RESUMEN
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.
Asunto(s)
Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Fase G2/efectos de los fármacos , Indoles/síntesis química , Xilenos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología , Neoplasias de la Mama , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Indoles/química , Indoles/farmacología , Relación Estructura-Actividad , Xilenos/química , Xilenos/farmacologíaRESUMEN
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.
Asunto(s)
Amidas/farmacología , Movimiento Celular/efectos de los fármacos , Neoplasias/patología , Pirroles/farmacología , Amidas/química , Western Blotting , Línea Celular Tumoral , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Humanos , Integrina beta1/metabolismo , Espectroscopía de Resonancia Magnética , Metástasis de la Neoplasia/prevención & control , Neoplasias/enzimología , Neoplasias/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirroles/química , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masa Bombardeada por Átomos Veloces , Espectrofotometría InfrarrojaRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Diseño de Fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Glutatión Transferasa/antagonistas & inhibidores , Neoplasias de la Mama/genética , Resistencia a Antineoplásicos/genética , Femenino , Glutatión Transferasa/metabolismo , Humanos , Modelos Moleculares , Relación Estructura-ActividadRESUMEN
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.
