Metal-Organic Frameworks Constructed from Branched Oligomers.

Metal-organic frameworks (MOFs) prepared from oligomeric or polymeric organic ligands have been studied and are termed oligoMOFs and polyMOFs, respectively. Herein, several oligoMOFs are described that have been prepared from branched oligomers with dendritic or star-like architectures. Branched oligomeric ligands with four (4(H2bdc)-b) or eight (8(H2bdc)-b) 1,4-benzene dicarboxylic acid (H2bdc) groups were prepared and used to synthesize isoreticular-type Zn(II)-based MOFs (IRMOF). A branched tetramer (4(H2bdc)-b) produced an oligoIRMOF-1 with improved ambient stability compared with IRMOF-1 or previously described oligoMOFs. To understand the effect of the ligand architecture, oligoIRMOFs were also prepared from a linear tetramer (4(H2bdc)-l). For a branched octamer (8(H2bdc)-b), it was found that the addition of an organic base was required to produce crystalline oligoIRMOFs. Multivariate MOFs (MTV-MOFs) could also be readily prepared with a combination of an octamer (8(H2bdc)-b) and H2bdc.

Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants.

Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PAN. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PAN using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PAN. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.

Catechol-O-Methyltransferase inhibition and alcohol use disorder: Evaluating the efficacy of tolcapone in ethanol-dependent rats.

Alcohol Use Disorder (AUD) is a significant public health issue in the United States. It affects millions of individuals and their families and contributes to substantial societal and economic burdens. Despite the availability of some pharmacological treatments, there is still a pressing need to develop more effective therapeutic strategies to address the diverse range of symptoms and challenges associated with AUD. Catechol-O-methyltransferase (COMT) inhibition recently emerged as a promising new approach to treating AUD due to its potential to improve cognitive effects commonly associated with AUD. Tolcapone, an FDA-approved COMT inhibitor, has shown some promise for treating AUD; however, its ability to decrease drinking in ethanol-dependent rats has not been well-established. In this study, we evaluated the effects of tolcapone on operant, oral ethanol self-administration in non-dependent and dependent rats, and in rats that self-administered oral saccharin. To induce dependence, rats underwent the chronic intermittent exposure to vapor model, and their drinking levels were assessed during acute withdrawal from ethanol. Our results demonstrated that tolcapone attenuated responding for ethanol in dependent rats only, without affecting self-administration in non-dependent rats or rats self-administering saccharin. Moreover, we found that tolcapone was differentially effective in different estrous phases in female rats. These findings suggest that COMT inhibition, specifically using tolcapone, may be a valuable pharmacotherapy for treating AUD, particularly in individuals who are physically dependent on alcohol. Further research is needed to elucidate the precise mechanisms underlying the observed effects and to assess the potential of COMT inhibitors in a broader population of individuals with AUD.

Reversible Postsynthetic Modification in a Metal-Organic Framework.

Postsynthetic modification (PSM) of metal-organic frameworks (MOFs) provides access to functional materials and advanced porous solid engineering. Herein, we report the reversible PSM of a multivariate isoreticular MOF by applying dynamic furan-maleimide Diels-Alder (DA) chemistry. The key step involves incorporating a furan group into the MOF via "click" PSM, which can then undergo repeated cycles of modification and de-modification with maleimides. The structural integrity, crystallinity, and porosity of the furan-appended MOF remained intact even after three consecutive PSM/de-modification cycles using three different functionalized maleimides.

Correction: Self-healing mixed matrix membranes containing metal-organic frameworks.

[This corrects the article DOI: 10.1039/D2SC04345A.].

Erratum: Further correction: Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery.

[This corrects the article DOI: 10.1039/C9SC05586J.].

Quantifying Ligand Binding to the Surface of Metal-Organic Frameworks.

The binding of molecules to the exterior surface of metal-organic frameworks (MOFs) is not a well-understood phenomenon. Herein, the surface chemistry of three MOFs, UiO-66, MIL-88B-NH2, and ZIF-8, is investigated using dye-displacement experiments. MOF particle surfaces were modified with ligand-appended BODIPY dyes. The ability of the coordinated dyes to be displaced by a variety of exogenous ligands was measured by ultraviolet-visible spectroscopy. This method allowed for measurement of apparent binding constants for different ligands to the MOF surface. As might be expected, ligand affinity was dependent on the nature of the underlying metal-ligand composition of the MOF. This work provides a quantitative evaluation of ligand binding to MOF surfaces and important insights for the modulation, modification, and manipulation of MOFs.

Unravelling Ultrafast Li Ion Transport in Functionalized Metal-Organic Framework-Based Battery Electrolytes.

Nonaqueous fluidic transport and ion solvation properties under nanoscale confinement are poorly understood, especially in ion conduction for energy storage and conversion systems. Herein, metal-organic frameworks (MOFs) and aprotic electrolytes are studied as a robust platform for molecular-level insights into electrolyte behaviors in confined spaces. By employing computer simulations, along with spectroscopic and electrochemical measurements, we demonstrate several phenomena that deviate from the bulk, including modulated solvent molecular configurations, aggregated solvation structures, and tunable transport mechanisms from quasi-solid to quasi-liquid in functionalized MOFs. Technologically, taking advantage of confinement effects may prove useful for addressing stability concerns associated with volatile organic electrolytes while simultaneously endowing ultrafast transport of solvates, resulting in improved battery performance, even at extreme temperatures. The molecular-level insights presented here further our understanding of structure-property relationships of complex fluids at the nanoscale, information that can be exploited for the predictive design of more efficient electrochemical systems.

A computational analysis on the impact of multilevel laryngotracheal stenosis on airflow and drug particle dynamics in the upper airway.

Laryngotracheal stenosis (LTS) is a type of airway narrowing that is frequently caused by intubation-related trauma. LTS can occur at one or multiple locations in the larynx and/or trachea. This study characterizes airflow dynamics and drug delivery in patients with multilevel stenosis. Two subjects with multilevel stenosis (S1 = glottis + trachea, S2 = glottis + subglottis) and one normal subject were retrospectively selected. Computed tomography scans were used to create subject-specific upper airway models. Computational fluid dynamics modeling was used to simulate airflow at inhalation pressures of 10, 25, and 40 Pa, and orally inhaled drug transport with particle velocities of 1, 5, and 10 m/s, and particle size range of 100 nm-40 µm. Subjects had increased airflow velocity and resistance at stenosis with decreased cross-sectional area (CSA): S1 had the smallest CSA at trachea (0.23 cm2) and resistance = 0.3 Pa·s/mL; S2 had the smallest CSA at glottis (0.44 cm2), and resistance = 0.16 Pa·s/mL. S1 maximal stenotic deposition was 4.15% at trachea; S2 maximal deposition was 2.28% at glottis. Particles of 11-20 µm had the greatest deposition, 13.25% (S1-trachea) and 7.81% (S2-subglottis). Results showed differences in airway resistance and drug delivery between subjects with LTS. Less than 4.2% of orally inhaled particles deposited at stenosis. Particle sizes with most stenotic deposition were 11-20 µm and may not represent typical particle sizes emitted by current-use inhalers.

Dysphagia in Older Adults is Associated With Food Insecurity and Being Homebound.

Objective: Our aim was to evaluate relationships between swallowing difficulty (dysphagia) and social determinants of health (SDOH) in older adults ≥65 years. Method: Cross-sectional analyses were performed in community-dwelling Medicare beneficiaries from the National Health & Aging Trends Study (NHATS). The primary exposure was self-reported difficulty chewing/swallowing in the prior month. Dependent measures included a variety of SDOH outcomes (e.g., food insecurity [FI]). Weighted logistic regression models were estimated to determine associations between dysphagia and SDOH outcomes. Results: Of 4041 participants, 428 (10.6%) self-reported dysphagia. In the adjusted model, dysphagia was associated with significantly increased odds for FI (odds ratio [OR] = 1.48, 95% confidence interval [CI] = 1.06, 2.07, p = .023) and being homebound (OR = 1.32, 95% CI = 1.13, 1.55, p= < .001). Discussion: Older adults with dysphagia had increased odds of FI and being homebound. These associations have implications for health-promoting interventions at the individual and policy levels in older adults.

Self-Reported Dysphagia and Psychosocial Health Among Community-Dwelling Older Adults: Results of a National Study.

BACKGROUND: The risk of dysphagia increases with age, affecting up to 33% of adults over the age of 65. Older adults with dysphagia are at increased risk for negative physical health outcomes such as aspiration pneumonia and death. However, the relationship between dysphagia and psychosocial health is uncertain in this population. OBJECTIVE: We aimed to assess the associations between dysphagia and psychosocial health among older adults (≥ 65) with self-reported dysphagia. DESIGN: We performed a cross-sectional assessment of the National Health and Aging Trends Study (NHATS) conducted in 2019. MAIN MEASURES: Weighted logistic and linear regression models were used to assess the relationship between self-reported dysphagia and psychosocial health using established patient-reported outcome measures including those for depression, anxiety, and social isolation previously used in NHATS analyses, while adjusting for demographics, comorbid conditions, and risk factors for dysphagia identified by purposeful selection. KEY RESULTS: Among the 4041 adults in this cohort, almost half (40%) were between 70 and 74 years old, more than half were female (55%), and a significantly higher proportion were White, non-Hispanic respondents (78.1%, p < 0.01) compared with other races and ethnicities. There were 428 (10.5%) respondents reporting dysphagia symptoms within the previous month. In the multivariable model, dysphagia was associated with significantly increased odds of anxiety (OR 1.33 [1.06, 1.67]) and a significantly decreased sense of well-being (coefficient - 1.10 [- 1.66, - 0.54]), but no association was detected for social isolation. CONCLUSIONS: When accounting for factors associated with underlying physical health status, self-reported dysphagia is independently associated with negative psychosocial health and warrants attention by healthcare providers. Future studies should aim to identify causal factors and the extent to which interventions may mitigate these factors.

Experimental Approaches for the Synthesis of Low-Valent Metal-Organic Frameworks from Multitopic Phosphine Linkers.

Metal-organic frameworks (MOFs) are the subject of intense research focus due to their potential applications in gas storage and separation, biomedicine, energy, and catalysis. Recently, low-valent MOFs (LVMOFs) have been explored for their potential use as heterogeneous catalysts, and multitopic phosphine linkers have been shown to be a useful building block for the formation of LVMOFs. However, the synthesis of LVMOFs using phosphine linkers requires conditions that are distinct from those in the majority of the MOF synthetic literature, including the exclusion of air and water and the use of unconventional modulators and solvents, making it somewhat more challenging to access these materials. This work serves as a general tutorial for the synthesis of LVMOFs with phosphine linkers, including information on the following: 1) the judicious choice of the metal precursor, modulator, and solvent; 2) the experimental procedures, air-free techniques, and required equipment; 3) the proper storage and handling of the resultant LVMOFs; and 4) useful characterization methods for these materials. The intention of this report is to lower the barrier to this new subfield of MOF research and facilitate advancements toward novel catalytic materials.

Correction: Masking thiol reactivity with thioamide, thiourea, and thiocarbamate-based MBPs.

Correction for 'Masking thiol reactivity with thioamide, thiourea, and thiocarbamate-based MBPs' by Hyeonglim Seo et al., Chem. Commun., 2023, 59, 2283-2286, https://doi.org/10.1039/D2CC06596G.

Comparative Treatment Outcomes for Idiopathic Subglottic Stenosis: 5-Year Update.

The North American Airway Collaborative (NoAAC) previously published a 3-year multi-institutional prospective cohort study showing variation in treatment effectiveness between 3 primary surgical techniques for idiopathic subglottic stenosis (iSGS). In this report, we update these findings to include 5 years of data evaluating treatment effectiveness. Patients in the NoAAC cohort were re-enrolled for 2 additional years and followed using the prespecified published protocol. Consistent with prior data, prospective observation of 487 iSGS patients for 5 years showed treatment effectiveness differed by modality. Cricotracheal resection maintained the lowest rate of recurrent operation (5%), followed by endoscopic resection with adjuvant medical therapy (30%) and endoscopic dilation (50%). These data support the initial observations and continue to provide value to providers and patients navigating longitudinal decision-making. Level of evidence: 2-prospective cohort study.

A Coordination Polymer of Vaska's Complex as a Heterogeneous Catalyst for the Reductive Formation of Enamines from Amides.

Low-valent metal-organic frameworks (LVMOFs) and related materials have gained interest due to their potential applications in heterogeneous catalysis. However, of the few LVMOFs that have been reported, none have shown catalytic activity. Herein, a low-valent metal-organic material constructed from phosphine linkers and IrI nodes is reported. This material is effectively a crystalline, insoluble analogue of Vaska's complex. As such, the material reversibly binds O2 and catalyzes the reductive formation of enamines from amides.

Association of Visit Volume and Sociodemographic Characteristics With Vocal Improvement Among Older US Adults With a Self-reported Voice Problem.

This cross-sectional study evaluates the association of sociodemographic characteristics and care utilization with improved voice function among a large sample of older US adults.

Enantioselective inhibition of the SARS-CoV-2 main protease with rhenium(i) picolinic acid complexes.

Infections of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have triggered a global pandemic with millions of deaths worldwide. Herein, the synthesis of functionalized Re(i) tricarbonyl complexes as inhibitors of the SARS-CoV-2 main protease, also referred to as the 3-chymotrypsin-like protease (3CLpro), is presented. The metal complexes were found to inhibit the activity of the enzyme with IC50 values in the low micromolar range. Mass spectrometry revealed that the metal complexes formed a coordinate covalent bond with the enzyme. Chiral separation of the enantiomers of the lead compound showed that one enantiomer was significantly more active than the other, consistent with specific binding and much like that observed for conventional organic small molecule inhibitors and druglike compounds. Evaluation of the lead compound against SARS-CoV-2 in a cell-based infection assay confirmed enantiospecific inhibition against the virus. This study represents a significant advancement in the use of metal complexes as coordinate covalent inhibitors of enzymes, as well as a novel starting point for the development of novel SARS-CoV-2 inhibitors.

Masking thiol reactivity with thioamide, thiourea, and thiocarbamate-based MBPs.

Thioamides, thioureas, and thiocarbamates are introduced as stable, sulfur-based metal-binding pharmacophores (MBPs) for use in metalloenzyme fragment-based drug discovery (mFBDD). MBP reactivity, bioactivity, and structural studies show that these molecules can act as ligands for Zn(II)-dependent metalloenzymes including human carbonic anhydrase II (hCAII) and matrix metalloproteinase-2 (MMP-2).

Development of Human Carbonic Anhydrase II Heterobifunctional Degraders.

Human carbonic anhydrase II (hCAII) is a metalloenzyme essential to critical physiological processes in the body. hCA inhibitors are used clinically for the treatment of indications ranging from glaucoma to epilepsy. Targeted protein degraders have emerged as a promising means of inducing the degradation of disease-implicated proteins by using the endogenous quality control mechanisms of a cell. Here, a series of heterobifunctional degrader candidates targeting hCAII were developed from a simple aryl sulfonamide fragment. Degrader candidates were functionalized to produce either cereblon E3 ubiquitin ligase (CRBN) recruiting proteolysis targeting chimeras (PROTACs) or adamantyl-based hydrophobic tags (HyTs). Screens in HEK293 cells identified two PROTAC small-molecule degraders of hCA. Optimization of linker length and composition yielded a degrader with sub-nanomolar potency and sustained depletion of hCAII over prolonged treatments. Mechanistic studies suggest that this optimized degrader depletes hCAII through the same mechanism as previously reported CRBN-recruiting heterobifunctional degraders.

Rhenium(V) Complexes as Cysteine-Targeting Coordinate Covalent Warheads.

Interest in covalent enzyme inhibitors as therapeutic agents has seen a recent resurgence. Covalent enzyme inhibitors typically possess an organic functional group that reacts with a key feature of the target enzyme, often a nucleophilic cysteine residue. Herein, the application of small, modular ReV complexes as inorganic cysteine-targeting warheads is described. These metal complexes were found to react with cysteine residues rapidly and selectively. To demonstrate the utility of these ReV complexes, their reactivity with SARS-CoV-2-associated cysteine proteases is presented, including the SARS-CoV-2 main protease and papain-like protease and human enzymes cathepsin B and L. As all of these proteins are cysteine proteases, these enzymes were found to be inhibited by the ReV complexes through the formation of adducts. These findings suggest that these ReV complexes could be used as a new class of warheads for targeting surface accessible cysteine residues in disease-relevant target proteins.