RESUMEN
Derived from the extensive work in the area of small molecule zinc(II) ion sensors, chelating fragment libraries of quinoline- and benzimidazole-sulfonamides have been prepared and screened against several different zinc(II)-dependent matrix metalloproteinases (MMPs). The fragments show impressive inhibition of these metalloenzymes and preferences for different MMPs based on the nature of the chelating group. The findings show that focused chelator libraries are a powerful strategy for the discovery of lead fragments for metalloprotein inhibition.
Asunto(s)
Bencimidazoles/química , Inhibidores de la Metaloproteinasa de la Matriz , Quinolinas/química , Quinolinas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Descubrimiento de Drogas , Concentración 50 Inhibidora , Metaloproteinasas de la Matriz/química , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Zinc/metabolismoRESUMEN
The synthesis, structure, and solution spectroscopy of several (2-sulfonamidophenyl)benzimidazole metal complexes are reported. These ligands, which have been reported as selective molecular sensors for Zn(2+), readily form complexes with Co(2+), Ni(2+), Cu(2+), and Zn(2+). Surprisingly, the ligand adopts different binding modes depending on the metal ion. The work here provides insight into the coordination chemistry of these ligands, which may allow for the development of improved metal-ion sensors and metalloprotein inhibitors.
Asunto(s)
Bencimidazoles/química , Complejos de Coordinación/química , Sulfonamidas/química , Colorantes , Complejos de Coordinación/síntesis química , Cristalografía por Rayos X , Estructura MolecularRESUMEN
Lack of enzyme inhibition selectivity is frequently the major drawback preventing the development of enzyme inhibitors. Sulfonylhydrazides have recently been suggested to act as zinc ligands. Consequently, such derivatives potentially possess important industrial or therapeutic implications. DFT calculations (B3LYP/6-31G**+LANL2DZ theory level) of the binding modes and free energies of binding of a variety of N-acetyl-N'-sulfonylhydrazides in the presence of a Zn(2+) ion embedded in an MMP active site model show that protonated and deprotonated sulfonylhydrazides bind the Zn(2+) ion according to different modes. These results strongly suggest that sulfonylhydrazides can be developed as selective metalloprotease inhibitors, and the results of molecular docking computations fully support this hypothesis.
Asunto(s)
Biología Computacional , Inhibidores de la Metaloproteinasa de la Matriz , Metaloproteinasas de la Matriz/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Dominio Catalítico , Histidina/química , Hidrazinas/química , Imidazoles/química , Metaloproteinasas de la Matriz/metabolismo , Modelos Moleculares , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/metabolismo , Teoría Cuántica , Estereoisomerismo , Termodinámica , Zinc/químicaRESUMEN
Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC(50)=3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br-C6H4)-C6H4-SO(2)-). Interaction with the S2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation.
Asunto(s)
Benceno/farmacología , Hidrazinas/farmacología , Indoles/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/farmacología , Ácidos Sulfónicos/farmacología , Algoritmos , Benceno/química , Hidrazinas/síntesis química , Ácidos Hidroxámicos , Indoles/síntesis química , Concentración 50 Inhibidora , Modelos Moleculares , Inhibidores de Proteasas/síntesis química , Relación Estructura-Actividad , Ácidos Sulfónicos/químicaRESUMEN
The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn2+-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation. A fragment-based drug discovery (FBDD) approach was utilized to identify fragments with activity against Rpn11. Screening of a library of metal-binding pharmacophores (MBPs) revealed that 8-thioquinoline (8TQ, IC50 value â¼2.5 µM) displayed strong inhibition of Rpn11. Further synthetic elaboration of 8TQ yielded a small molecule compound (35, IC50 value â¼400 nM) that is a potent and selective inhibitor of Rpn11 that blocks proliferation of tumor cells in culture.
Asunto(s)
Inhibidores de Proteasoma/química , Inhibidores de Proteasoma/farmacología , Quinolinas/química , Quinolinas/farmacología , Transactivadores/antagonistas & inhibidores , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Transactivadores/metabolismo , Zinc/metabolismoRESUMEN
Matrix metalloproteinase inhibitors (MMPi) utilize zinc-binding groups (ZBGs) to chelate the catalytic Zn(II) ion resulting in enzyme inhibition. Adapting findings from the literature of Zn(II) ion sensors, we previously reported chelating sulfonamide inhibitors of MMP-2, some of which showed excellent selectivity over other gelatinases (MMP-9). Herein, we greatly expand our investigation of chelating sulfonamides as MMP inhibitors (MMPi) with the synthesis and screening of several new libraries consisting of 2-phenyl-7-sulfonamidobenzimidazole, 2-phenyl-7-sulfonamidobenzoxazole, 7-sulfonamidobenzimidazole, 7-sulfonamidobenzoxazole, and 2-(2-sulfonamidophenyl)-quinoline ZBG derivatives. A novel microwave irradiation synthetic procedure was utilized to rapidly and efficiently prepare these molecules. To better understand the coordination chemistry underlying these ZBGs, crystal structures of representative molecules with several first row transition metals were determined and differences in coordination preferences were considered. Surprisingly, only compounds with the 2-phenyl-7-sulfonamidobenzimidazole ZBG showed inhibition of MMP-2, suggesting that the specific structure of the ZBG can have a pronounced effect of inhibitory activity.
Asunto(s)
Quelantes/química , Inhibidores de la Metaloproteinasa de la Matriz , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Sulfonamidas/química , Sulfonamidas/farmacología , Humanos , Ligandos , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/síntesis química , Sulfonamidas/síntesis química , Zinc/químicaRESUMEN
Numerous metalloproteins are important therapeutic targets that are gaining increased attention in the medicinal and bioinorganic chemistry communities. This Perspective article describes some emerging trends and recent findings in the area of metalloprotein inhibitor discovery and development. In particular, increasing recognition of the importance of the metal-ligand interactions in these systems calls for more input and consideration from the bioinorganic community to address questions traditionally confined to the medicinal chemistry community.