RESUMEN
Our previous studies demonstrated that two cytotoxic ß-nitrostyrene derivatives, 3,4-methylenedioxy-ß-nitrostyrene (MNS) and 4-O-benzoyl-3-methoxy-ß-nitrostyrene (BMNS) exhibit potent anti-platelet activities. In this study, a series of ß-nitrostyrenes were synthesized and subjected to anti-platelet aggregation assay and cytotoxicity assay. The mono- and di-substitutions on the B ring of BMNS tended to increase the anti-platelet activity and decrease the cytotoxic activity. Of these, compounds 19 and 24 exhibited the most potent inhibitory effects on thrombin- and collagen-induced platelet aggregation (IC(50)≤0.7 µM) without significant cytotoxicity on a human cancer cell line (up to 20 µM). Further studies indicated that compounds 19 and 24 inhibited platelet aggregation via prevention of glycoprotein IIb/IIIa activation. The potent and novel effects of BMNS derivatives make them attractive candidates for the development of new anti-platelet agents.
Asunto(s)
Inhibidores de Agregación Plaquetaria/síntesis química , Agregación Plaquetaria/efectos de los fármacos , Estirenos/química , Línea Celular Tumoral , Humanos , Integrina beta3/metabolismo , Inhibidores de Agregación Plaquetaria/química , Inhibidores de Agregación Plaquetaria/toxicidad , Relación Estructura-Actividad , Estirenos/síntesis química , Estirenos/toxicidadRESUMEN
Fifty-two 2-benzoylaminobenzoate analogs were synthesized and subjected to anti-platelet aggregation assay using arachidonic acid (AA), collagen (Col), thrombin (Thr), and U46619 as inducers. The results revealed that most of 2-benzoylaminobenzoic acid derivatives showed a selectively inhibitory effect on AA-induced platelet aggregation. As a result of the 2-benzoylaminobenzoic acid derivatives (18, 44, and 46), there were no inhibitory effects on platelet aggregation induced by U46619, but these elicited an inhibitory effect on thromboxane B(2) formation at 1.0microM. These 2-benzoylaminobenzoate analogs were therefore proposed as cyclooxygenase inhibitors.
Asunto(s)
Aminobenzoatos/síntesis química , Aminobenzoatos/farmacología , Inhibidores de Agregación Plaquetaria/síntesis química , Inhibidores de Agregación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Aminobenzoatos/química , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Inhibidores de Agregación Plaquetaria/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Forty-seven 2-benzoylaminobenzoic esters were synthesized and evaluated in anti-platelet aggregation, inhibition of superoxide anion generation, and inhibition of neutrophil elastase release assays. Most 2-benzoylamino-4-chlorobenzoic acid derivatives showed selective inhibitory effects on arachidonic acid (AA)-induced platelet aggregation. Among them, compounds 6b and 7b exhibited more potent inhibitory effects (ca. 200-fold) than aspirin. Additionally, compounds 1a and 5a showed strong inhibitory effects on neutrophil superoxide generation with IC(50) values of 0.65 and 0.17 microM, respectively. However, compounds 6d and 6e exhibited dual inhibitory effects on platelet aggregation and neutrophil elastase (NE) release; therefore, these two compounds may be new leads for development as anti-inflammatory and anti-platelet aggregatory agents.