RESUMEN
Analogues of the bioactive natural alkoxynaphthalene pycnanthulignene D were synthesized by an efficient method. The starting plant allylalkoxybenzenes (1) are easily available from the plant essential oils of sassafras, dill, and parsley. The target 1-arylalkoxynaphthalenes (5) exhibited antiproliferative activity in a phenotypic sea urchin embryo assay.
Asunto(s)
Lignanos/síntesis química , Anethum graveolens/química , Animales , Antineoplásicos/farmacología , Lignanos/química , Estructura Molecular , Aceites Volátiles , Petroselinum/química , Aceites de Plantas/química , Sassafras/química , Erizos de Mar/efectos de los fármacos , Erizos de Mar/embriologíaRESUMEN
A regioselective synthesis of both 5-amino- and 3-aminodiarylisoxazoles substituted with polyalkoxyaryl pharmacophores has been validated. Starting materials for the synthetic scheme were easily available from plant extracts. The targeted molecules were further tested in the phenotypic sea urchin embryo assay to identify compounds with antimitotic microtubule destabilizing activity. Structure-activity relationship studies suggested that the structural features essential for potent antiproliferative activity include: 1) 5-aminoisoxazole bridge linking biaryl substituents (rings A and B); 2) unsubstituted 5-amino group; 3) 3,4,5-methoxy substituted benzene and 4-methoxy benzene pharmacophores as rings A and B, respectively. The most potent compounds also showed strong in vitro cytotoxicity in NCI60 anticancer drug screen against a panel of 60 human cancer cell lines, including multi-drug resistant cells.
Asunto(s)
Antineoplásicos/síntesis química , Isoxazoles/síntesis química , Moduladores de Tubulina/síntesis química , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Blástula/efectos de los fármacos , Blástula/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Humanos , Isoxazoles/química , Isoxazoles/farmacología , Estructura Molecular , Erizos de Mar/efectos de los fármacos , Erizos de Mar/embriología , Erizos de Mar/metabolismo , Relación Estructura-Actividad , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologíaRESUMEN
A series of 4-azapodophyllotoxin derivatives with modified rings B and E have been synthesized using allylpolyalkoxybenzenes from parsley seed oil. The targeted molecules were evaluated in vivo in a phenotypic sea urchin embryo assay for antimitotic and tubulin destabilizing activity. The most active compounds identified by the in vivo sea urchin embryo assay featured myristicin-derived ring E. These molecules were determined to be more potent than podophyllotoxin. Cytotoxic effects of selected molecules were further confirmed and evaluated by conventional assays with A549 and Jurkat human leukemic T-cell lines including cell growth inhibition, cell cycle arrest, cellular microtubule disruption, and induction of apoptosis. The ring B modification yielded 6-OMe substituted molecule as the most active compound. Finally, in Jurkat cells, compound induced caspase-dependent apoptosis mediated by the apical caspases-2 and -9 and not caspase-8, implying the involvement of the intrinsic caspase-9-dependent apoptotic pathway.