RESUMEN
Novel mansonone F derivative MSN54 (9-bromo-2,3-diethylbenzo[de]chromene-7,8-dione) exhibited significant cytotoxicity against twelve human tumor cell lines in vitro, with particularly strong potency against HL-60/MX2 cell line resistant to Topo II poisons. MSN54 was found to have IC50 of 0.69 and 1.43 µM against HL-60 and HL-60/MX2 cells, respectively. The resistance index is 10 times lower than that of the positive control VP-16 (etoposide). Various biological assays confirmed that MSN54 acted as a Topo IIα specific non-intercalative catalytic inhibitor. Furthermore, MSN54 exhibited good antitumor efficacy and low toxicity at a dose of 5 mg/kg in A549 tumor xenograft models. Thus, compound MSN54 is a promising candidate for the development of novel antitumor agents.
Asunto(s)
Antineoplásicos/farmacología , Proteínas de Unión a Poli-ADP-Ribosa/antagonistas & inhibidores , Inhibidores de Topoisomerasa II/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Relación Estructura-Actividad , Inhibidores de Topoisomerasa II/síntesis química , Inhibidores de Topoisomerasa II/químicaRESUMEN
A novel series of benzo[a]phenazin derivatives bearing alkylamino side chains were designed, synthesized and evaluated for their topoisomerases inhibitory activity as well as cytotoxicity against four human cancer cell lines (HL-60, K-562, HeLa, and A549). These compounds were found to be dual inhibitors of topoisomerase (Topo) I and Topo II, and exhibited excellent antiproliferative activity, in particular against HL-60 cells with submicromolar IC50 values. Further mechanistic studies showed that this class of compounds acted as Topo I poisons by stabilizing the Topo I-DNA cleavage complexes and Topo II catalytic inhibitors by inhibiting the ATPase activity of hTopo II. Molecular docking studies revealed the binding modes of these compounds for Topo I and Topo II.
Asunto(s)
Aminas/química , Diseño de Fármacos , Fenazinas/farmacología , Inhibidores de Topoisomerasa I/química , Inhibidores de Topoisomerasa I/farmacología , Inhibidores de Topoisomerasa II/química , Inhibidores de Topoisomerasa II/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/metabolismo , ADN-Topoisomerasas de Tipo II/metabolismo , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HL-60 , Células HeLa , Humanos , Células K562 , Estructura Molecular , Fenazinas/síntesis química , Fenazinas/química , Relación Estructura-Actividad , Inhibidores de Topoisomerasa I/síntesis química , Inhibidores de Topoisomerasa II/síntesis químicaRESUMEN
Two series of novel C-9 chloro- and bromo-substituted mansonone E derivatives with triazole moieties at the C-3 position were prepared by using copper-catalysed azide-alkyne cycloaddition click chemistry. These compounds were found as potent inhibitors of topoisomerase II (Topo II) and topoisomerase I (Topo I). The Topo II-mediated pBR322 DNA relaxation and cleavage assay showed that the derivatives might act as catalytic inhibitors. Their cytotoxic activities against A549, HL-60, K562 and HeLa cells were evaluated, indicating that these compounds were potent antitumour agents. Their structure activity relationships and molecular docking study revealed that the substituents of the triazole were particularly important for cytotoxicity.