RESUMEN
In a previous study, a novel anthraquinone analog BW-AQ-101 was identified as a potent inducer of MDM2 degradation, leading to upregulation of p53 and apoptosis in cell culture studies. In animal models of acute lymphocytic leukemia, treatment with BW-AQ-101 led to complete disease remission. In this study, we systematically investigated the effect of substitution patterns of the core anthraquinone scaffold. Through cytotoxicity evaluation in two leukemia cell lines, the structure-activity relationship of thirty-two analogs has been examined. Several analogs with comparable or improved potency over BW-AQ-101 have been identified. Western-blot assays verified the effect of the potent compounds on the MDM2-p53 axis. The study also suggests new chemical space for further optimization work.
Asunto(s)
Antraquinonas/farmacología , Antineoplásicos/farmacología , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Antraquinonas/síntesis química , Antraquinonas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Células K562 , Estructura Molecular , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Azido nitrobenzoxadiazole (NBD) was observed to undergo a 'reduction' reaction in the absence of an obvious reducing agent, leading to amine formation. In the presence of an excess amount of DMSO, a sulfoxide conjugate was also formed. The ratio of these two products was both temperature- and solvent-dependent, with the addition of water significantly enhancing the ratio of the 'reduction' product. Two intermediates of the azido-NBD reaction in DMSO were trapped and characterized by low-temperature EPR spectroscopy. One was an organic free radical (S=1/2) and another was a triplet nitrene (S=1) species. A mechanism was proposed based on the characterized free radical and triplet intermediates.
RESUMEN
The feasibility of a neighboring boronic acid-facilitated facile condensation of an aldehyde is described. This reaction is bio-orthogonal, complete at room temperature within minutes, and suitable for bioconjugation chemistry. The boronic acid group serves the dual purpose of catalyzing the condensation reaction and being a handle for secondary functionalization.