RESUMEN
A series of twenty-six carbamates derived from aminocombretastatin A-4 (AmCA-4) were synthesized and evaluated for their capacity to affect cell proliferation, tubulin polymerization, mitotic cell arrest, microtubule network organization, apoptosis and endothelial tubular structures in vitro. The anti-proliferative activity of the synthetic carbamates was measured on several human tumor cell lines (i.e. HT-29, MCF-7, HeLa, A-549, MDA-MB-231, HL-60) as well as on the endothelial cell line HMEC-1 and the non-tumor cell line HEK-293. The compounds showed anti-proliferative activity in the nanomolar range thereby exceeding by far the activity of combretastatin A-4 (CA-4) and, in some cases, the activity of AmCA-4. The most active compounds proved to be the carbamates bearing chloro, bromo or methoxy groups in the meta position of the phenyl ring. Moreover, all carbamates inhibited in vitro tubulin polymerization, in a similar manner to that of CA-4 and AmCA-4 by interacting with the colchicine binding site in tubulin. The synthetic carbamates proved as active as AmCA-4 in causing mitotic arrest, as assessed in A549 human lung cancer cells, and disruption of the microtubule cellular network. Some selected carbamates induced apoptosis at concentrations as low as 10â¯nM, being more active than AmCA-4. Finally, these selected carbamates displayed a vascular disrupting activity on endothelial cells in a dose-dependent manner. In conclusion, our data indicate that carbamates derived from aminocombretastatin A-4 represent interesting lead compounds for the design of vascular disrupting agents.
Asunto(s)
Antineoplásicos/farmacología , Carbamatos/farmacología , Células Endoteliales/efectos de los fármacos , Estilbenos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Carbamatos/síntesis química , Carbamatos/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células Endoteliales/metabolismo , Humanos , Microtúbulos/efectos de los fármacos , Microtúbulos/metabolismo , Mitosis/efectos de los fármacos , Estructura Molecular , Polimerizacion/efectos de los fármacos , Estilbenos/síntesis química , Estilbenos/química , Relación Estructura-Actividad , Tubulina (Proteína)/metabolismoRESUMEN
We here describe the preparation of a series of hybrid molecules containing a combretastatin A-4 moiety and a pironetin analogue fragment connected through a spacer of variable length which includes a 1,2,3-triazole ring. The cytotoxic activities of these compounds have been measured. Relations between structure and cytotoxicity are discussed. Some of the tested compounds showed cytotoxicity values of the same order of magnitude as combretastatin A-4 and were less toxic than the latter compound for normal cells.
Asunto(s)
Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/farmacología , Bibencilos/química , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Neoplasias/tratamiento farmacológico , Pironas/química , Triazoles/química , Células Cultivadas , Ensayos de Selección de Medicamentos Antitumorales , Citometría de Flujo , Células HEK293 , Humanos , Estructura Molecular , Neoplasias/metabolismo , Relación Estructura-ActividadRESUMEN
The first syntheses of the polyhydroxylated alkaloids (iminosugars) broussonetines D and M, glycosidase inhibitors of the pyrrolidine class, have been performed in a convergent, stereocontrolled way from D-serine as the chiral starting material. A cross metathesis step was one key feature of the synthesis. The versatility of the synthetic concept chosen permits the access to many members of this compound family, both natural ones and analogues thereof.