RESUMO
Embedded in a polymer: A hydrophobic organic molecule that fluoresces in the near-infraredâ II (NIR-II) region was made water-soluble and biocompatible by its embedment in a polymer nanoparticle, which was then coated with hydrophilic poly(ethylene glycol) chains. The resulting nanoparticles exhibit bright fluorescence in the NIR-II window and high photostability in aqueous media and were used for inâ vivo imaging in mice.
Assuntos
Corantes Fluorescentes/química , Nanopartículas/química , Polímeros/química , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Resinas Acrílicas/química , Animais , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Camundongos , Camundongos Nus , Microscopia de Força Atômica , Fosfatidiletanolaminas/química , Polietilenoglicóis/químicaRESUMO
We designed and synthesized hydroxamic acid derivatives bearing a 4-(3-pyridyl)phenyl group as a cap structure, and found that they exhibit potent histone deacetylase (HDAC) inhibitory activity. A representative compound, 17a, showed more potent growth-inhibitory activity against pancreatic cancer cells and greater upregulation of p21(WAF1/CIP1) expression than the clinically used HDAC inhibitor suberoylanilide hydroxamic acid (Zolinza).
Assuntos
Antineoplásicos/síntese química , Inibidor de Quinase Dependente de Ciclina p21/biossíntese , Inibidores Enzimáticos/síntese química , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/química , Indóis/química , Neoplasias Pancreáticas/tratamento farmacológico , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Humanos , Ácidos Hidroxâmicos/farmacologia , Regulação para Cima , VorinostatRESUMO
A series of hydroxamic acid derivatives bearing a cyclic amide/imide group as a linker and/or cap structure, prepared during our structural development studies based on thalidomide, showed class-selective potent histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that the steric character of the substituent introduced at the cyclic amide/imide nitrogen atom, the presence of the amide/imide carbonyl group, the hydroxamic acid structure, the shape of the linking group, and the distance between the zinc-binding hydroxamic acid group and the cap structure are all important for HDAC-inhibitory activity and class selectivity. A representative compound (30w) showed potent p21 promoter activity, comparable with that of trichostatin A (TSA), and its cytostatic activity against cells of the human prostate cell line LNCaP was more potent than that of the well-known HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA).
Assuntos
Amidas/química , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Ácidos Hidroxâmicos/química , Imidas/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Histona Desacetilases/química , Histona Desacetilases/metabolismo , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Several hydroxamic acid derivatives with a substituted phthalimide group as a linker and/or cap structure, prepared during structural development studies based on thalidomide, were found to have histone deacetylase (HDAC)-inhibitory activity. Structure-activity relationship studies indicated that nature of the substituent introduced at the phthalimide nitrogen atom, introduction of a hydroxamic acid structure, and distance between the N-hydroxyl group and the cap structure are important for HDAC-inhibitory activity.
Assuntos
Inibidores Enzimáticos/química , Inibidores de Histona Desacetilases , Ftalimidas/química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ftalimidas/síntese química , Ftalimidas/farmacologia , Relação Estrutura-AtividadeRESUMO
Thalidomide (Thal: 1) and its two metabolites, 5-hydroxythalidomide (5-HT: 2) and N-hydroxythalidomide (N-HT: 3), showed an enhancing effect on all-trans retinoic acid (ATRA)-induced HL-60 cell differentiation. 5-HT and N-HT showed tubulin polymerization-inhibiting activity, but thalidomide did not.
