RESUMEN
Novel purine-pyrazole hybrids combining thiazoles, thiazolidinones and rhodanines, were designed and tested as 15-LOX inhibitors, potential anticancer and antioxidant agents. All tested compounds were found to be potent 15-LOX inhibitors with IC50 ranging from 1.76 to 6.12⯵M. The prepared compounds were evaluated in vitro against five cancer cell lines: A549 (lung), Caco-2 (colon), PC3 (prostate), MCF-7 (breast) and HepG-2 (liver). Compounds 7b and 8b displayed broad spectrum anticancer activity against the five tested cell lines (IC50â¯=â¯18.5-95.39⯵M). While, compound 7h demonstrated moderate anticancer activity against lung A549 and colon Caco-2 cell lines. Antioxidant screening revealed that six compounds (5a, 5b, 6b, 7b, 7h and 8b) with IC50 ranging from 0.93 to 14.43⯵g/ml were found to be more potent scavengers of 2,2- diphenyl-1-picrylhydrazyl (DPPH) than the reference ascorbic acid with IC50 value of 15.34⯵g/ml. Compounds 7b, 7h and 8b, when evaluated for their antioxidant activity, where found to be potent DPPH scavengers. Moreover, compound 7b displayed twice the potency of ascorbic acid as NO scavenger. Docking study was performed to elucidate the possible binding mode of the most active compounds with the active site of 15-LOX enzyme. Collectively, the purine-pyrazole hybrids having thiazoline or thizolidinone moieties (7b, 7h and 8b) constitute a promising scaffold in designing more potent 15-LOX inhibitors with anticancer and antioxidant potential.
Asunto(s)
Antineoplásicos/farmacología , Antioxidantes/farmacología , Araquidonato 15-Lipooxigenasa/metabolismo , Inhibidores de la Lipooxigenasa/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Antioxidantes/síntesis química , Antioxidantes/química , Compuestos de Bifenilo/antagonistas & inhibidores , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/química , Simulación del Acoplamiento Molecular , Estructura Molecular , Picratos/antagonistas & inhibidores , Purinas/química , Purinas/farmacología , Pirazoles/química , Pirazoles/farmacología , Rodanina/química , Rodanina/farmacología , Relación Estructura-Actividad , Tiazoles/química , Tiazoles/farmacología , Tiazolidinas/química , Tiazolidinas/farmacologíaRESUMEN
AIM: Targeting apoptosis regulators such as caspases aiming at inducing apoptosis is an attractive strategy in cancer therapy. MATERIALS & METHODS: 8-substituted purine incorporating pyrazole moiety were designed, synthesized and evaluated for their anticancer and antioxidant activities. RESULTS: Compounds 7a and 8a displayed potent and selective anticancer activity against lung cancer A549 cell line with low cytotoxicity on peripheral blood mononuclear normal cells. Compounds 7a and 8a induced caspase dependent apoptotic death and DNA damage in all cancer cell lines. In addition, compounds 2, 5, 6a, 7a, 8a, 8c, 11a, 11b and 12b showed good antioxidant activity higher than that of the standard ascorbic acid. CONCLUSION: Compounds 7a and 8a can be considered promising dual anticancer and antioxidant leads inducing caspase-dependent apoptotic death and DNA damage.