RESUMEN
The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17beta-cyanomethylestra-1,3,5(10)-trien-3-ol ( 14), but not the related 2-ethyl derivative 7, and the related 3- O-sulfamates 8 and 15 display potent antiproliferative effects (MCF-7 GI 50 300, 60 and 70 nM, respectively) against human cancer cells in vitro. Investigation of the SAR reveals that a sterically unhindered hydrogen bond acceptor attached to C-17 is most likely key to the enhanced activity. Compound 8 displayed significant in vitro antiangiogenic activity, and its ability to act as a microtubule disruptor was confirmed. Inhibitory activity of the sulfamate derivatives against steroid sulfatase and carbonic anhydrase II (hCAII) was also observed, and the interaction between 15 and hCAII was investigated by protein crystallography. The potential of these multimechanism anticancer agents was confirmed in vivo, with promising activity observed for both 14 and 15 in an athymic nude mouse MDA-MB-231 human breast cancer xenograft model.
Asunto(s)
Antineoplásicos/síntesis química , Estradiol/análogos & derivados , Estrenos/síntesis química , Modelos Moleculares , Nitrilos/síntesis química , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Inhibidores de la Angiogénesis/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Anhidrasa Carbónica II/metabolismo , Inhibidores de Anhidrasa Carbónica/síntesis química , Inhibidores de Anhidrasa Carbónica/química , Inhibidores de Anhidrasa Carbónica/farmacología , Línea Celular Tumoral , Cristalografía por Rayos X , Ensayos de Selección de Medicamentos Antitumorales , Estradiol/síntesis química , Estradiol/química , Estradiol/farmacología , Estrenos/química , Estrenos/farmacología , Femenino , Humanos , Ratones , Ratones Desnudos , Conformación Molecular , Trasplante de Neoplasias , Nitrilos/química , Nitrilos/farmacología , Estereoisomerismo , Esteril-Sulfatasa/antagonistas & inhibidores , Relación Estructura-Actividad , Trasplante Heterólogo , Moduladores de Tubulina/síntesis química , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
A series of combretastatins substituted with epoxides, amides and small alkyl groups has been synthesised and evaluated for cytotoxicity and their ability to inhibit the assembly of tubulin. The methyl and ethyl substituted phenols 36, 44 have shown potent antimitotic effects whilst exhibiting reduced cytotoxicity.
Asunto(s)
Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Bibencilos/síntesis química , Bibencilos/farmacología , Estilbenos/síntesis química , Estilbenos/farmacología , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Antineoplásicos/química , Bibencilos/química , Ciclo Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Compuestos Epoxi/síntesis química , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Formazáns/química , Humanos , Concentración 50 Inhibidora , Células K562 , Espectroscopía de Resonancia Magnética , Estructura Molecular , Espectrofotometría Ultravioleta , Estilbenos/química , Sales de Tetrazolio/química , Tubulina (Proteína)/metabolismo , Moduladores de TubulinaRESUMEN
A series of combretastatins possessing both a trimethoxy unit and other substituents on ring A has been synthesised and tested for cytotoxicity and their ability to interact with the protein tubulin. All previous studies have indicated that the trimethoxy unit is essential for interaction with tubulin. The studies herein show that molecules possessing functionalities other than trimethoxy can also interact with tubulin. Importantly a trimethyl substituted agent 52a has shown reduced cytotoxicity, but increased potency in its ability to inhibit the assembly of tubulin.