Synthesis of 2,3,5,6-tetra-O-benzyl-D-galactofuranose for α-glycosidation

The synthesis of 2,3,5,6-tetra-O-benzyl-D-galactofuranose, a useful compound for α-glycosylation studies, is described. Direct anomeric O-alkylation of galactose was employed for alpha-allylation to yield pure allyl α-D-galactofuranoside, which is a versatile precursor for the synthesis of galactofuranose-containing oligosaccharides. Allyl removal of the benzylated galactofuranosyl derivative was performed using palladium (II) chloride as catalyst. ©ARKAT.Fil:Gandolfi-Donadío, L. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.Fil:Gallo-Rodriguez, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Sapientia, 1984, Vol. XXXIX, nº 154 (número completo)

Contenido: Aspectos fundamentales del conocimiento humano. IV. Acto, ser e inteligencia / Octavio N. Derisi -- Fundamentación ontológica de la libertad psicológica / Luis Bogliolo -- Libertad-necesidad en la Quaestio Disputata de Malo, VI / María C. Donadío Maggi de Gandolfi -- Compatibilidad entre la presciencia divina y la libertad de los actos humanos / María L. Lukac de Stier -- Valor y valor moral / Octavio N. Derisi -- El pensamiento filosófico-religioso de Manuel Demetrio Pizarro / Alberto Caturelli -- Notas y comentarios -- Bibliografí

Sapientia, 1985, Vol. XL, nº 156 (número completo)

Contenido: La verdad (II). La verdad en la inteligencia humana / Octavio N. Derisi -- Notas sobre la fundamentación de la ética aristotélica / Beatriz Bossi de Kirchner -- Juicios morales y verdad / María C. Donadío Maggi de Gandolfi -- Algunos aspectos de la doctrina tomista del entendimiento posible / María L. Lukac de Stier -- El racionalismo en el inicio del inmanentismo jurídico / Guillermo J. Yacobucci -- Notas y comentarios -- Bibliografí

Sapientia, 1984, Vol. XXXIX, nº 154 (número completo)

Contenido: Aspectos fundamentales del conocimiento humano. IV. Acto, ser e inteligencia / Octavio N. Derisi -- Fundamentación ontológica de la libertad psicológica / Luis Bogliolo -- Libertad-necesidad en la Quaestio Disputata de Malo, VI / María C. Donadío Maggi de Gandolfi -- Compatibilidad entre la presciencia divina y la libertad de los actos humanos / María L. Lukac de Stier -- Valor y valor moral / Octavio N. Derisi -- El pensamiento filosófico-religioso de Manuel Demetrio Pizarro / Alberto Caturelli -- Notas y comentarios -- Bibliografí

Design, Synthesis, and Characterization of Novel sn-1 Heterocyclic DAG-Lactones as PKC Activators

DAG-lactones represent useful templates for the design of potent and selective C1 domain ligands for PKC isozymes. The ester moiety at the sn-1 position, a common feature in this template, is relevant for C1 domain interactions, but it represents a labile group susceptible to endogenous esterases. An interesting challenge involves replacing the ester group of these ligands while still maintaining biological activity. Here, we present the synthesis and functional characterization of novel diacylglycerol-lactones containing heterocyclic ring substituents at the sn-1 position. Our results showed that the new compound 10B12, a DAG-lactone with an isoxazole ring, binds PKCα and PKCϵ with nanomolar affinity. Remarkably, 10B12 displays preferential selectivity for PKCϵ translocation in cells and induces a PKCϵ-dependent reorganization of the actin cytoskeleton into peripheral ruffles in lung cancer cells. We conclude that introducing a stable isoxazole ring as an ester surrogate in DAG-lactones emerges as a novel structural approach to achieve PKC isozyme selectivity.Fil: Elhalem, Eleonora. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Bellomo Peraza, Ana Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Cooke, Mariana. Albert Einstein Healthcare Network; Estados Unidos. University of Pennsylvania; Estados UnidosFil: Scravaglieri, Antonella. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Pearce, Larry V.. National Cancer Institute; Estados UnidosFil: Peach, Megan L.. National Institutes of Health; Estados UnidosFil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Kazanietz, Marcelo Gabriel. University of Pennsylvania; Estados UnidosFil: Comin, Maria Julieta. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Sapientia, 1985, Vol. XL, nº 156 (número completo)

Contenido: La verdad (II). La verdad en la inteligencia humana / Octavio N. Derisi -- Notas sobre la fundamentación de la ética aristotélica / Beatriz Bossi de Kirchner -- Juicios morales y verdad / María C. Donadío Maggi de Gandolfi -- Algunos aspectos de la doctrina tomista del entendimiento posible / María L. Lukac de Stier -- El racionalismo en el inicio del inmanentismo jurídico / Guillermo J. Yacobucci -- Notas y comentarios -- Bibliografí

Exploring the influence of indololactone structure on selectivity for binding to the C1 domains of PKCα, PKCε, and RasGRP

C1 domain-containing proteins, such as protein kinase C (PKC), have a central role in cellular signal transduction. Their involvement in many diseases, including cancer, cardiovascular disease, and immunological and neurological disorders has been extensively demonstrated and has prompted a search for small molecules to modulate their activity. By employing a diacylglycerol (DAG)-lactone template, we have been able to develop ultra potent analogs of diacylglycerol with nanomolar binding affinities approaching those of complex natural products such as phorbol esters and bryostatins. One current challenge is the development of selective ligands capable of discriminating between different protein family members. Recently, structure-activity relationship studies have shown that the introduction of an indole ring as a DAG-lactone substituent yielded selective Ras guanine nucleotide-releasing protein (RasGRP1) activators when compared to PKCα and PKCε. In the present work, we examine the effects of ligand selectivity relative to the orientation of the indole ring and the nature of the DAG-lactone template itself. Our results show that the indole ring must be attached to the lactone moiety through the sn-2 position in order to achieve RasGRP1 selectivity.Fil: Elhalem, Eleonora. Instituto Nacional de Tecnología Industrial; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Zhou, Xiaoling. National Cancer Institute; Estados UnidosFil: Lewin, Nancy E.. National Cancer Institute; Estados UnidosFil: Garcia, Lia Cynthia. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Lai, Christopher C.. National Institutes of Health; Estados UnidosFil: Kelley, James A.. National Institutes of Health; Estados UnidosFil: Peach, Megan L.. National Institutes of Health; Estados UnidosFil: Blumberg, Peter M.. National Cancer Institute; Estados UnidosFil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentin

Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP

The development of selective agents capable of discriminating between protein kinase C (PKC) isoforms and other diacylglycerol (DAG)-responsive C1 domain-containing proteins represents an important challenge. Recent studies have highlighted the role that Ras guanine nucleotide-releasing protein (RasGRP) isoforms play both in immune responses as well as in the development of prostate cancer and melanoma, suggesting that the discovery of selective ligands could have potential therapeutic value. Thus far, the N-methyl-substituted indololactone 1 is the agonist with the highest reported potency and selectivity for RasGRP relative to PKC. Here we present the synthesis, binding studies, cellular assays and biophysical analysis of interactions with model membranes of a family of regioisomers of 1 (compounds 2–5) that differ in the position of the linkage between the indole ring and the lactone moiety. These structural variations were studied to explore the interaction of the active complex (C1 domain-ligand) with cellular membranes, which is believed to be an important factor for selectivity in the activation of DAG-responsive C1 domain containing signaling proteins. All compounds were potent and selective activators of RasGRP when compared to PKCα with selectivities ranging from 6 to 65 fold. However, the parent compound 1 was appreciably more selective than any of the other isomers. In intact cells, modest differences in the patterns of translocation of the C1 domain targets were observed. Biophysical studies using giant vesicles as model membranes did show substantial differences in terms of molecular interactions impacting lipid organization, dynamics and membrane insertion. However, these differences did not yield correspondingly large changes in patterns of biological response, at least for the parameters examined.Fil: Garcia, Lia C.. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Gandolfi Donadío, Lucía. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Mann, Ella. Ben Gurion University of The Negev; IsraelFil: Kolusheva, Sofiya. Ben Gurion University of The Negev; IsraelFil: Kedei, Noemi. National Cancer Institute. Bethesda; Estados UnidosFil: Lewin, Nancy E.. National Cancer Institute. Bethesda; Estados UnidosFil: Hill, Collin S.. National Cancer Institute. Bethesda; Estados UnidosFil: Kelsey, Jessica S.. National Cancer Institute. Bethesda; Estados UnidosFil: Yang, Jing. National Cancer Institute. Bethesda; Estados UnidosFil: Esch, Timothy E.. National Cancer Institute. Bethesda; Estados UnidosFil: Santos, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; ArgentinaFil: Peach, Megan L.. National Institutes of Health; Estados UnidosFil: Kelley, James A.. National Institutes of Health; Estados UnidosFil: Blumberg, Peter M.. National Cancer Institute. Bethesda; Estados UnidosFil: Jelinek, Raz. Ben Gurion University of The Negev; IsraelFil: Marquez, Victor E.. National Institutes of Health; Estados UnidosFil: Comin, Maria Julieta. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnología Industrial; Argentin

Sapientia, 1988, Vol. XLIII, nº 167-168 (número completo)

Contenido: El tema de la libertad en Santo Tomás : fuentes y desarrollo / Gustavo E. Ponferrada – Emergencia y sentido del hombre en la reflexión ética de la Suma contra Gentiles / Julio R. Méndez – Azar y contingencia / Juan J. Sanguineti – Indeterminismo y racionalidad : en torno al problema de la causalidad en física / Ramón Queraltó – La tridimensionalidad crítica de la reflexión completa / Stanislavs Ladusans – Humanismo y humanismos / Iulio Brandao – Limitación de la antropología filosófica / José M. de Estrada – Afectividad, obrar humano, moralidad / María C. Donadío de Gandolfi – Naturaleza y ética en Hobbes y Tomás de Aquino / María L. Lukac de Stier – Derecho, pensamiento y lenguaje / Carlos I. Massini-Correas – Derecho natural y positivismo jurídico / Ylves J. de Miranda Guimaraes – La verdad política es el ideal de una sociedad participativa / José P. Galvao de Sousa – Hombre y moral : la “pietas” patriótica / Héctor H. Hernández – Filosofía, teología y cultura cristiana en el pensamiento de San Agustín / Battista Mondin – Amor Ruibal, genial renovador de la filosofía cristiana / Emilio Silva de Castro – La problemática filosófica de las ciencias humanas / Edgardo J. Castr