RESUMEN
Various 5-amino group-substituted indeno[1,2-c]isoquinolines 7a-f were synthesized based on the previous QSAR study as rigid structures of 3-arylisoquinolines. Amino group-substituted compounds, especially 5-piperazinyl indeno[1,2-c]isoquinoline 7f, displayed potent topoisomerase I inhibitory activity as well as cytotoxicities against five different tumor cell lines. A Surflex-Dock docking model of 7f was also studied.
Asunto(s)
ADN-Topoisomerasas de Tipo I/química , Isoquinolinas/química , Piperazinas/síntesis química , Inhibidores de Topoisomerasa I/síntesis química , Sitios de Unión , Línea Celular Tumoral , Simulación por Computador , ADN-Topoisomerasas de Tipo I/metabolismo , Diseño de Fármacos , Humanos , Isoquinolinas/síntesis química , Isoquinolinas/toxicidad , Piperazinas/química , Piperazinas/toxicidad , Relación Estructura-Actividad Cuantitativa , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/toxicidadRESUMEN
Induction of differentiation is a new and promising approach to cancer therapy, well illustrated by the treatment of acute myeloid leukemia with all-trans retinoic acid (ATRA). Using combination of ATRA and chemotherapy, adverse effects such as retinoic acid syndrome have decreased, and long-term survival has improved. In this study, we demonstrated that the indeno[1,2-c]isoquinolines markedly enhanced differentiation of human myeloid leukemia HL-60 and NB4 cells when simultaneously combined with a low dose of ATRA. Of the tested compounds, 6-(4-methoxybenzyl)-2,11-dimethyl-6H,11H-indeno[1,2-c]isoquinolin-5-one (IIQ-16), an indeno[1,2-c]isoquinoline derivative, showed the highest differentiation-enhancing activity via a pathway involved with protein kinase C, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. The ability to enhance the differentiation potential of ATRA by IIQ-16 may improve outcomes in the therapy of acute promyelocytic leukemia.
Asunto(s)
Diferenciación Celular/efectos de los fármacos , Indenos/química , Isoquinolinas/química , Isoquinolinas/farmacología , Leucemia Mieloide/patología , Tretinoina/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Humanos , Isoquinolinas/síntesis química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
11-hydroxyindeno[1,2-c]isoquinolines 12a-c were prepared as constrained forms of 3-arylisoquinolines through an intramolecular cyclization reaction. Among the synthesized compounds, the 11-(i)butoxy analog 15l displayed potent in vitro cytotoxicity against four different tumor cell lines as well as topoisomerase 1 inhibitory activity. A FlexX docking study was performed to explain the topoisomerase 1 activity of 15l.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Isoquinolinas/síntesis química , Inhibidores de Topoisomerasa I , Línea Celular Tumoral , ADN-Topoisomerasas de Tipo I/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Enlace de Hidrógeno , Isoquinolinas/química , Isoquinolinas/farmacología , Modelos Moleculares , Estructura MolecularRESUMEN
An intramolecular radical cyclization reaction of 4-bromo-3-arylisoquinolines 11a-c allowed the efficient synthesis of 11-methylindenoisoquinolines 2a-c. 5-(2-Aminoethylamino)indeno[1,2-c]isoquinolin-11-one 4 was also prepared in the convenient manner. The synthesized compounds were tested in vitro for cytotoxicity and DNA-topoisomerase 1 (top 1) inhibitory activity. The dramatic enhancement of top 1 inhibitory activity of 4 was explained by a docking study using the FlexX program.