Discovery of an Inhibitor of the Proteasome Subunit Rpn11.

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.

Investigating chelating sulfonamides and their use in metalloproteinase inhibitors.

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.

Emerging trends in metalloprotein inhibition.

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.

Illuminating metal-ion sensors: benzimidazolesulfonamide metal complexes.

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.

From sensors to silencers: quinoline- and benzimidazole-sulfonamides as inhibitors for zinc proteases.

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.

In silico study of MMP inhibition.

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.

Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with improved selectivity.

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.

The effect of endoscopic injections of dextranomer based implants on continence and bladder capacity: a prospective study of 31 patients.

Purpose: A prospective study was conducted to assess the efficacy of dextranomer based implants as a new bulking agent for endoscopic treatment of pediatric structural incontinence.

Materials And Methods: A total of 33 children and adolescents 5 to 18 years old with severe incontinence due to sphincteric incompetence (exstrophy-epispadias in 13, neuropathic bladder in 16, bilateral ectopic ureters in 4) were enrolled in the study. All but 1 patient wore diapers.

The Malone antegrade colonic enema isolated or associated with urological incontinence procedures: evaluation from patient point of view.

Purpose: Fecal and urinary incontinence in patients with congenital or acquired spinal cord defects represents a handicap that impairs chances of integration in society. Associated with the management of urinary incontinence, the Malone antegrade colonic enema is a generally successful procedure for resolving refractory fecal incontinence. We report the results of the evaluation of this technique from the patient perspective.

[Pathology of the ureterovesical junction in neurogenic bladders in children and adolescents. A retrospective study of 119 patients].

Ureterovesical junction dysfunction in congenital or acquired neurogenic bladders represents a threat for the renal parenchyma. In order to evaluate the incidence, mechanisms of development and preventive and curative treatments proposed in diseases of the ureterovesical junction associated with neurogenic bladders, the files of 119 children were retrospectively evaluated. 68 patients suffered from congenital neurogenic bladder and 51 had an acquired neurogenic bladder.

Correlation of flexion contractures with upper extremity function and pain for spinal muscular atrophy and congenital myopathy patients.

To ascertain the patients' perception of the consequences of elbow flexion contractures and better understand the circumstances at their inception, we surveyed 405 spinal muscular atrophy and congenital myopathy patients. Diagrams of various elbow angles and questions concerning the effect of elbow contractures on daily activities were part of the survey. Of 108 completed responses, effectively a 24% response rate, 49 reported elbow flexion contractures.

[Echocardiography study of hemodynamic changes in pregnancy].

The purpose of this study is to monitor the haemodynamic changes that occur in pregnancy using ultrasound. Although all previous studies do demonstrate an increase in frequency and the volume of the cardiac output, the results seem to be different as far as variations in volume during systole occur and the mechanisms by which they occur. These differences can be explained by problems associated with the different methods used.