RESUMEN
An indazole based series of glucocorticoid receptor agonists is reported. The SAR exploration of this scaffold yielded compounds with nanomolar affinity for the glucocorticoid receptor with indications of selectivity for the preferred transrepression mechanism; in vivo efficacy was observed in the mouse LPS induced TNFalpha model for compound 28.
Asunto(s)
Antiinflamatorios/química , Indazoles/química , Receptores de Glucocorticoides/agonistas , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/farmacología , Indazoles/síntesis química , Indazoles/farmacología , Ratones , Receptores de Glucocorticoides/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).
Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Purinas/síntesis química , Purinas/química , Roscovitina , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
C-6 Biarylmethylamino purine derivatives of roscovitine (1) inhibit cyclin dependent kinases and demonstrate potent antiproliferative activity. Replacement of the aryl rings of the C-6 biarylmethylamino group with heterobiaryl rings has provided compounds with significantly improved activity. In particular, derivatives 18 g and 9 c demonstrated 1000-fold and 1250-fold improvements, respectively, in the growth inhibition of HeLa cells compared to roscovitine (1).
Asunto(s)
Antineoplásicos/farmacología , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Purinas/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Purinas/síntesis química , Purinas/química , Roscovitina , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Versatile intermediates 12'-iodovinblastine, 12'-iodovincristine and 11'-iodovinorelbine were utilized as substrates for transition metal based chemistry which led to the preparation of novel analogues of the vinca alkaloids. The synthesis of key iodo intermediates, their transformation into final products, and the SAR based upon HeLa and MCF-7 cell toxicity assays is presented. Selected analogues 27 and 36 show promising anticancer activity in the P388 murine leukemia model.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Vinblastina/análogos & derivados , Alcaloides de la Vinca/síntesis química , Alcaloides de la Vinca/farmacología , Vincristina/análogos & derivados , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Modelos Animales de Enfermedad , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Leucemia P388 , Ratones , Estructura Molecular , Relación Estructura-Actividad , Vinblastina/síntesis química , Vinblastina/química , Vinblastina/farmacología , Alcaloides de la Vinca/química , Vincristina/síntesis química , Vincristina/química , Vincristina/farmacologíaRESUMEN
A series of A-ring and E-ring analogues of the natural product luotonin A, a known topoisomerase I poison, was evaluated for growth inhibition in human carcinoma and leukemia cell lines. Rational design of structures was based on analogues of the related alkaloid camptothecin, which has been demonstrated to exert cytotoxic effects by the same mechanism of action. When compared to luotonin A, several compounds exhibited an improved topoisomerase I-dependent growth inhibition of a human leukemia cell line.
