RESUMEN
A series of 3,7-diaryl-6,7-dihydroisothiazolo [4,5-b]pyridin-5(4H)-ones 8 and 9 was synthesized by multicomponent condensation of 3-aryl-5-isothiazolecarboxylic acid esters 4a-f with aromatic (or thienyl) aldehydes 7 and Meldrum's acid in an acidic medium. The targeted compounds were evaluated for their antimitotic microtubule destabilizing activity using in vivo phenotypic sea urchin embryo model and in vitro human cancer cell-based assays. Selected dihydroisothiazolopyridinones altered sea urchin egg cleavage in 2-10 nM concentrations together with significant cytotoxicity against cancer cells including chemoresistant cell lines (IC50 in submicromolar - low nanomolar concentration range). Both approaches confirmed antimitotic microtubule destabilizing mechanism of action of the izothiazole derivatives. Structure-activity relationship study determined the importance of p-methoxybenzene A-ring for the antiproliferative effect. The most potent compound 9b containing p-methoxybenzene A-ring and thiophene B-ring caused mitotic arrest and disintegration of cell microtubules.
Asunto(s)
Mitosis/efectos de los fármacos , Pirimidinas/síntesis química , Pirimidinas/farmacología , Erizos de Mar/efectos de los fármacos , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Antimitóticos/síntesis química , Antimitóticos/química , Antimitóticos/farmacología , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Embrión no Mamífero/efectos de los fármacos , Humanos , Microtúbulos/efectos de los fármacos , Estructura Molecular , Pirimidinas/química , Relación Estructura-Actividad , Tiazoles/químicaRESUMEN
We have synthesized a series of novel cis-restricted 4,5-polyalkoxydiaryl-3-aminopyrazole analogues of combretastatins via short synthetic sequences using building blocks isolated from dill and parsley seed extracts. The resulting compounds were tested in vivo in the phenotypic sea urchin embryo assay to reveal their antimitotic and antitubulin effects. The most potent aminopyrazole, 14a, altered embryonic cell division at 10 nM concentration, exhibiting microtubule-destabilizing properties. Compounds 12a and 14a displayed pronounced cytotoxicity in the NCI60 anticancer drug screen, with the ability to inhibit growth of multi-drug-resistant cancer cells.
Asunto(s)
Bibencilos/química , Pirazoles/química , Anethum graveolens/química , Animales , Antimitóticos/farmacología , Antineoplásicos/farmacología , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Embrión no Mamífero/efectos de los fármacos , Humanos , Resonancia Magnética Nuclear Biomolecular , Petroselinum/química , Pirazoles/farmacología , Erizos de Mar/embriología , Estereoisomerismo , Relación Estructura-Actividad , Moduladores de Tubulina/farmacologíaRESUMEN
Phenstatin and its derivatives with the modified ring A have been synthesized, using plant allylpolyalkoxybenzenes as a starting material. The targeted molecules were evaluated in a phenotypic sea urchin embryo assay for antiproliferative activity. It was found that phenstatin ring A modifications yielded antimitotic compounds. The most effective myristicin derivative 7d (combretastatin A-2 analogue) was determined to be ca. 10 times more potent than phenstatin, displaying antimitotic tubulin-destabilizing activity at the same concentration range as combretastatins. In contrast to combretastatins, 7d featured the steric stability with potential for further design as anticancer agent.