RESUMO
Current chemical and biological interest in indole-3-carbinol (I3C) and its metabolites has resulted in the discovery of new biologically active indoles. As part of a program aimed at the development of indole analogues, tetraindoles 1-15 were prepared and their antiproliferative effects on human breast cancer cells were evaluated. The results show that the 5-hydroxy-tetraindole 8 (SK228) has optimum antiproliferative activity against breast adenocarcinoma (MCF 7 and MDA-MB-231) cells and that this activity involves G(2)-phase arrest of the cell cycle with a distinctive increase in the expression of cyclin B1 and phospho-cdc2. Further observations suggest that 5-hydroxy-tetraindole 8 induces apoptosis through externalization of membrane phosphatidylserine, DNA fragmentation, and activation of caspase-3. Given the fact that I3C and its metabolites have been shown to improve therapeutic efficacy and to have a broad range of antitumor activities in human cancer cells, the current findings have important pharmacological relevance as they open a promising route to the development of a potential chemotherapeutic application of tetraindoles as agents for the treatment of breast cancer.
Assuntos
Antineoplásicos/síntese química , Apoptose/efeitos dos fármacos , Fase G2/efeitos dos fármacos , Indóis/síntese química , Xilenos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/química , Indóis/farmacologia , Relação Estrutura-Atividade , Xilenos/química , Xilenos/farmacologiaRESUMO
Isomalyngamide A (1) and A-1 (2) were isolated from the Taiwanese Lyngbya majuscule and the latter structure was elucidated by a combination of NMR spectroscopic analysis and HRESIMS measurement. We report the isolation of isomalyngamide A (1), discovery of isomalyngamide A-1 (2) and their synthetic analogs (3-9), which are further demonstrated to have therapeutic potential against tumor cell migration at the level of nanomolar to micromolar ranges, perhaps, by inactivating the expression of p-FAK, FAK, p-Akt and Akt through ß1 integrin-mediated antimetastatic pathway.
Assuntos
Amidas/farmacologia , Movimento Celular/efeitos dos fármacos , Neoplasias/patologia , Pirróis/farmacologia , Amidas/química , Western Blotting , Linhagem Celular Tumoral , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Integrina beta1/metabolismo , Espectroscopia de Ressonância Magnética , Metástase Neoplásica/prevenção & controle , Neoplasias/enzimologia , Neoplasias/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirróis/química , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas de Bombardeamento Rápido de Átomos , Espectrofotometria InfravermelhoRESUMO
A new type of competitive human GST inhibitors has been developed via the bioisostere and structure activity profile strategies; we report their discovery, preparation, inhibitory activity, and synergetic effect in combination with chemotherapy drugs against breast cancer cells.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Desenho de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glutationa Transferase/antagonistas & inibidores , Neoplasias da Mama/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Glutationa Transferase/metabolismo , Humanos , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
This study describes the synthesis and structure-activity relationships of a series of furazan-3,4-diamide analogs. 1,2,5-Oxadiazole ring and electron-withdrawing substituent on the phenyl ring are proposed to be the important elements which contribute to a significant extent maximal potency of anti-proliferation effect.
