RESUMEN
[11C]Clorgyline selectively binds to MAO A in the human brain. This contrasts with a recent report that [11C]clorgyline (in contrast to other labeled MAO A inhibitors) is not retained in the rhesus monkey brain [4]. To explore this difference, we compared [11C]clorgyline in the baboon brain before and after clorgyline pretreatment and we also synthesized deuterium substituted [11C]clorgyline (and its nor-precursor) for comparison. [11C]Clorgyline was not retained in the baboon brain nor was it influenced by clorgyline pretreatment or by deuterium substitution, contrasting to results in humans. This suggests a species difference in the susceptibility of MAO A to inhibition by clorgyline and represents an unusual example of where the behavior of a radiotracer in the baboon brain does not predict its behavior in the human brain.
Asunto(s)
Encéfalo/metabolismo , Clorgilina/farmacocinética , Inhibidores de la Monoaminooxidasa/farmacocinética , Monoaminooxidasa/metabolismo , Radiofármacos/farmacocinética , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/enzimología , Radioisótopos de Carbono/farmacocinética , Clorgilina/análogos & derivados , Deuterio , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Indicadores y Reactivos , Marcaje Isotópico , Papio , Radiofármacos/síntesis química , Especificidad de la Especie , Tomografía Computarizada de EmisiónRESUMEN
A series of new taxoids derived from 14 beta-hydroxy-10-deacetylbaccatin III was synthesized by means of the beta-lactam synthon method. Most of the new taxoids thus synthesized possess excellent cytotoxicity against human ovarian (A121), non-small-cell lung (A549), colon (HT-29), and breast (MCF-7) cancer cell lines, and several of these taxoids show subnanomolar IC50 values which are severalfold to 1 order of magnitude better than those of paclitaxel and docetaxel. Modifications at the 3'- and 3'-N-positions exert marked effects on the activity. For the substituents at C-3', the cytotoxicity decreases in the order 2-furyl approximately 2-methyl-1-propenyl > or = 2-methylpropyl > (E)-1-propenyl > or = n-propyl > phenyl > > 2,2-dimethylpropyl. For the 3'-N substituents, the activity decreases in the order t-BuOCO > Ph > n-hexanoyl. A significant increase in the cytotoxicity against the doxorubicin-resistant human breast cancer cell line MCF7-R that expresses the multidrug resistance (MDR) phenotype is observed by the proper modification of the substituent at C-10. The observed remarkable effects of the substituents at C-10 on the activity against MCF7-R can be ascribed to the effective inhibition of the binding of these new taxoids to P-glycoprotein that is responsible for MDR.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Paclitaxel/análogos & derivados , Taxoides , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/metabolismo , Docetaxel , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Estructura Molecular , Paclitaxel/síntesis química , Paclitaxel/química , Paclitaxel/metabolismo , Paclitaxel/farmacología , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
A series of substituted pyrazinoic acid esters has been prepared and examined for their in vitro activity against Mycobacterium avium and Mycobacterium kansasii as well as Mycobacterium tuberculosis. Modification of both the pyrazine nucleus and the ester functionality have been very successful in expanding the activity of pyrazinamide to include M. avium and M. kansasii, organisms normally not susceptible to pyrazinamide. Several of these compounds have activities 100-1000-fold greater than that of pyrazinamide against M. tuberculosis.
Asunto(s)
Antibacterianos/farmacología , Mycobacterium/efectos de los fármacos , Pirazinamida/análogos & derivados , Ésteres/farmacología , Pruebas de Sensibilidad Microbiana , Pirazinamida/farmacología , Relación Estructura-ActividadRESUMEN
A series of pyrazinoic acid esters has been prepared and evaluated for in vitro antimycobacterial activity. Several of the pyrazinoate esters have substantially better activity than the first-line antituberculous agent pyrazinamide against susceptible isolates of Mycobacterium turberculosis as well as activity against pyrazinamide-resistant isolates. The minimal inhibitory concentrations (MICs) were lower for each organism and at each pH than the MICs for pyrazinamide. The esters have activity against Mycobacterium bovis and Mycobacterium kansasii, two species resistant to pyrazinamide, but not against Mycobacterium avium complex.