Facultad de Economia y Empresa de la UB ( DOI: 10.1344/401.000002955 ), consistente en la produccion de un libro de Moodle para dar soporte a aquellos estudiantes de A.D.E. (Administracion y Direccion de Empresas) que se enfrentan, al final de sus estudios, al reto de realizar su TFG (Trabajo de Fin de Grado). Esta especialmente disenado para aquellos que tienen pensado realizar un TFG en el que las tecnicas estadisticas vayan a tener un papel relevante en el contenido de su estudio. Efectivamente, constatada la falta de conocimientos que manifiestan muchos de estos estudiantes sobre el proceso a seguir a la hora de elaborar un trabajo de investigacion de una cierta entidad, como lo es el TFG, y la ansiedad que esa situacion les genera, se decidio producir este recurso docente , accesible sin coste desde la plataforma Moodle con la que los estudiantes ya estan familiarizados y que, ademas, tiene la ventaja anadida de disponer de una serie de herramientas auxiliares interesantes que pueden potenciar aun mas la utilidad del material. El libro viene a ser un manual, que se pretendio conciso y practico, para resolver airosamente la cuestion del TFG de principio a fin: desde la produccion de la idea clave del trabajo (desde la definicion del tema), pasando por la generacion/recogida de datos y su posterior analisis, y por la imprescindible extraccion de conclusiones, hasta la etapa final de redaccion de la memoria y presentacion publica del trabajo que implica tambien la confeccion de un poster. De forma paralela al libro se elaboraron una serie de cuestionarios para medir: i) los conocimientos previos de los estudiantes sobre el tema, ii) los conocimientos adquiridos tras el uso del material y iii) la valoracion por parte de los estudiantes del recurso. Sin embargo, todavia no es posible evaluar en que medida la herramienta ha sido util a aquellos para la que se creo: el periodo docente 2017-2018, es el primer curso academico en que se pone el material a disposicion del alumnado. A final de curso sera posible realizar ya un primer analisis de los datos proporcionados por esos cuestionarios.