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1.
Biomaterials ; 74: 200-16, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26461115

RESUMEN

Following neurotrauma, oxidative stress is spread via the astrocytic syncytium and is associated with increased aquaporin 4 (AQP4), inflammatory cell infiltration, loss of neurons and glia and functional deficits. Herein we evaluate multimodal polymeric nanoparticles functionalized with an antibody to an extracellular epitope of AQP4, for targeted delivery of an anti-oxidant as a therapeutic strategy following partial optic nerve transection. Using fluorescence microscopy, spectrophotometry, correlative nanoscale secondary ion mass spectrometry (NanoSIMS) and transmission electron microscopy, in vitro and in vivo, we demonstrate that functionalized nanoparticles are coated with serum proteins such as albumin and enter both macrophages and astrocytes when administered to the site of a partial optic nerve transection in rat. Antibody functionalized nanoparticles synthesized to deliver the antioxidant resveratrol are effective in reducing oxidative damage to DNA, AQP4 immunoreactivity and preserving visual function. Non-functionalized nanoparticles evade macrophages more effectively and are found more diffusely, including in astrocytes, however they do not preserve the optic nerve from oxidative damage or functional loss following injury. Our study highlights the need to comprehensively investigate nanoparticle location, interactions and effects, both in vitro and in vivo, in order to fully understand functional outcomes.


Asunto(s)
Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Nanopartículas , Polímeros/uso terapéutico , Animales , Acuaporina 4/genética , Femenino , Polímeros/química , Ratas
2.
Eur J Neurosci ; 25(3): 744-52, 2007 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-17328773

RESUMEN

During development, gradients of EphA receptors (nasal(low)-temporal(high)) and their ligands ephrin-As (rostral(low)-caudal(high)) are involved in establishing topography between retinal ganglion cells (RGCs) and the superior colliculus (SC). EphA5-expressing RGC axons are repulsed by ephrin-A2-expressing SC neurones. In adult rats RGCs maintain graded EphA5 expression but ephrin-A2 expression is down-regulated in the SC to a weak gradient. At 1 month after optic nerve transection, EphA5 expression is reduced in the few remaining RGCs and is no longer graded; by contrast, SC ephrin-A2 is up-regulated to a rostral(low)-caudal(high) gradient. Here we examined expression in adult rat 1 month after bridging the retina and SC with a peripheral nerve graft, a procedure that enhances RGC survival and permits RGC axon regeneration. Double labelling with cell markers revealed preservation of a nasal(low)-temporal(high) EphA5 gradient in RGCs and establishment of a rostral(low)-caudal(high) ephrin-A2 gradient within neurones of the SC. The results suggest a potential for guidance cues to restore the topography of RGC axons in the SC. However, high ephrin-A2 levels were also found in astrocytes surrounding the peripheral nerve graft insertion site. The repulsive ephrin-A2 environment offers at least a partial explanation for the observation that only a limited number of RGC axons can exit the graft to enter target central nervous system tissue.


Asunto(s)
Efrina-A2/genética , Efrina-A5/genética , Regeneración Nerviosa/fisiología , Nervio Óptico/fisiología , Nervio Ciático/trasplante , Animales , Axones/fisiología , Axotomía , Supervivencia Celular/fisiología , Efrina-A2/metabolismo , Efrina-A5/metabolismo , Femenino , Expresión Génica/fisiología , Nervio Óptico/citología , Ratas , Ratas Endogámicas , Células Ganglionares de la Retina/fisiología , Células Ganglionares de la Retina/ultraestructura , Nervio Ciático/citología , Colículos Superiores/citología , Colículos Superiores/fisiología , Vías Visuales
3.
Eur J Neurosci ; 22(8): 1840-52, 2005 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-16262624

RESUMEN

Following unilateral optic nerve section in adult PVG hooded rat, the axon guidance cue ephrin-A2 is up-regulated in caudal but not rostral superior colliculus (SC) and the EphA5 receptor is down-regulated in axotomised retinal ganglion cells (RGCs). Changes occur bilaterally despite the retino-collicular projection being mostly crossed. Here we investigate the dynamics of Eph/ephrin expression using in situ hybridization and semi-quantitative immunohistochemistry after localized retinal lesions. Unilateral krypton laser lesions to dorso-nasal retina ablated contralaterally projecting RGCs (DN group); ventro-temporal lesions ablated contralaterally and ipsilaterally projecting RGCs (VT group). Lesions of the entire retina served as controls (Total group). Results are compared to normal animals in which tectal ephrin-A2 and retinal EphA5 are expressed, respectively, as shallow ascending rostro-caudal and naso-temporal gradients. In both SCs of DN and Total groups, tectal ephrin-A2 was up-regulated caudally; in the VT group, expression remained normal bilaterally. Unilateral collicular ablation indicated that bilateral changes in ephrin-A2 expression are mediated via intercollicular pathways. EphA5 expression in the VT group was elevated in the intact nasal region of experimental retinae. For each experimental group, EphA5 expression was also elevated in nasal retina of the opposite eye, resulting in uniform expression across the naso-temporal axis. Up-regulation of ephrin-A2 in caudal, but not rostral, SC suggests the enhancement of developmental positional information as a result of injury. Bilateral increases in retinal EphA5 expression demonstrate that signals for up-regulation operate interocularly. The study demonstrates that signals regulating guidance cue expression are both localized and relayed transneuronally.


Asunto(s)
Efrinas/metabolismo , Receptores de la Familia Eph/metabolismo , Retina/metabolismo , Colículos Superiores/metabolismo , Regulación hacia Arriba/fisiología , Animales , Recuento de Células/métodos , Toxina del Cólera/metabolismo , Desnervación/métodos , Efrinas/genética , Femenino , Lateralidad Funcional/fisiología , Inmunohistoquímica , Hibridación in Situ/métodos , Modelos Neurológicos , Ratas , Receptores de la Familia Eph/genética , Retina/lesiones , Colículos Superiores/lesiones
4.
Prev Vet Med ; 70(1-2): 17-28, 2005 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-15967239

RESUMEN

Thirty industry or regulatory professionals, with extensive experience in the local infectious salmon-anemia (ISA) epidemic, were queried on their opinions regarding the spread and impact of ISA in Maine, USA and New Brunswick, Canada. Subjective probability-estimation techniques were used to elicit likelihood ratios (LR) for risk factors of potential relevance to the epidemic. Experts were asked to answer questions based on their direct and local experience with ISA, rather than through knowledge gained from scientific references or experience in other regions. The results found the strongest independent predictors of ISA infection to include (1) a site's proximity to other farms with clinically infected fish, (2) a previous history of ISA on the site, (3) whether a site fallows for a month or more between year classes and (4) whether the site employs harvest vessels practicing full containment of blood and stun water. The strongest predictors of ISA severity included (1) stocking density, (2) the length of time between infection and removal of infected fish, (3) whether fish are moved between pens (after infection) and (4) a farm's sea-lice (Lepeophtheirus salmonis) status. Experts believed that transmission of ISA virus during the local epidemic was influenced by proximity (spatial and temporal) to activities resulting in large-scale shedding of virus into a shared water column, and that severity of infection corresponded more to infected-fish removal practices and certain husbandry decisions. Personnel and equipment biosecurity measures were not seen as strong predictors of either infection or severity in this analysis, though their perceived level of importance was greater among government than industry experts.


Asunto(s)
Enfermedades de los Peces/epidemiología , Isavirus/aislamiento & purificación , Infecciones por Orthomyxoviridae/epidemiología , Crianza de Animales Domésticos , Animales , Acuicultura , Brotes de Enfermedades/veterinaria , Enfermedades de los Peces/virología , Maine , Nuevo Brunswick , Factores de Riesgo , Salmón
5.
Mol Cell Neurosci ; 25(1): 56-68, 2004 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-14962740

RESUMEN

During visual system development, interactions between Eph tyrosine kinase receptors and their ligands, the ephrins, guide retinal ganglion cell (RGC) axons to their topographic targets in the optic tectum. Here we show that Eph/ephrin interactions are also involved in restoring topography during RGC axon regeneration in goldfish. Following optic nerve crush, EphA/ephrin-A interactions were blocked by intracranial injections of recombinant Eph receptor (EphA3-AP) or phospho-inositol phospholipase-C. Topographic errors with multiple inputs to some tectal loci were detected electrophysiologically and increased projections to caudal tectum demonstrated by RT-97 immunohistochemistry. In EphA3-AP-injected fish, ephrin-A2-expressing cells in the retino-recipient tectal layers were reduced in number compared to controls and their distribution was no longer graded. The findings, supported by in vitro studies, implicate EphA/ephrin-A interactions in restoring precise topography and in regulating ephrin-A2 expression during regeneration.


Asunto(s)
Efrina-A2/metabolismo , Carpa Dorada/fisiología , Regeneración Nerviosa/fisiología , Traumatismos del Nervio Óptico/metabolismo , Nervio Óptico/fisiología , Receptores de la Familia Eph/metabolismo , Animales , Tipificación del Cuerpo/fisiología , Comunicación Celular/fisiología , Señales (Psicología) , Efrina-A2/genética , Regulación del Desarrollo de la Expresión Génica , Conos de Crecimiento/metabolismo , Conos de Crecimiento/ultraestructura , Regeneración Nerviosa/efectos de los fármacos , Nervio Óptico/citología , Nervio Óptico/efectos de los fármacos , Receptor EphA3/genética , Receptor EphA3/metabolismo , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Colículos Superiores/citología , Colículos Superiores/crecimiento & desarrollo , Colículos Superiores/metabolismo , Fosfolipasas de Tipo C/farmacología
6.
Neuroscience ; 102(3): 647-54, 2001.
Artículo en Inglés | MEDLINE | ID: mdl-11226701

RESUMEN

In the lizard, Ctenophorus ornatus, the optic nerve regenerates but animals remain blind via the experimental eye, presumably as a result of axons failing to consolidate a retinotopic map in the optic tectum. Here we have examined immunohistochemically the expression of the growth-associated protein GAP-43 and the low-molecular-weight intermediate filament protein gefiltin, up to one year after optic nerve crush. Both proteins were found to be permanently up-regulated, suggesting that regenerating axons are held in a permanent state of re-growth. We speculate that, in the lizard, the continued expression of GAP-43 and the failure to switch from the expression of low- to high-molecular-weight intermediate filament proteins are associated with the inability to consolidate a retinotopic projection.


Asunto(s)
Axones/fisiología , Proteínas de Peces , Proteína GAP-43/genética , Regulación de la Expresión Génica/fisiología , Proteínas de Filamentos Intermediarios/genética , Regeneración Nerviosa/fisiología , Nervio Óptico/fisiología , Animales , Axones/ultraestructura , Proteína GAP-43/análisis , Inmunohistoquímica , Hibridación in Situ , Proteínas de Filamentos Intermediarios/análisis , Lagartos , Compresión Nerviosa , Fibras Nerviosas/fisiología , Neuronas/fisiología , Nervio Óptico/citología , Colículos Superiores/fisiología , Factores de Tiempo
7.
Exp Neurol ; 166(1): 196-200, 2000 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-11031096

RESUMEN

During development, a graded expression of ephrin A2 has been implicated in retinotectal map formation. Here we have examined ephrin A2 expression during optic nerve regeneration in the mature goldfish. In the tecta of normal animals, a gradient of ephrin A2 expression is detected in cell bodies within the stratum fibrosum et griseum superficiale with more immunopositive cells caudally than rostrally. The gradient in the mature animal presumably reflects the plasticity associated with continued retinal and tectal neurogenesis. During optic nerve regeneration, expression throughout the tectum is increased by 1 month as a strong rostrocaudal gradient. The gradient declines to normal by 3 months. The up-regulation of ephrin A2 during optic nerve regeneration is likely to be instrumental in reestablishing the retinotectal map.


Asunto(s)
Axones/metabolismo , Regeneración Nerviosa/fisiología , Plasticidad Neuronal/fisiología , Nervio Óptico/crecimiento & desarrollo , Colículos Superiores/crecimiento & desarrollo , Factores de Transcripción/metabolismo , Vías Visuales/crecimiento & desarrollo , Animales , Axones/ultraestructura , Efrina-A2 , Carpa Dorada/anatomía & histología , Carpa Dorada/crecimiento & desarrollo , Carpa Dorada/metabolismo , Compresión Nerviosa/efectos adversos , Nervio Óptico/citología , Nervio Óptico/metabolismo , Células Ganglionares de la Retina/citología , Células Ganglionares de la Retina/metabolismo , Colículos Superiores/citología , Colículos Superiores/metabolismo , Factores de Tiempo , Regulación hacia Arriba/fisiología , Vías Visuales/citología , Vías Visuales/metabolismo
8.
J Neurocytol ; 29(4): 285-300, 2000 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-11276180

RESUMEN

Fish optic nerve fibres quickly regenerate after injury, but the onset of remyelination is delayed until they reach the brain. This recapitulates the timetable of CNS myelinogenesis during development in vertebrate animals generally, and we have used the regenerating fish optic nerve to obtain evidence that it is the axons, not the myelinating glial cells, that determine when myelin formation begins. In fish, the site of an optic nerve injury becomes remyelinated by ectopic Schwann cells of unknown origin. We allowed these cells to become established and then used them as reporters to indicate the time course of pro-myelin signalling during a further round of axonal outgrowth following a second upstream lesion. Unlike in the mammalian PNS, the ectopic Schwann cells failed to respond to axotomy and to the initial outgrowth of new optic axons. They only began to divide after the axons had reached the brain. Shortly afterwards, small numbers of Schwann cells began to leave the dividing pool and form myelin sheaths. More followed gradually, so that by 3 months remyelination was almost completed and few dividing cells were left. Moreover, remyelination occurred synchronously throughout the optic nerve, with the same time course in the pre-existing Schwann cells, the new ones that colonised the second injury, and the CNS oligodendrocytes elsewhere. The optic axons are the only common structures that could synchronise myelin formation in these disparate glial populations. The responses of the ectopic Schwann cells suggest that they are controlled by the regenerating optic axons in two consecutive steps. First, they begin to proliferate when the growing axons reach the brain. Second, they leave the cell cycle to differentiate individually at widely different times during the ensuing 2 months, during the critical period when the initial rough pattern of axon terminals in the optic tectum becomes refined into an accurate map. We suggest that each axon signals individually for myelin ensheathment once it completes this process.


Asunto(s)
Axones/metabolismo , Comunicación Celular/fisiología , Sistema Nervioso Central/metabolismo , Vaina de Mielina/metabolismo , Regeneración Nerviosa/fisiología , Nervio Óptico/metabolismo , Células de Schwann/metabolismo , Animales , Axones/ultraestructura , Axotomía/efectos adversos , Axotomía/métodos , Diferenciación Celular/fisiología , División Celular/fisiología , Sistema Nervioso Central/ultraestructura , Regulación hacia Abajo/fisiología , Carpa Dorada/anatomía & histología , Carpa Dorada/crecimiento & desarrollo , Carpa Dorada/metabolismo , Inmunohistoquímica , Microscopía Electrónica , Modelos Animales , Vaina de Mielina/ultraestructura , Oligodendroglía/metabolismo , Oligodendroglía/ultraestructura , Nervio Óptico/cirugía , Nervio Óptico/ultraestructura , Proteínas S100/metabolismo , Células de Schwann/ultraestructura , Factores de Tiempo
9.
J Med Chem ; 40(5): 677-83, 1997 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-9057854

RESUMEN

Six new diphenyl sulfoxide and five new diphenyl sulfones were designed, synthesized, and tested for their inhibition of human and Escherichia coli thymidylate synthase (TS) and of the growth of cells in tissue culture. The best sulfoxide inhibitor of human TS was 3-chloro-N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4- (phenylsulfinyl)-N-(prop-2-ynyl)-aniline (7c) that had a Ki of 27 nM. No sulfone improved on TS inhibition by the previously reported 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2- ynylamino)phenyl phenyl sulfone (Ki = 12 nM). Nevertheless, one sulfone, 4-((2-chlorophenyl)sulfonyl)-N-((3,4-dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl)-N-(prop-2-ynyl)aniline, was selected, on the basis of its inhibition of both TS and cell growth, for antitumor testing; it gave a 61% increase in life span to mice bearing the thymidino kinase-deficient L5178Y (TK-) lymphoma. A crystal structure of N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4-((2- methylphenyl)sulfinyl)-N-(prop-2-ynyl)aniline complexed with E. coli TS was solved and revealed selective binding of one sulfoxide enantiomer. AMBER calculations showed that the enantioselection was due to asymmetric electrostatic effects at the mouth of the active site. In contrast, a similar crystal structure of the sulfoxide 7c, along with AMBER calculations, indicated that both enantiomers bound, but with different affinities. The side chain of Phe176 shifted in order to structurally accommodate the chlorine of the more weakly bound enantiomer.


Asunto(s)
Antineoplásicos/farmacología , Inhibidores Enzimáticos/farmacología , Quinazolinas/farmacología , Sulfonas/farmacología , Sulfóxidos/farmacología , Timidilato Sintasa/antagonistas & inhibidores , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , División Celular/efectos de los fármacos , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Escherichia coli/enzimología , Humanos , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Neoplasias Experimentales/tratamiento farmacológico , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-Actividad , Sulfonas/síntesis química , Sulfonas/química , Sulfóxidos/síntesis química , Sulfóxidos/química , Células Tumorales Cultivadas
10.
J Med Chem ; 39(4): 904-17, 1996 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-8632414

RESUMEN

To develop novel lipophilic thymidylate synthase (TS) inhibitors, the X-ray structure of Escherichia coli TS in ternary complex with FdUMP and the inhibitor 10-propargyl-5,8-dideazafolic acid (CB3717) was used as a basis for structure-based design. A total of 31 novel lipophilic TS inhibitors, lacking a glutamate residue, were synthesized; 26 of them had in common a N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylaniline+ ++ structure in which the aniline was appropriately substituted with simple lipophilic substituents either in position 3 or 4, or in both. Compounds were tested for their inhibition of E. coli TS and human TS and also for their inhibition of the growth in tissue culture of a murine leukemia, a human leukemia, and a thymidine kinase-deficient human adenocarcinoma. The crystal structures of five inhibitors complexed with E. coli TS were determined. Five main conclusions are drawn from this study. (i) A 3-substituent such as CF(3), iodo, or ethynyl enhances binding by up to 1 order of magnitude and in the case of CF(3) was proven to fill a nearby pocket in the enzyme. (ii) A simple strongly electron-withdrawing substituent such as NO(2) or CF(3)SO(2) in the 4-position enhances binding by 2 orders of magnitude; it is hypothesized that the transannular dipole so induced interacts favorably with the protein. (iii) Attempts to combine the enhancements of i and ii in the same molecule were generally unsuccessful (iv) A 4-C(6)H(5)SO(2) substituent provided both electron withdrawal and a van der Waal's interaction of the phenyl group with a hydrophobic surface at the mouth of the active site. The inhibition (K(is) = 12 nM) of human TS by this compound, 7n, showed that C(6)H(5)SO(2) provided virtually as much binding affinity as the CO-glutamate which it had replaced. (v) The series of compounds were poorly water soluble, and also the potent TS inhibition shown by several of them did not translate into good cytotoxicity. Compounds with large cyclic groups linked to position 4 by an SO or SO(2) group did, however, have IC(50)'s in the range 1-5 microM. Of these, 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2-ynylamino )phenyl phenyl sulfone, 7n, had IC(50)'s of about 1 microM and was chosen for further elaboration.


Asunto(s)
Antineoplásicos/síntesis química , Inhibidores Enzimáticos/síntesis química , Antagonistas del Ácido Fólico/síntesis química , Quinazolinas/síntesis química , Timidilato Sintasa/antagonistas & inhibidores , Adenocarcinoma , Animales , Antineoplásicos/química , Antineoplásicos/toxicidad , Sitios de Unión , Línea Celular , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Escherichia coli/enzimología , Antagonistas del Ácido Fólico/química , Antagonistas del Ácido Fólico/farmacología , Humanos , Leucemia , Leucemia L1210 , Ratones , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Conformación Proteica , Quinazolinas/química , Quinazolinas/farmacología , Relación Estructura-Actividad , Timidilato Sintasa/química , Células Tumorales Cultivadas
11.
Cancer Chemother Pharmacol ; 37(6): 509-17, 1996.
Artículo en Inglés | MEDLINE | ID: mdl-8612303

RESUMEN

3,4-Dihydro-2-amino-6 methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (AG337) is a water-soluble, lipophilic inhibitor of thymidylate synthase (TS) designed using X-ray structure - based methodologies to interact at the folate cofactor binding site of the enzyme. The aim of the design program was to identify TS inhibitors with different pharmacological characteristics from classical folate analogs and, most notably, to develop non-glutamate-containing molecules which would not require facilitated transport for uptake and would not undergo intracellular polyglutamylation. One molecule which resulted from this program, AG337, inhibits purified recombinant human TS with a Ki of 11 nM, and displays non-competitive inhibition kinetics. It was further shown to inhibit cell growth in a panel of cell lines of murine and human origin, displaying an IC50 of between 0.39 microM 6.6 microM. TS was suggested as the locus of action of AG337 by the ability of thymidine to antagonize cell growth inhibition and the direct demonstration of TS inhibition in whole cells using a tritium release assay. The demonstration, by flow cytometry, that AG337-treated L1210 cells were arrested in the S phase of the cell cycle was also consistent with a blockage of TS, as was the pattern of ribonucleotide and deoxyribonucleotide pool modulation in AG337-treated cells, which showed significant reduction in TTP levels. The effects of AG337 were quickly reversed on removal of the drug, suggesting, as would be expected for a lipophilic agent, that there is rapid influx and efflux from cells and no intracellular metabolism to derivatives with enhanced retention. In vivo, AG337 was highly active against the thymidine kinase-deficient murine L5178Y/TK-lymphoma implanted either i.p. or i.m. following i.p. or oral delivery. Prolonged dosing periods of 5 or 10 days were required for activity, and efficacy was improved with twice-daily dose administration. Dose levels of 25 mg/kg delivered i.p. twice daily for 10 days, 50 mg/kg once daily for 10 days, or 100 mg/kg once daily for 5 days elicited 100% cures against the i.p. tumor. Doses required for activity against the i.m. tumor were higher (100 mg/kg i.p. twice daily for 5 or 10 days) but demonstrated the ability of AG337 to penetrate solid tissue barriers. Oral delivery required doses of > or = 150 mg/kg twice daily for periods of 5-10 days to produce 100% cure rates against both i.m. and i.p. implanted tumors. These results were consistent with the pharmacokinetics parameters determined in rats, for which oral bioavailability of 30-50% was determined, together with a relatively short elimination half life of 2h. Clinical studies with AG337 are currently in progress.


Asunto(s)
Inhibidores Enzimáticos/farmacología , Antagonistas del Ácido Fólico/farmacología , Quinazolinas/farmacología , Timidilato Sintasa/antagonistas & inhibidores , Administración Oral , Animales , Antimetabolitos Antineoplásicos/química , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/farmacología , Ciclo Celular/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Antagonistas del Ácido Fólico/química , Antagonistas del Ácido Fólico/farmacocinética , Inhibidores de Crecimiento/farmacología , Humanos , Leucemia L1210 , Leucemia L5178/tratamiento farmacológico , Ratones , Quinazolinas/farmacocinética , Ratas , Solubilidad
12.
J Med Chem ; 38(11): 1892-903, 1995 May 26.
Artículo en Inglés | MEDLINE | ID: mdl-7783121

RESUMEN

The design, synthesis, and biochemical and biological evaluations of a novel series of 2,6-diaminobenz[cd]indole-containing inhibitors of human thymidylate synthase (TS) are described. The compounds are characterized by having either a pyridine or pyridazine ring in place of the (phenylsulfonyl)morpholinyl group of the known inhibitor N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2,6-diaminobenz[ cd]indole glucuronate (i). Active compounds from this series showed human TS inhibition constants below the 10 nM level and were potent, selective submicromolar antitumor agents in cell culture. The compounds were synthesized by reductive alkylation of a substituted 6-aminobenz[cd]indole or reductive cyclization of a substituted 1-cyano-8-nitronaphthalene.


Asunto(s)
Indoles/síntesis química , Indoles/farmacología , Timidilato Sintasa/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Animales , Proteínas Bacterianas/antagonistas & inhibidores , División Celular/efectos de los fármacos , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Escherichia coli/enzimología , Glucuronatos/síntesis química , Glucuronatos/química , Glucuronatos/farmacología , Humanos , Indoles/química , Leucemia/tratamiento farmacológico , Leucemia/patología , Leucemia L1210/tratamiento farmacológico , Leucemia L1210/patología , Ratones , Conformación Proteica , Piridinas/síntesis química , Piridinas/química , Piridinas/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas/efectos de los fármacos
13.
Harv Bus Rev ; 70(5): 124-32, 1992.
Artículo en Inglés | MEDLINE | ID: mdl-10121314

RESUMEN

To compete around the world, a company needs three strategic capabilities: global-scale efficiency, local responsiveness, and the ability to leverage learning worldwide. No single "global" manager can build these capabilities. Rather, groups of specialized managers must integrate assets, resources, and people in diverse operating units. Such managers are made, not born. And how to make them is--and must be--the foremost question for corporate managers. Drawing on their research with leading transnational corporations, Christopher Bartlett and Sumantra Ghoshal identify three types of global managers. They also illustrate the responsibilities each position involves through a close look at the careers of successful executives: Leif Johansson of Electrolux, Howard Gottlieb of NEC, and Wahib Zaki of Procter & Gamble. The first type is the global business or product-division manager who must build worldwide efficiency and competitiveness. These managers recognize cross-border opportunities and risks as well as link activities and capabilities around the world. The second is the country manager whose unit is the building block for worldwide operations. These managers are responsible for understanding and interpreting local markets, building local resources and capabilities, and contributing to--and participating in--the development of global strategy. Finally, there are worldwide functional specialists--the managers whose potential is least appreciated in many traditional multinational companies. To transfer expertise from one unit to another and leverage learning, these managers must scan the company for good ideas and best practice, cross-pollinate among units, and champion innovations with worldwide applications.


Asunto(s)
Personal Administrativo/normas , Industrias/organización & administración , Perfil Laboral , Administración de Línea de Producción/organización & administración , Competencia Económica , Industrias/economía , Relaciones Interpersonales , Administración de Línea de Producción/economía , Competencia Profesional , Rol , Estados Unidos
14.
J Med Chem ; 35(4): 663-76, 1992 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-1542093

RESUMEN

The X-ray crystal-structure-based design, synthesis, and biological activity of a novel family of benz[cd]indole-containing inhibitors of thymidylate synthase (TS) are described. The structure-activity of the lead compound was studied by conceptually dividing the molecule into four regions and independently optimizing the substituents for each region. Combination of favored substituents for each region led to inhibitors with Ki's against the human enzyme in the range of 10-20 nM. Thymidine shift experiments suggested that the cytotoxic properties of the best enzyme inhibitors were due to TS targeting in cells. The inhibitors were synthesized from substituted 6-aminobenz[cd]indol-2(1H)-ones by alkylation with both a simple alkyl group and a substituted benzylic portion. The 2,6-diaminobenz[cd]indoles were prepared from the corresponding lactams by conversion to the thiolactam, alkylation to the methylated thiolactam, and then displacement with a substituted or unsubstituted amine.


Asunto(s)
Antineoplásicos/química , Diseño de Fármacos , Indoles/química , Piperazinas/química , Timidilato Sintasa/antagonistas & inhibidores , Alquilación , Animales , Antineoplásicos/farmacología , Sitios de Unión , División Celular/efectos de los fármacos , Cristalización , Escherichia coli/enzimología , Humanos , Indoles/síntesis química , Indoles/farmacología , Leucemia L1210/patología , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/farmacología , Relación Estructura-Actividad , Células Tumorales Cultivadas , Difracción de Rayos X
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