Enantiospecific synthesis of heterocycles linked to purines: different apoptosis modulation of enantiomers in breast cancer cells.

The issue of chiral drug is now a major theme in the design, discovery and development of new drugs. It has been shown for many pharmaceuticals that only one enantiomer contains the desired activity, and the synthesis of such drug molecules in their optically pure form is becoming increasingly important. Mitsunobu reaction was carried out between (R)- and (S)-3,4-dihydro-2H-1,5-benzoxathiepin-3-ol and purines under microwave irradiation. A contraction into a six-membered ring takes place with concomitant inversion at the stereocentre with excellent enatiomeric excesses giving rise to the homochiral 9-(2,3-dihydro-1,4-benzoxathiin-3-ylmethyl)-9H-purines. The anti-tumour activity of all enantiomers is reported against the caspase-3-deficient MCF-7 and the wild type SKBR-3 human breast cancer cells. The most active homochiral compound displays an IC50 of 1.85 µM and induces inhibition of the translation initiation factor eIF2α. All homochiral compounds included in this study show different apoptotic effects between both enantiomers with levels up to 99%. We have analyzed caspase-mediated apoptotic pathways on enantiomers and racemates. We have found a homochiral derivative that activates the canonical intrinsic caspase-8/caspase-3 apoptotic pathway on the MCF-7 cells, and a racemic compound that induces caspase-2 activation. Moreover, we demonstrate the involvement of caspase activation during cell death induced by these compounds in SKBR-3 cells.

Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors.

The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/Herceptin™ and cetuximab/Erbitux™) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa™ and erlotinib/Tarceva™). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb™), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.

Uso de una aplicación web – SciFinder - como complemento para el desarrollo de la asignatura de Química Orgánica en la Licenciatura de Farmacia / The use of a web application – SciFinder to complement the Organic Chemistry teaching to the student of the Degree in Pharmacy

La necesidad de motivación del alumno, además de la adaptación de la actual enseñanza a los créditosECTS, han sido los motores que nos han llevado a proponer el uso de una aplicación web denominadaSciFinder en la enseñanza de la Química Orgánica. Se trata de una herramienta imprescindible en lainvestigación avanzada que se utiliza en cualquier laboratorio de síntesis química.La Universidad de Granada dispone de una suscripción que permite 6 usos simultáneos a la que elalumno puede acceder a través de un acceso directo a SciFinder on Web en el sólo es necesarioregistrarse como usuario.Permitir al alumno transportarse a un laboratorio virtual es una de las múltiples posibilidades queofrece esta aplicación web ayudándoles a complementar los conocimientos científicos básicos que sehan explicado en clase.Durante el desarrollo de los distintos temas que componen la asignatura se plantearán reaccionesconcretas que el alumno deberá ampliar con la información que esta aplicación les proporciona:reactivos empleados en dichas reaccionescondiciones de reacción (estequiometría, tiempo, temperatura…)bibliografía actual.Al final del curso académico se evaluará esta nueva experiencia mediante encuestas de opinión delalumnado para determinar dos aspectos fundamentales de la misma, el aumento de interés por laasignatura durante el desarrollo del trabajo y la dificultad en la realización del mismo(AU)

The need to motivate the students, besides adapting the teaching to the ECTS credits, have been thedriving force that leads us to propose the use of a web application called Sci Finder in the education ofOrganic Chemistry. It is an essential tool used in any advanced research laboratory of syntheticchemistry.The University of Granada provides a subscription with 6 simultaneous accesses. The students mayaccede directly to the SciFinder on Web being only necessary the registration as users.One of the many possibilities that offers this web application allows to the student be transported to avirtual laboratory and complement the basic scientific knowledge explained in class.During the development of the different topics, specific reactions will be presented to the student andthey may increase the information by using this application:reagents of the reactionsreaction conditions (stoichiometry, time, temperature…)up-to-date bibliographyAt the end of the academic year this new experience will be evaluate through opinion poll to thestudent in order to determinate two essential aspect, the interest increase for the subject during thedevelopment of this work and the difficulty in carrying out it(AU)

Eficacia del topiramato en niños y adolescentes con problemas en el control de los impulsos: resultados preliminares / Efficacy of topiramate in children and adolescent with problems in impulse control: preliminary results

Introducción. Si bien el topiramato en el terreno farmacológico ha mostrado probada eficacia en los trastornos del control de impulsos (TCI), este hecho no ha sido constatado con la misma evidencia en niños y adolescentes. Nuestro objetivo consiste en valorar la mejoría sintomática de diversos TCI en dichas edades tras la introducción del topiramato.Caso clínico. Once casos con TCI (criterios DSM-IV) fueron evaluados mediante la escala de impulsividad de Barrat (EIB) de forma basal y al mes y los 3 meses del inicio de tratamiento con topiramato.Resultados. Encontramos diferencias significativas en la subescala de impulsividad cognitiva (p = 0,040) y en la puntuación global de la EIB (p=0,043) entre la puntuación basal y al mes de tratamiento; a los 3 meses también la subescala de impulsividad motora mostró diferencias significativas con respecto a la basal (p=0,015).Conclusiones. Las reducciones significativas en la puntuación de la EIB en pacientes valorados en consulta de psiquiatría infantojuvenil por TCI bajo criterios consensuados hacen considerar el topiramato un fármaco eficaz en el control de la impulsividad asociada a diversos trastornos psiquiátricos también en niños y adolescentes. Son necesarios más estudios que incluyan un número mayor de casos y con grupo control para confirmar estos resultados

Introduction. Although in the pharmacological field topiramate has shown proved efficacy in impulsive behavioral disorders (IBD), this fact has not been demonstrated with the same evidence in children and adolescents. The aim of this study is to evaluate improvement of symptoms in different IBD in those ages after treatment with topiramate. ;;Clinical case. Eleven cases of IBD (DSM-IV criteria) were evaluated with the Barrat Impulsivity Scale (BIS), obtaining scores at zero, one and three months after starting treatment with topiramate. Results. We found significant differences in the cognitive impulsivity subscale (p=0.040) and total score of the BIS (p=0.043) when BIS scale was measured after one month of treatment; after three months of treatment, the motor impulsivity subscale also showed significant differences (p=0.015). Conclusions. The significant reductions at BIS scores in child and adolescents outpatients who have IBD make us consider topiramate as an effective pharmacological option for treatment of impulsivity in several psychiatric disorders, also in childhood and adolescence. More studies are needed to confirm these results, with bigger samples and control groups

[Efficacy of topiramate in children and adolescent with problems in impulse control: preliminary results]. / Eficacia del topiramato en niños y adolescentes con problemas en el control de los impulsos: resultados preliminares.

INTRODUCTION: Although in the pharmacological field topiramate has shown proved efficacy in impulsive behavioral disorders (IBD), this fact has not been demonstrated with the same evidence in children and adolescents. The aim of this study is to evaluate improvement of symptoms in different IBD in those ages after treatment with topiramate. CLINICAL CASE: Eleven cases of IBD (DSM-IV criteria) were evaluated with the Barrat Impulsivity Scale (BIS), obtaining scores at zero, one and three months after starting treatment with topiramate. RESULTS: We found significant differences in the cognitive impulsivity subscale (p=0.040) and total score of the BIS (p=0.043) when BIS scale was measured after one month of treatment; after three months of treatment, the motor impulsivity subscale also showed significant differences (p=0.015). CONCLUSIONS: The significant reductions at BIS scores in child and adolescents outpatients who have IBD make us consider topiramate as an effective pharmacological option for treatment of impulsivity in several psychiatric disorders, also in childhood and adolescence. More studies are needed to confirm these results, with bigger samples and control groups.

[Complications of dysmorphophobia. Description of a self-mutilation case]. / Complicaciones de la dismorfofobia. Descripción de un caso de automutilación.

Dysmorphophobia, also known as Body Dysmorphic Disorder (BDD), can become a serious illness that results in severe complications such as social isolation, self-mutilations, suicide attempts, and even suicide. Many authors currently include BDD among the spectrum of obsessive-compulsive disorders. There are two distinguishable variants of BDD: psychotic and non-psychotic. The current trend considers these variants as one same disorder characterized by an insight spectrum. However, the psychotic variant exhibits more severe symptoms. We present a case of dysmorphophobia with psychotic symptoms that required psychiatric hospitalization due to serious complications. We discuss the presence of tactile and propioceptive sensations in some BDD patients and their contribution to their distress. Finally, we discuss a great propensity of BDD patients to conceal their symptoms. Thus, it is important for the clinician to specifically inquire about these symptoms, especially in high-risk groups, to prevent occurrence of serious complications.

Complicaciones de la dismorfofobia. Descripción de un caso de automutilación / Complications of dysmorphophobia. Description of a self-mutilation case

La dismorfofobia, o trastorno dismórfico corporal, puede alcanzar una gravedad importante y originar severas complicaciones, como aislamiento social, automutilaciones, intentos de suicidio e incluso suicidio consumado. La tendencia actual de muchos autores es incluirla dentro de los trastornos del llamado espectro obsesivo-compulsivo. En la dismorfofobia se distinguen una variante psicótica y una no psicótica, aunque actualmente se tiende a considerar que ambas formas constituyen un mismo trastorno caracterizado por un espectro de insight en el que los pacientes afectados por la forma delirante muestran mayor gravedad. Presentamos un caso de dismorfofobia con síntomas psicóticos que requirió un ingreso psiquiátrico debido a las graves complicaciones derivadas de este trastorno. Discutimos la presencia de sensaciones táctiles y propioceptivas presentes en algunos pacientes con dismorfofobia y la contribución de éstas al aumento de su malestar. Por último discutimos la tendencia de los pacientes a ocultar sus síntomas, que hace recomendable interrogar explícitamente acerca de ellos, en especial en grupos de alto riesgo

Dysmorphophobia, also known as Body Dysmorphic Disorder (BDD), can become a serious illness that results in severe complications such as social isolation, self-mutilations, suicide attempts, and even suicide. Many authors currently include BDD among the spectrum of obsessive-compulsive disorders. There are two distinguishable variants of BDD: psychotic and non-psychotic. The current trend considers these variants as one same disorder characterized by an insight spectrum. However, the psychotic variant exhibits more severe symptoms. We present a case of dysmorphophobia with psychotic symptoms that required psychiatric hospitalization due to serious complications. We discuss the presence of tactile and propioceptive sensations in some BDD patients and their contribution to their distress. Finally, we discuss a great propensity of BDD patients to conceal their symptoms. Thus, it is important for the clinician to specifically inquire about these symptoms, especially in high-risk groups, to prevent occurrence of serious complications

(Q)SAR studies to design new human choline kinase inhibitors as antiproliferative drugs.

Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function. Mutations which deregulate their expression or their function or both result in cancers. Therefore, protein kinase inhibitors have become the focus of development of new therapies for cancer. A comprehensive review of Choline kinase (ChoK) was published by us in 2003. Since then, molecular information of ChoK inhibitors has been accumulated. In this review, we intend to summarize the new lines of evidence that will include the design of the most active antiproliferative agents so far described against ChoK. Studies have been aimed at the establishment of structure-activity relationships and the structural parameters that define ChoK inhibitory and antiproliferative activities of a set of twenty-five acyclic biscationic pyridophane and forty acyclic biscationic quinolinephane compounds. The corresponding QSAR equation was obtained for the whole set of bisquinolinium compounds for the antiproliferative activity, taking into consideration the electronic parameter sigma(R) of R(4), the molar refractivity (MR) of R(8), and the lipophilic parameters clog P and pi(linker). The most potent antiproliferative agent shows an IC(50) = 0.45 microM, predicted by the QSAR equation, whilst its experimental value is IC(50) = 0.20 microM. Finally, toxicity assays were performed for the most promising compounds because of their interesting antiproliferative activities [IC(50 HT-29) = 0.70, 0.80, 1.50 and 1.90 microM] and low toxicity [LD(50) = 16.7, 12.5, > 25 and > 20 mg/kg of mouse]. These biological activities justify further analysis for antitumoral assays under in vivo conditions.

Characterization of latex-antineoplastic drug complexes by differential scanning calorimetry and microphotography.

Choline kinase inhibitors have recently been identified as potentially useful antitumoral agents. Here we determine the best conditions for obtaining drug-polymer complexes with 5-fluorouracil (5-FU), and JCR791B, a new drug representing a significant advance in the development of new molecules to inhibit tumour proliferation. As polymers we used the cellulose derivatives Aquacoat and Aquateric. The variables in the adsorption process measured were time to adsorbent-adsorbate equilibrium, pH and concentration. The drug-polymer complexes were characterized by differential scanning calorimetry and microphotography. Our results show that adsorption of 5-FU and JCR was similar with both polymers although slightly greater with Aquacoat. The chemical structure of the drug and its solubility in water and oil are fundamental characteristics that determine the performance of polymers as drug carriers able to provide controlled release.

QSAR-derived choline kinase inhibitors: how rational can antiproliferative drug design be?

This review presents an overview of Choline Kinase (ChoK) inhibitors with antiproliferative activity. The consideration of ChoK as a novel target for the development of new anticancer drugs is justified. The synthesis of several derivatives based on structural modifications of hemicholinium-3 (HC-3) is not accompanied by potentiation of the neurological toxicity of HC-3. The increment of both ChoK inhibitory and antiproliferative activities was successfully obtained by the two following changes: a) substitution of the oxazonium moiety of HC-3 by several aromatic heterocycles, and b) using the 1,2-ethylene(bisbenzyl) moiety instead of the 4,4'-biphenyl fragment. In an attempt to understand the ChoK inhibitory activity, a quantitative structure-activity relationship was developed. The QSAR equations have described the forces involved in quantitative terms. The electron characteristic of the substituent at position 4 of the heterocycle and the lipophilic character of the whole molecule were found to significantly affect the antitumour activity in compounds 17-95. Trispyridinium compounds 91-95 are more potent than the bispyridinium ones 87-89 as ChoK inhibitors. Nevertheless, 91-95 are less active than 87-89 as antiproliferative agents because the latter show better lipophilicities to cross the cytosolic membranes. Inhibition of the growth of human tumours in nude mice has been demonstrated: Antitumour activity of compound 64 against human HT-29 produced a decrease of up to 70% in the size of the tumour in nude mice. These results indicate that ChoK can be used as a general target for anticancer drug design against Ras-dependent tumourigenesis.