Showing papers by "Seth M. Cohen published in 2017"

The Postsynthetic Renaissance in Porous Solids

Abstract: Metal–organic frameworks (MOFs) have rapidly grown into a major area of chemical research over the last two decades. MOFs represent the development of covalent chemistry “beyond the molecule” and into extended structures. MOFs also present an unprecedented scaffold for performing heterogeneous organic transformations in the solid state, allowing for deliberate and precise preparation of new materials. The development of these transformations has given rise to the “postsynthetic renaissance”, a suite of methods by which these materials can be transformed in a single-crystal-to-single-crystal manner. Postsynthetic modification, postsynthetic deprotection, postsynthetic exchange, postsynthetic insertion, and postsynthetic polymerization have exploited the unique features of both the organic and inorganic components of MOFs to create crystalline, porous solids of unique complexity and functionality.

Dipicolinic Acid Derivatives as Inhibitors of New Delhi Metallo-β-lactamase-1.

Abstract: The efficacy of β-lactam antibiotics is threatened by the emergence and global spread of metallo-β-lactamase-(MBL) mediated resistance, specifically New Delhi-Metallo-β- lactamase-1 (NDM-1). Utilizing fragment-based drug discovery (FBDD), a new class of inhibitors for NDM-1 and two related β-lactamases, IMP-1 and VIM-2, was identified. Based on 2,6-dipicolinic acid (DPA), several libraries were synthesized for structure-activity relationship (SAR) analysis. Inhibitor 36 (IC50 = 80 nM) was identified to be highly selective for MBLs when compared to other Zn(II) metalloenzymes. While DPA displayed a propensity to chelate metal ions from NDM-1, 36 formed a stable NDM-1:Zn(II):inhibitor ternary complex, as demonstrated by 1H NMR, electron paramagnetic resonance (EPR) spectroscopy, equilibrium dialysis, intrinsic tryptophan fluorescence emission, and UV-Vis spectroscopy. When co-administered with 36 (at concentrations non-toxic to mammalian cells), the minimum inhibitory concentration (MIC) of imipenem against...

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11

Abstract: The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.

Photocatalytic metal–organic frameworks for organic transformations

Abstract: Metal–organic frameworks (MOFs) have attracted increasing attention for applications in heterogeneous photocatalysis. Modifications of metal nodes and organic linkers, as well as encapsulation of active species in the pores of MOFs enable the generation of photoactive materials for catalyzing organic transformations. MOF composites integrating noble metal nanoparticles or traditional photoactive semiconductors can combine the advantages of both materials, and also improve the photocatalytic performance via synergistic effects. In this Highlight, we discuss recent examples of photoactive MOFs and their use as photocatalysts for organic reactions.

Metal–Organic Frameworks as Micromotors with Tunable Engines and Brakes

Abstract: Herein, we report that UiO-type (UiO = University of Oslo) metal–organic frameworks (MOFs) can be transformed into self-propelled micromotors by employing several different metal-based propulsion systems. Incorporation of a bipyridine ligand into the UiO-67 lattice transforms the crystallites, upon metalation, into single-site, metal-based catalytic “engines” to power the micromotors with chemical fuel. The “engine performance” (i.e., propulsion) of the single-site powered micromotors has been tuned by the choice of the metal ion utilized. In addition, a chemical “braking” system was achieved by adding chelating agents capable of sequestering the metal ion engines and thereby suppressing the catalytic activity, with different chelators displaying different deceleration capacities. These results demonstrate that MOFs can be powered by various engines and halted by different brakes, resulting in a high degree of motion design and control at the nanoscale.

Discovery of an Inhibitor of the Proteasome Subunit Rpn11.

Abstract: 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 ∼2.5 μM) displayed strong inhibition of Rpn11. Further synthetic elaboration of 8TQ yielded a small molecule compound (35, IC50 value ∼400 nM) that is a potent and selective inhibitor of Rpn11 that blocks proliferation of tumor cells in c...

Pore Breathing of Metal–Organic Frameworks by Environmental Transmission Electron Microscopy

Abstract: Metal–organic frameworks (MOFs) have emerged as a versatile platform for the rational design of multifunctional materials, combining large specific surface areas with flexible, periodic frameworks that can undergo reversible structural transitions, or “breathing”, upon temperature and pressure changes, and through gas adsorption/desorption processes. Although MOF breathing can be inferred from the analysis of adsorption isotherms, direct observation of the structural transitions has been lacking, and the underlying processes of framework reorganization in individual MOF nanocrystals is largely unknown. In this study, we describe the characterization and elucidation of these processes through the combination of in situ environmental transmission electron microscopy (ETEM) and computer simulations. This combined approach enables the direct monitoring of the breathing behavior of individual MIL-53(Cr) nanocrystals upon reversible water adsorption and temperature changes. The ability to characterize structura...

A Bioinorganic Approach to Fragment-Based Drug Discovery Targeting Metalloenzymes

Abstract: ConspectusMetal-dependent enzymes (i.e., metalloenzymes) make up a large fraction of all enzymes and are critically important in a wide range of biological processes, including DNA modification, protein homeostasis, antibiotic resistance, and many others. Consequently, metalloenzymes represent a vast and largely untapped space for drug development. The discovery of effective therapeutics that target metalloenzymes lies squarely at the interface of bioinorganic and medicinal chemistry and requires expertise, methods, and strategies from both fields to mount an effective campaign. In this Account, our research program that brings together the principles and methods of bioinorganic and medicinal chemistry are described, in an effort to bridge the gap between these fields and address an important class of medicinal targets.Fragment-based drug discovery (FBDD) is an important drug discovery approach that is particularly well suited for metalloenzyme inhibitor development. FBDD uses relatively small but diverse...

Voice disorders and associated risk markers among young adults in the United States.

Abstract: Objectives/Hypothesis To examine the prevalence of voice disorders in young adults and identify sociodemographic factors, health conditions, and behaviors associated with voice disorder prevalence. Study Design Cross-sectional analysis of data from the National Longitudinal Study of Adolescent to Adult Health. Methods During home interviews, 14,794 young adults, aged 24 to 34 years, reported their health conditions and behaviors. Presence and duration of voice disorders were reported over the past 12 months. We computed overall and stratified prevalence estimates by age, gender, race/ethnicity, medical conditions, smoking, and alcohol use. Multiple logistic regression was used to identify independent risk factors for a voice disorder while accounting for the complex sample design. Results Six percent of participants reported a voice disorder lasting at least 3 days. Females had 56% greater odds of voice disorders than males. Number of days drinking alcohol was associated with voice disorders, but number of smoking days was not. Conditions that increased the likelihood of voice disorders included hypertension (OR = 1.42 [95% confidence interval {CI}: 1.07-1.89]), tinnitus (OR = 1.53 [95% CI: 1.06-2.20]), and anxiety/panic disorder (OR = 1.26 [95% CI: 1.00-1.60]). Results were independent of gender, alcohol consumption, upper respiratory symptoms, and lower respiratory conditions including asthma, bronchitis/emphysema, and gastrointestinal symptoms (diarrhea/nausea/vomiting). Conclusions Voice disorders in young adulthood were associated with hypertension, tinnitus, and anxiety. Greater awareness of these relationships may facilitate voice evaluation among people who seek healthcare for these chronic conditions. Level of Evidence 2b Laryngoscope, 127:2093–2099, 2017

Factors Influencing Likelihood of Voice Therapy Attendance.

Abstract: Objective To identify factors associated with the likelihood of attending voice therapy among patients referred for it in the CHEER (Creating Healthcare Excellence through Education and Research) practice-based research network infrastructure. Study Design Prospectively enrolled cross-sectional study. Setting CHEER network of community and academic sites. Methods Data were collected on patient-reported demographics, voice-related diagnoses, voice-related handicap (Voice Handicap Index-10), likelihood of attending voice therapy (VT), and opinions on factors influencing likelihood of attending VT. The relationships between patient characteristics/opinions and likelihood of attending VT were investigated. Results A total of 170 patients with various voice-related diagnoses reported receiving a recommendation for VT. Of those, 85% indicated that they were likely to attend it, regardless of voice-related handicap severity. The most common factors influencing likelihood of VT attendance were insurance/copay, relief that it was not cancer, and travel. Those who were not likely to attend VT identified, as important factors, unclear potential improvement, not understanding the purpose of therapy, and concern that it would be too hard. In multivariate analysis, factors associated with greater likelihood of attending VT included shorter travel distance, age (40-59 years), and being seen in an academic practice. Conclusions Most patients reported plans to attend VT as recommended. Patients who intended to attend VT reported different considerations in their decision making from those who did not plan to attend. These findings may inform patient counseling and efforts to increase access to voice care.

Trends in Otolaryngology Consultation Patterns at an Academic Quaternary Care Center.

Abstract: Importance The consultation patterns of an otolaryngology–head and neck surgery service have not previously been reported. The time, resources, and attention required to operate such a consultation service are unknown. Objective To assess trends in otolaryngology–head and neck surgery consultations conducted in emergency departments (EDs) and inpatient services. Design, Setting, and Participants A retrospective analysis was conducted of the medical records of patients at a quaternary care center receiving inpatient otolaryngology consultations from January 1 to December 31, 2014. Exposure Clinical evaluation and bedside and operative procedures performed by the otolaryngology–head and neck surgery service. Main Outcomes and Measures Demographics, reason for consultation, diagnosis, bedside procedures, operative interventions, and admission variables. Results A total of 1491 consultations were completed for adult (1091 [73.2%]; 854 men and 637 women; mean [SD] age 50.3 [19.3] years) and pediatric (400 [26.8%]; 232 boys and 168 girls; mean [SD] age, 4.0 [5.2] years) patients. Of the 1491 consultations, 766 (51.4%) originated from inpatient teams vs 725 (48.6%) from the ED. A total of 995 of all consultations (66.7%) resulted in a bedside procedure, and 243 (16.3%) required operative intervention. Consultations regarding airway evaluation (362 [47.3%] vs 143 [19.7%]), management of epistaxis (78 [10.2%] vs 33 [4.6%]), and rhinologic evaluation (79 [10.3%] vs 18 [2.5%]) were more frequent from inpatient teams than from the ED. Consultations regarding management of head and neck infections (162 [22.3%] vs 32 [4.2%]), facial trauma (235 [32.4%] vs 16 [2.1%]), and postoperative complications (73 [10.1%] vs 2 [0.3%]) were more frequent in the ED. Of the 725 consultations performed in the ED, 212 patients (29.2%) required hospitalization. Conclusions and Relevance The consultation volume of an otolaryngology–head and neck surgery service requires significant time and resources. Consultations are most often for rhinologic or laryngologic issues and are reflective of the clinical setting in which the patient is evaluated. Cost savings may be realized by increasing health care access points for nonurgent concerns that can be evaluated in an outpatient setting.

National Database Analysis of Single-Level versus Multilevel Sleep Surgery.

Abstract: Objective Recent evidence suggests that multilevel sleep surgery improves outcomes when compared with palate surgery alone for most patients. The study objective was to compare demographic and outcomes data for palate surgery (uvulopalatopharyngoplasty [UPPP]) alone versus multilevel surgery through a national insurance claims database. Study Design Retrospective cohort study. Setting National insurance claims database. Subjects and Methods An adult cohort undergoing single-level UPPP versus UPPP with nasal and/or tongue/hypopharyngeal surgery was identified in the Truven Health Analytics MarketScan Research Databases for the years 2010 through 2012. Demographic and outcomes data were assessed at short-term (≤14 days), intermediate (15-60 days), and long-term (61-183 days) intervals via a multivariate regression model adjusted for age, sex, geographic region, insurance type, and the Charlson-Deyo comorbidity score. The primary long-term complication considered was positive airway pressure (PAP) equipment supply, implying possible treatment failure. Results The cohort included 14,633 patients: 7559 (51.6%), UPPP alone; 5219 (35.7%), UPPP + nasal surgery; 1164 (7.95%), UPPP + tongue/hypopharyngeal surgery; and 691 (4.7%), UPPP + nasal + tongue/hypopharyngeal surgery. Demographic data were similar among the groups. UPPP alone had lower rates of postoperative bleeding than UPPP + tongue/hypopharyngeal surgery (4.31% vs 6.19%, P = .004). Multivariate modeling indicated that the addition of either nasal surgery (odds ratio = 1.21, 95% CI = 1.10-1.34, P < .001) or tongue/hypopharyngeal surgery (odds ratio = 1.15, 95% CI = 1.00-1.32, P = .048) to UPPP was associated with increased odds of postoperative continuous positive airway pressure. Conclusions UPPP alone is currently the predominant form of sleep surgery in the United States. Multilevel surgery had greater odds of postoperative bleeding and positive airway pressure equipment supply than UPPP alone. Dedicated studies formally evaluating single- versus multilevel sleep surgery and the impact of possible surgeon/patient selection bias should be a priority.

Coordinative Alignment To Achieve Ordered Guest Molecules in a Versatile Molecular Crystalline Sponge

Abstract: A Mn2+-based metal–organic framework (coordination porous framework-5, CPF-5) can serve as a crystalline sponge for single crystal X-ray structural characterization of a variety of compounds using a combination of coordinative alignment and second coordination sphere interactions (e.g., hydrogen bonding). This technique requires only a conventional X-ray source to obtain high quality crystallographic data.

Are Neuromodulating Medications Effective for the Treatment of Chronic Neurogenic Cough

Abstract: BACKGROUND Chronic cough is vexing for patients and is an extremely common chief complaint in ambulatory settings. A cough persisting longer than 8 weeks is considered chronic, and many patients seek evaluation by an otolaryngologist. After considering a broad differential, including reflux, chronic rhinitis/sinusitis, primary pulmonary diagnosis, and medication side effects, the diagnosis of chronic neurogenic cough can be considered. Both peripheral neuropathy and central sensitization/potentiation of the cough reflex have been implicated in the pathophysiology of chronic neurogenic cough. Thus pharmacologic neuromodulators have been used in patients with chronic neurogenic cough to reduce cough severity and to improve cough-related quality of life.

Effect of donor atom identity on metal-binding pharmacophore coordination.

Abstract: The inhibition and binding of three metal-binding pharmacophores (MBPs), 2-hydroxycyclohepta-2,4,6-trien-1-one (tropolone), 2-mercaptopyridine-N-oxide (1,2-HOPTO), and 2-hydroxycyclohepta-2,4,6-triene-1-thione (thiotropolone) to human carbonic anhydrase II (hCAII) and a mutant protein hCAII L198G were investigated. These MBPs displayed bidentate coordination to the active site Zn(II) metal ion, but the MBPs respond to the mutation of L198G differently, as characterized by inhibition activity assays and X-ray crystallography. The L198G mutation increases the active site volume thereby decreasing the steric pressure exerted on MBPs upon binding, allowing changes in MBP coordination to be observed. When comparing the binding mode of tropolone to thiotropolone or 1,2-HOPTO (O,O versus O,S donor sets), structural modifications of the hCAII active site were shown to have a stronger effect on MBPs with an O,O versus O,S donor set. These findings were corroborated with density functional theory (DFT) calculations of model coordination complexes. These results suggest that the MBP binding geometry is a malleable interaction, particularly for certain ligands, and that the identity of the donor atoms influences the response of the ligand to changes in the protein active site environment. Understanding underlying interactions between a MBP and a metalloenzyme active site may aid in the design and development of potent metalloenzyme inhibitors.

The effect of metalloprotein inhibitors on cellular metal ion content and distribution.

Abstract: With metalloproteins garnering increased interest as therapeutic targets, designing target-specific metalloprotein inhibitors (MPi) is of substantial importance. However, in many respects, the development and evaluation of MPi lags behind that of conventional small molecule therapeutics. Core concerns around MPi, such as target selectivity and potential disruption of metal ion homeostasis linger. Herein, we used a suite of analytical methods, including energy-dispersive X-ray spectroscopy (EDX), inductively coupled plasma atomic emission spectroscopy (ICP-OES), and synchrotron X-ray fluorescence microscopy (SXRF) to investigate the effect of several MPi on cellular metal ion distribution and homeostasis. The results reveal that at therapeutically relevant concentrations, the tested MPi have no significant effects on cellular metal ion content or distribution. In addition, the affinity of the metal-binding pharmacophore (MBP) utilized by the MPi does not have a substantial influence on the effect of the MPi on cellular metal distribution. These studies provide an important, original data set indicating that metal ion homeostasis is not notably perturbed by MPi, which should encourage the development of and aid in designing new MPi, guide MBP selection, and clarify the effect of MPi on the ‘metallome’.

Chronicity of Voice-Related Health Care Utilization in the General Medicine Community

Abstract: Objectives To examine voice-related health care utilization of patients in the general medical community without otolaryngology evaluation and explore factors associated with prolonged voice-related health care. Study Design Retrospective cohort analysis. Setting Large, national administrative US claims database. Subjects and Methods Patients with voice disorders per International Classification of Diseases, Ninth Revision, Clinical Modification ( ICD-9-CM) codes from January 1, 2010, to December 31, 2012, seen by a general medical physician, and who did not see an otolaryngologist in the subsequent year were included. Voice-related health care utilization, patient demographics, comorbid conditions, and index laryngeal diagnosis were collected. Logistic regression with variable selection was performed to evaluate the association between predictors and ≥30 days of voice-related health care use. Results In total, 46,205 unique voice-disordered patients met inclusion criteria. Of these patients, 8.5%, 10.0%, and 12.5% had voice-related health care use of ≥90, ≥60, and ≥30 days, respectively. Of the ≥30-day subset, 80.3% and 68.5%, respectively, had ≥60 and ≥90 days of voice-related health care utilization. The ≥30-day subset had more general medicine and nonotolaryngology specialty physician visits, more prescriptions and procedures, and 4 times the voice-related health care costs compared with those in the <30-day subset. Age, sex, employment status, initial voice disorder diagnosis, and comorbid conditions were related to ≥30 days of voice-related health care utilization. Conclusions Thirty days of nonotolaryngology-based care for a voice disorder may represent a threshold beyond which patients are more likely to experience prolonged voice-related health care utilization. Specific factors were associated with extended voice-related health care.

Compositions and methods for inhibiting influenza rna polymerase pa endonuclease

Abstract: There are provided inter alia metalloenzyme inhibitors, such as inhibitors of influenza A RNA dependent RNA polymerase PA subunit endonuclease, and methods of synthesis and use of the same.

Substituent Effects on the Coordination Chemistry of Metal-Binding Pharmacophores

Abstract: A combination of XAS, UV–vis, NMR, and EPR was used to examine the binding of a series of α-hydroxythiones to CoCA. All three appear to bind preferentially in their neutral, protonated forms. Two of the three clearly bind in a monodentate fashion, through the thione sulfur alone. Thiomaltol (TM) appears to show some orientational preference, on the basis of the NMR, while it appears that thiopyromeconic acid (TPMA) retains rotational freedom. In contrast, allothiomaltol (ATM), after initially binding in its neutral form, presumably through the thione sulfur, forms a final complex that is five-coordinate via bidentate coordination of ATM. On the basis of optical titrations, we speculate that this may be due to the lower initial pKa of ATM (8.3) relative to those of TM (9.0) and TPMA (9.5). Binding through the thione is shown to reduce the hydroxyl pKa by ∼0.7 pH unit on metal binding, bringing only ATM’s pKa close to the pH of the experiment, facilitating deprotonation and subsequent coordination of the hy...