RESUMEN
Activating the intrinsic apoptosis pathway with small molecules is now a clinically validated approach to cancer therapy. In contrast, blocking apoptosis to prevent the death of healthy cells in disease settings has not been achieved. Caspases have been favored, but they act too late in apoptosis to provide long-term protection. The critical step in committing a cell to death is activation of BAK or BAX, pro-death BCL-2 proteins mediating mitochondrial damage. Apoptosis cannot proceed in their absence. Here we show that WEHI-9625, a novel tricyclic sulfone small molecule, binds to VDAC2 and promotes its ability to inhibit apoptosis driven by mouse BAK. In contrast to caspase inhibitors, WEHI-9625 blocks apoptosis before mitochondrial damage, preserving cellular function and long-term clonogenic potential. Our findings expand on the key role of VDAC2 in regulating apoptosis and demonstrate that blocking apoptosis at an early stage is both advantageous and pharmacologically tractable.
Asunto(s)
Apoptosis/fisiología , Bibliotecas de Moléculas Pequeñas/metabolismo , Canal Aniónico 2 Dependiente del Voltaje/fisiología , Proteína Destructora del Antagonista Homólogo bcl-2/fisiología , Animales , Ratones , Unión Proteica , Canal Aniónico 2 Dependiente del Voltaje/metabolismoRESUMEN
Avibactam is a non ß-lactam ß-lactamase inhibitor that has recently been approved in association with a ß-lactam antibiotic for the treatment of severe infections caused by otherwise resistant bacteria. Its therapeutic success encouraged the development of many congeners based on its particular diazabicyclooctane scaffold. This review presents a detailed overview of the synthetic strategies that have been implemented to acces these complex bicyclic compounds with a particular focus on those that are currently on the market or in clinical trials.
Asunto(s)
Compuestos Aza/síntesis química , Compuestos de Azabiciclo/síntesis química , Ciclooctanos/síntesis química , Inhibidores de beta-Lactamasas/síntesis química , Compuestos Aza/química , Compuestos Aza/farmacología , Compuestos de Azabiciclo/química , Compuestos de Azabiciclo/farmacología , Ciclooctanos/química , Ciclooctanos/farmacología , Ciclopropanos/química , Inhibidores de beta-Lactamasas/química , Inhibidores de beta-Lactamasas/farmacologíaRESUMEN
Five different halofunctionalizations of acyclic monoterpenoids were performed using a combination of a hypervalent iodine(III) reagent and a halide salt. In this manner, the dibromination, the bromo(trifluoro)acetoxylation, the bromohydroxylation, the iodo(trifluoro)acetoxylation or the ene-type chlorination of the distal trisubstituted double bond occurred with excellent selectivity and moderate to good yields.