RESUMEN
Natural, nonribosomal cyclotetrapeptides have traditionally been a rich source of inspiration for design of potent histone deacetylase (HDAC) inhibitors. We recently disclosed the total synthesis and full HDAC profiling of the naturally occurring azumamides ( J. Med. Chem. 2013 , 56 , 6512 ). In this work, we investigate the structural requirements for potent HDAC inhibition by macrocyclic peptides using the azumamides along with a series of unnatural analogues obtained through chemical synthesis. By solving solution NMR structures of selected macrocycles and combining these findings with molecular modeling, we pinpoint crucial enzyme-ligand interactions required for potent inhibition of HDAC3. Docking of additional natural products confirmed these features to be generally important. Combined with the structural conservation across HDACs 1-3, this suggests that while cyclotetrapeptides have provided potent and class-selective HDAC inhibitors, it will be challenging to distinguish between the three major class I deacetylases using these chemotypes.
Asunto(s)
Química Farmacéutica/métodos , Inhibidores de Histona Desacetilasas/química , Péptidos Cíclicos/química , Línea Celular Tumoral , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Inhibidores de Histona Desacetilasas/síntesis química , Humanos , Concentración 50 Inhibidora , Cinética , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Unión Proteica , Conformación ProteicaRESUMEN
Cyclic tetrapeptide and depsipeptide natural products have proven useful as biological probes and drug candidates due to their potent activities as histone deacetylase (HDAC) inhibitors. Here, we present the syntheses of a class of cyclic tetrapeptide HDAC inhibitors, the azumamides, by a concise route in which the key step in preparation of the noncanonical disubstituted ß-amino acid building block was an Ellman-type Mannich reaction. By tweaking the reaction conditions during this transformation, we gained access to the natural products as well as two epimeric homologues. Thus, the first total syntheses of azumamides B-D corroborated the originally assigned structures, and the synthetic efforts enabled the first full profiling of HDAC inhibitory properties of the entire selection of azumamides A-E. This revealed unexpected differences in the relative potencies within the class and showed that azumamides C and E are both potent inhibitors of HDAC10 and HDAC11.
Asunto(s)
Inhibidores de Histona Desacetilasas/síntesis química , Inhibidores de Histona Desacetilasas/farmacología , Péptidos Cíclicos/síntesis química , Péptidos Cíclicos/farmacología , Cristalografía por Rayos X , Espectroscopía de Resonancia Magnética , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
A crystal structure suggests four water molecules are present in the binding cavity of thapsigargin in sarco/endoplasmic reticulum calcium ATPase (SERCA). Computational chemistry indicates that three of these water molecules mediate an extensive hydrogen-bonding network between thapsigargin and the backbone of SERCA. The orientation of the thapsigargin molecule in SERCA is crucially dependent on these interactions. The hypothesis has been verified by measuring the affinity of newly synthesized model compounds, which are prevented from participating in such water-mediated interactions as hydrogen-bond donors.