RESUMO
Analogues of the natural product noscapine were synthesized and their potential as antitumor agents evaluated. The discovery of a novel regioselective O-demethylation facilitated the synthesis of the potent aniline 6, which arrests mammalian cells in the G2/M phase of the cell cycle at 0.1 microM and also affects tubulin polymerization. Aniline 6 is orally bioavailable and is 250-fold more potent than noscapine in reducing cell proliferation in rapidly dividing cells.
Assuntos
Antineoplásicos/síntese química , Noscapina/análogos & derivados , Noscapina/síntese química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Biopolímeros , Linhagem Celular , Ensaios de Seleção de Medicamentos Antitumorais , Fase G2/efeitos dos fármacos , Células HeLa , Humanos , Camundongos , Microtúbulos/efeitos dos fármacos , Noscapina/farmacocinética , Noscapina/farmacologia , Estereoisomerismo , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
The 5-HT2C receptor has been implicated in the regulation of appetite. As such, small molecule agonists to this receptor may serve as novel therapies to combat obesity. We describe here the identification, synthesis, and SAR of a 5-HT2C agonist from a unique pyrimidine-diazabicyclo[3.3.0]octane series. This compound displayed good potency at the 5-HT2C receptor, modest selectivity relative to other 5-HT2 receptors, and was efficacious in an acute feeding study in rats.
Assuntos
Compostos Aza/química , Compostos Aza/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor 5-HT2 de Serotonina , Aminas/química , Animais , Compostos Aza/síntese química , Compostos Bicíclicos com Pontes/síntese química , Estrutura Molecular , Pirimidinas/síntese química , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
5-HT2C agonists have shown efficacy in limiting food consumption and thus may serve as an important drug class in combating obesity. We describe the design and synthesis of a novel tricyclic single-nitrogen scaffold that was used to produce 5-HT2C agonists. SAR was developed around this chemotype and compounds were identified that were potent (Ki<15 nM) and selective relative to other 5-HT2 receptors. The most promising compound displayed a good pharmacokinetic profile in multiple animal species, and was efficacious in an acute feeding study in rats.
Assuntos
Nitrogênio/química , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/síntese química , Agonistas do Receptor de Serotonina/farmacologia , Animais , Cães , Desenho de Fármacos , Comportamento Alimentar/efeitos dos fármacos , Meia-Vida , Ratos , Agonistas do Receptor de Serotonina/química , Agonistas do Receptor de Serotonina/farmacocinética , Relação Estrutura-AtividadeRESUMO
Overexpression of endoplasmic reticulum-localized NADPH: cytochrome c (P450) reductase (NPR) in Chinese hamster ovary cells increases the hypoxic/aerobic differential toxicity of the mitomycins. Because considerable evidence indicates that DNA cross-links are the major cytotoxic lesions generated by the mitomycins, we proposed that bioactivation of the mitomycins in the nucleus close to the DNA target would influence the cytotoxicity of these drugs. The simian virus 40 large T antigen nuclear localization signal was fused to the amino-terminal end of a human NPR protein that lacked its membrane anchor sequence. Immunofluorescent imaging of transfected cell lines expressing the fusion protein confirmed the nuclear location of the enzyme. Regardless of the oxygenation state of the cell, mitomycin C (MC) cytotoxicity was enhanced in cells with overexpressed NPR localized to the nuclear compartment compared with cells overexpressing an endoplasmic reticulum localized enzyme. Enhanced cytotoxicity in cells treated under hypoxic conditions correlated with increases in genomic DNA alkylations, with more MC-DNA adducts being formed when the enzyme was expressed closer to its DNA target. No change was observed in the hypoxic/aerobic differential toxicity as a function of enzyme localization. These findings indicate that drug efficacy is increased when the subcellular site of drug activation corresponds to its site of action.