RESUMEN
A novel series of (7-aryl-1,5-naphthyridin-2-yl)ureas was discovered as dual ERK2 and Aurora B kinases inhibitors. Several analogues were active at micromolar and submicromolar range against ERK2 and Aurora B, associated with very promising antiproliferative activity toward various cancer cell lines. Synthesis, structure activity relationship and docking study are reported. In vitro ADME properties and safety data are also discussed.
Asunto(s)
Antineoplásicos/farmacología , Aurora Quinasa B/antagonistas & inhibidores , Descubrimiento de Drogas , Proteína Quinasa 1 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Urea/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Aurora Quinasa B/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HCT116 , Humanos , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/químicaRESUMEN
The synthesis and study of the structure-activity relationships of cytotoxic compounds based on N-pyridinyl or N-aryl-2-(1-benzylindol-3-yl)glyoxamide skeleton, represented by the lead structures D-24241 and D-24851, are described. The presence of N-(pyridin-4-yl) moiety was crucial for activity and 2-[1-(4-chloro-3-nitrobenzyl)-1H-indol-3-yl]-2-oxo-N-(pyridin-4-yl)acetamide (55), the most potent derivative, showed IC(50)=39 nM, 51 nM and 11 nM against HeLa/KB (human cervix carcinoma), L1210 (murine leukemia) and SKOV3 (human ovarian carcinoma) cell lines proliferation assay, respectively, as active as the lead compounds.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Indoles/química , Indoles/farmacología , Compuestos de Sulfonilurea/química , Compuestos de Sulfonilurea/farmacología , Animales , Antineoplásicos/síntesis química , Carcinoma/tratamiento farmacológico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Células HeLa , Humanos , Indoles/síntesis química , Leucemia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Relación Estructura-Actividad , Compuestos de Sulfonilurea/síntesis química , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
New series of analogues of N-(pyridin-4-yl)-2-[1-(4-chlorobenzyl)-indol-3-yl]glyoxamide D-24851 were synthesized, characterized and tested for their in vitro anticancer properties. In the first series, an amino acid spacer was introduced in the glyoxamide chain of D-24851. In the second series, the glyoxamide chain was moved to positions 4 and 5 of indole skeleton. These new compounds were tested on four cancer cell lines (KB, SK-OV-3, NCI-H460 and SF-268), with promising activity for the glycine derivative.
Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Antineoplásicos/síntesis química , Indoles/química , Indoles/farmacología , Antineoplásicos/farmacología , Línea Celular Tumoral , Glicina , Humanos , Relación Estructura-ActividadRESUMEN
As part of our research projects to identify new chemical entities of biological interest, we developed a synthetic approach and the biological evaluation of (7-aryl-1,5-naphthyridin-4-yl)ureas as a novel class of Aurora kinase inhibitors for the treatment of malignant diseases based on pathological cell proliferation. 1,5-Naphthyridine derivatives showed excellent inhibitory activities toward Aurora kinases A and B, and the most active compound, 1-cyclopropyl-3-[7-(1-methyl-1H-pyrazol-4-yl)-1,5-naphthyridin-4-yl]urea (49), displayed IC50 values of 13 and 107â nM against Aurora kinases A and B, respectively. In addition, the selectivity toward a panel of seven cancer-related protein kinases was highlighted. In vitro ADME properties were also determined in order to rationalize the difficulties in correlating antiproliferative activity with Aurora kinase inhibition. Finally, the good safety profile of these compounds imparts promising potential for their further development as anticancer agents.
Asunto(s)
Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa B/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/análogos & derivados , Urea/análogos & derivados , Animales , Aurora Quinasa A/genética , Aurora Quinasa A/metabolismo , Aurora Quinasa B/genética , Aurora Quinasa B/metabolismo , Células CACO-2 , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Células HCT116 , Semivida , Humanos , Ratones , Microsomas Hepáticos/metabolismo , Naftiridinas/química , Unión Proteica , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Relación Estructura-Actividad , Urea/farmacocinética , Urea/farmacologíaRESUMEN
A novel series of 2,3-diarylimidazo[1,2-a]pyridines was synthesized and evaluated for their antileishmanial activities. Four derivatives exhibited good activity against the promastigote and intracellular amastigote stages of Leishmania major, coupled with a low cytotoxicity against the HeLa human cell line. The impact of compound lipophilicity on antiparasitic activities was investigated by Log D comparison. Although LmCK1 could be the parasitic target for three compounds (13, 18, 21), the inhibition of another target is under study to explain the antileishmanial effect of the most promising compounds.