Synthesis of Simplified Azasordarin Analogs as Potential Antifungal Agents

A new series of simplified azasordarin analogs was synthesized using as key steps a Diels–Alder reaction to generate a highly substituted bicyclo[2.2.1]heptane core, followed by a subsequent nitrile alkylation. Several additional strategies were investigated for the generation of the key tertiary nitrile or aldehyde thought to be required for inhibition at the fungal protein eukaryotic elongation factor 2. This new series also features a morpholino glycone previously reported in semisynthetic sordarin derivatives with broad spectrum antifungal activity. Despite a lack of activity against Candida albicans for these early de novo analogs, the synthetic route reported here permits more comprehensive modifications of the bicyclic core and structure–activity relationship studies that were not heretofore possible

DFT-Assisted Design and Evaluation of Bifunctional Amine/Pyridine-Oxazoline Metal Catalysts for Additions of Ketones to Unactivated Alkenes and Alkynes

Bifunctional catalyst systems for the direct addition of ­ketones to unactivated alkenes/alkynes were designed and modeled by density functional theory (DFT). The designed catalysts possess bidentate ligands suitable for binding of pi-acidic group 10 metals capable of activating alkenes/alkynes, and a tethered organocatalyst amine to ­activate the ketone via formation of a nucleophilic enamine intermediate. The structures of the designed catalysts before and after C–C bond formation were optimized using DFT, and reaction steps involving group 10 metals were predicted to be significantly exergonic. A novel oxazoline precatalyst with a tethered amine separated by a meta-substituted benzene spacer was synthesized via a 10-step sequence that ­includes a key regioselective epoxide ring-opening step. It was combined with group 10 metal salts, including cationic Pd(II) and Pt(II), and screened for the direct addition of ketones to several alkenes and an ­internal alkyne. 1H NMR studies suggest that catalyst-catalyst inter­actions with this system via amine–metal coordination may preclude the desired addition reactions. The catalyst design approach disclosed here, and the promising calculations obtained with square planar group 10 metals, light a path for the discovery of novel bifunctional catalysts for C–C bond formation

Antihumanismo o autonomía del individuo ante las estructuras sociales: La relación individuo-sociedad en la teoría de Niklas Luhmann

The individual-society relationship remains a central issue in the social sciences which has not yet reached a consensual explanation. This article presents the way in which Niklas Luhmann’s theory of social systems deals with the subject. I discuss some of the critical approaches this theory has arises. Then I present social system’s concepts and partial theories that describe the individual- society relationship. I conclude with some reflections about what we consider to be “theoretical advantages” regarding Luhmann’s theory vis-a-vis common explanations in sociology. This, because in Luhmann’s theory of social systems –contrary to critical judgments-, individuals are theoretically placed in society’s environment, thus maintaining a relative autonomy which allows them to consider without idealism their actual possibilities to influence society.La relación individuo-sociedad continúa siendo un problema central en las ciencias sociales, sin haber encontrado aún una solución teórica que alcance un mínimo consenso. Este artículo discute el abordaje al tema por parte de la teoría de sistemas sociales propuesta por Niklas Luhmann, considerando algunas de las críticas que ha suscitado. Se presentan los conceptos y teorías parciales con que la teoría de sistemas sociales describe la relación individuo-sociedad. Se concluye con una reflexión sobre lo que se pueden considerar “ventajas teóricas” respecto de la teoría luhmanniana en oposición a explicaciones tradicionales de la sociología, por cuanto, contrario a los juicios críticos, en la teoría de sistemas sociales los individuos concebidos teóricamente en el entorno de la sociedad conservan una autonomía relativa que les permite evaluar, sin idealizaciones, sus posibilidades concretas de influir en ella

She Has a Mouse

SHE has a mouse. A friend sent it in an old purple corsage box and she put it in a two-quart glass jar. It jumped out the first night that she had it, but it was on top of a dresser with two jewel boxes and a few bottles of half-gone perfume and a big oval mirror, and the mouse scrunched up and hid inside the back of one open jewel box with a coil of long rope beads. And she found it..

El espejismo de la institucionalización : evolución del sistema de partidos en Venezuela (1958-1998)

This paper examines the collapse of the Venezuelan party system within the frame of a hyperinstitutionalized system characterized by low levels of uncertainty, the indifference of citizens, a closed political market, low credibility of party leadership and latent anti-party feelings. It is argued that institutionalization of party systems as proposed by Mainwaring and Scully (1995) is insufficient to analyze hyperinstitutionalized systems, for they produce systemic dynamics that go beyond the continuum and criteria used by the institutionalization approach. En this case, high levels of electoral stability were rooted not so much in the parties' capacity to adjust themselves but rather in the existence of a closed political market and an electoral institutionality that generated stability and facilitated the dominance of old parties, AD and COPEI. The Venezuelan case provides clues for the study of other party systems where traditional indicators show high levels of institutionalization, such as Chile, Costa Rica and Uruguay.Como se examina en el artículo, el colapso del sistema partidista venezolano se incubó en el marco de un sistema de partidos hiperinstitucionalizado, caracterizado por bajos niveles de incertidumbre, ciudadanos indiferentes, un mercado político clausurado, baja credibilidad de los liderazgos partidistas y un antipartidismo latente. Como se discute, la perspectiva de la institucionalización del sistema de partidos propuesta por Mainwaring y Scully (1995) resulta insuficiente para analizar a los sistemas hiperinstitucionalizados. Estos producen dinámicas sistémicas que exceden el continuo y los criterios empleados por el enfoque de la institucionalización. En este caso, los altos niveles de estabilidad electoral se anclaron no tanto en la capacidad adaptativa y la competitividad de los partidos que componían el sistema, sino en la existencia de un mercado político cerrado y una institucionalidad electoral que fabricó estabilidad y facilitó el predominio de los viejos partidos, la AD y el COPEI. El caso venezolano proporciona pistas para el estudio de otros sistemas de partidos donde los indicadores convencionales arrojan altos niveles de institucionalización, como Chile, Costa Rica y Uruguay.

Proyecciones del concepto de sistema psíquico de Luhmann y su vinculación con la psicología

The purpose of this article is to pose questions about the applicability of the systemic and constructivist theory developed by Niklas Luhmann to the reflection about the object of study of psychology. We describe the central aspects of the concept of Luhmann's psychic system which is then contrasted with some questions that arise from psychology. In this context, we present some advantages for the theoretical and applied development of psychology to differentiate its object of study from those of the social and bio-medical sciences, moving from a pre-paradigmatic state to one that allows a greater accumulation of knowledge, thereby pushing its development as a scientific discipline.    Este artículo tiene por propósito abrir preguntas sobre la posibilidad de aplicar la teoría sistémica y constructivista desarrollada por Niklas Luhmann a la reflexión sobre el objeto de conocimiento de la psicología. Para ello se describen los aspectos centrales del concepto de sistema psíquico de Luhmann que luego se contrastan con algunas interrogantes que surgen desde la psicología. En este contexto, se plantean algunas ventajas que tendría para el desarrollo teórico y aplicado de la psicología diferenciar su objeto de estudio de aquellos de las ciencias sociales y bio-médicas, avanzando desde un estado pre-paradigmático a uno en que sea posible una mayor acumulación de conocimiento, empujando así su desarrollo como disciplina científica.  

Synthesis of a Novel Bicyclic Scaffold Inspired by the Antifungal Natural Product Sordarin

A simplified bicyclic scaffold inspired by the antifungal natural product sordarin was designed and synthesized which maintains the carboxylic acid/aldehyde (or nitrile) pharmacophore. Docking studies with the target for sordarin, the fungal protein eukaryotic elongation factor 2 (eEF2), suggested that the novel scaffolds may bind productively. A densely functionalized chiral cyclopentadiene was constructed in 8 steps and utilized in a Diels-Alder reaction with acrylonitrile. The resulting [2.2.1] cycloheptene was transformed into a scaffold possessing vicinal carboxylic acid and nitrile groups, with orientations predicted to provide high affinity for eEF2. The synthetic approach disclosed here sets the stage for a renewed medicinal chemistry campaign against eEF2