RESUMO
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.
Assuntos
Lignanas/síntese química , Anethum graveolens/química , Animais , Antineoplásicos/farmacologia , Lignanas/química , Estrutura Molecular , Óleos Voláteis , Petroselinum/química , Óleos de Plantas/química , Sassafras/química , Ouriços-do-Mar/efeitos dos fármacos , Ouriços-do-Mar/embriologiaRESUMO
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.
Assuntos
Antineoplásicos/síntese química , Isoxazóis/síntese química , Moduladores de Tubulina/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Blástula/efeitos dos fármacos , Blástula/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Isoxazóis/química , Isoxazóis/farmacologia , Estrutura Molecular , Ouriços-do-Mar/efeitos dos fármacos , Ouriços-do-Mar/embriologia , Ouriços-do-Mar/metabolismo , Relação Estrutura-Atividade , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologiaRESUMO
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.
Assuntos
Antimitóticos/síntese química , Compostos Aza/síntese química , Petroselinum/química , Podofilotoxina/análogos & derivados , Podofilotoxina/síntese química , Animais , Antimitóticos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Aza/farmacologia , Caspase 2/metabolismo , Caspase 9/metabolismo , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/fisiologia , Humanos , Microtúbulos/efeitos dos fármacos , Microtúbulos/ultraestrutura , Extratos Vegetais/química , Óleos de Plantas/química , Podofilotoxina/farmacologia , Ouriços-do-Mar/efeitos dos fármacos , Ouriços-do-Mar/embriologia , Sementes/química , Estereoisomerismo , Relação Estrutura-Atividade , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/farmacologiaRESUMO
We have devised a 'one-pot' phenotypic in vivo assay for the rapid evaluation of potential tubulin inhibitors using the sea urchin embryo model. An effect of a small molecule on two specific developmental stages of sea urchin embryo, namely: (i) fertilized egg test for antimitotic activity and (ii) behavioral monitoring of a free-swimming blastulae for changes in the embryo swimming pattern could be quantified by a threshold concentration resulting in respective abnormalities. Derivatives of the clinical candidate D-24851 featured good correlation between activity in tubulin polymerization assay and our in vivo data. Importantly, we demonstrated that in these series, the N-substitution of indole is non-essential to attain profound in vitro and cellular effects.