RESUMEN
(19)F-modified bithiazole correctors and phenylglycine potentiators of the ΔF508-CFTR chloride channel were synthesized and their function assayed in cells expressing human ΔF508-CFTR and a halide-sensitive fluorescent protein. Fluorine was incorporated into each scaffold using prosthetic groups for future biodistribution imaging studies using positron emission tomography (PET). The ΔF508-CFTR corrector and potentiator potencies of the fluorinated analogs were comparable to or better than those of the original compounds.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/química , Radioisótopos de Flúor , Tomografía de Emisión de Positrones/métodos , Humanos , Estructura MolecularRESUMEN
Irradiation of 1,2-dimethyl-3-hydroxyquinolinone (DMQ) leads to excited state intramolecular proton transfer (ESIPT) generating a 3-oxidoquinolinium species which undergoes [3 + 2] photocycloaddition with dipolarophiles. A parallel, fluorescence quenching assay using a microplate format has been developed to evaluate fluorescence quenching of this species with a range of dipolarophiles.
Asunto(s)
Flavonoides/química , Quinolonas/química , Fluorescencia , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Procesos Fotoquímicos , Protones , Quinolonas/efectos de la radiaciónRESUMEN
A number of novel benzo-1,3-dioxolo-, benzothiazolo-, pyrido-, and quinolino-fused 5H-benzo[d]pyrazolo[5,1-b][1,3]-oxazines and 1H-pyrazoles were synthesized utilizing an easy and effective N,N-bond forming heterocyclization reaction. In so doing, the substrate scope of this heterocyclization reaction, which starts with o-nitroheterocyclic aldehydes, was expanded to provide several unique heterocyclic compounds for biological screening. This work further demonstrates the versatility of this simple, base-mediated, one-pot heterocyclization method in the construction of novel heterocycles.
Asunto(s)
Derivados del Benceno/síntesis química , Benzotiazoles/síntesis química , Dioxoles/síntesis química , Compuestos Heterocíclicos de 4 o más Anillos/síntesis química , Pirazoles/síntesis química , Piridinas/síntesis química , Quinolinas/síntesis química , Aldehídos/química , Derivados del Benceno/química , Benzotiazoles/química , Técnicas Químicas Combinatorias , Ciclización , Dioxoles/química , Compuestos Heterocíclicos de 4 o más Anillos/química , Indazoles/síntesis química , Indazoles/química , Estructura Molecular , Oxazinas/síntesis química , Oxazinas/química , Pirazoles/química , Piridinas/química , Quinolinas/químicaRESUMEN
Integrin alpha(4)beta(1) is an attractive but poorly understood target for selective diagnosis and treatment of T-cell and B-cell lymphomas. This report focuses on the rapid microwave preparation, structure-activity relationships, and biological evaluation of medicinally pertinent benzimidazole heterocycles as integrin alpha(4)beta(1) antagonists. We documented tumor uptake of derivatives labeled with (125)I in xenograft murine models of B-cell lymphoma. Molecular homology models of integrin alpha(4)beta(1) predicted that docked halobenzimidazole carboxamides have the halogen atom in a suitable orientation for halogen-hydrogen bonding. The high-affinity halogenated ligands identified offer attractive tools for medicinal and biological use, including fluoro and iodo derivatives with potential radiodiagnostic ((18)F) or radiotherapeutic ((131)I) applications, or chloro and bromo analogues that could provide structural insights into integrin-ligand interactions through photoaffinity, cross-linking/mass spectroscopy, and X-ray crystallographic studies.
Asunto(s)
Bencimidazoles/farmacología , Integrina alfa4beta1/antagonistas & inhibidores , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Secuencia de Aminoácidos , Animales , Bencimidazoles/química , Bencimidazoles/farmacocinética , Femenino , Radioisótopos de Flúor/química , Integrina alfa4beta1/metabolismo , Radioisótopos de Yodo/química , Marcaje Isotópico , Linfoma de Células B/metabolismo , Linfoma de Células T/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Modelos Moleculares , Datos de Secuencia Molecular , Radiofármacos/química , Radiofármacos/farmacocinética , Radiofármacos/farmacología , Relación Estructura-Actividad , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The novel heterocycle 2,3-dihydrooxazolo[3,2-b]indazole has been synthesized and utilized to provide easy access to 1H-indazolones, particularly the previously unreported 2-(2-alkoxyethyl)-1H-indazol-3(2H)-ones. Mechanistic as well as optimization and reaction scope studies are reported.
Asunto(s)
Indazoles/síntesis química , Oxazoles/química , Alcoholes/química , Bencilaminas/química , Indazoles/química , Estructura MolecularRESUMEN
The parent 5H-indazolo[3,2-b]benzo[d]-1,3-oxazine heterocycle as well as a series of novel analogues have been synthesized utilizing two subsequent intramolecular heterocyclizations in one pot. A variety of diversity groups were added to explore the scope of this reaction and to provide a number of new compounds for biological screening.