RESUMO
Compound 2 (KU-32) is a first-generation novologue (a novobiocin-based, C-terminal, heat shock protein 90 (Hsp90) inhibitor) that decreases glucose-induced death of primary sensory neurons and reverses numerous clinical indices of diabetic peripheral neuropathy in mice. The current study sought to exploit the C-terminal binding site of Hsp90 to determine whether the optimization of hydrogen bonding and hydrophobic interactions of second-generation novologues could enhance neuroprotective activity. Using a series of substituted phenylboronic acids to replace the coumarin lactone of 2, we identified that electronegative atoms placed at the meta-position of the B-ring exhibit improved cytoprotective activity, which is believed to result from favorable interactions with Lys539 in the Hsp90 C-terminal binding pocket. Consistent with these results, a meta-3-fluorophenyl substituted novologue (13b) exhibited a 14-fold lower ED(50) for protection against glucose-induced toxicity of primary sensory neurons compared to 2.
Assuntos
Citoproteção/efeitos dos fármacos , Glucose/efeitos adversos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/química , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Técnicas de Química Sintética , Humanos , Modelos Moleculares , Fármacos Neuroprotetores/química , Conformação Proteica , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/metabolismoRESUMO
Phosphoinositide-3-kinase is a pivotal protein involved in a wide variety of signaling cascades and there has been a great deal of interest in the development of potent and selective inhibitors of this enzyme. In this review, the potency and selectivity of the known inhibitors is presented along with key structural information that helps rationalize the observed trends.
