A protocol for hydrogenation of aldehydes and ketones to alcohols in aqueous media at room temperature in high yields and purity.

In this paper, the hydrogenation of aldehydes and ketones using the RANEY® nickel catalyst was successfully applied for the synthesis of alcohol compounds without additional column chromatographic purification. This synthetic strategy features a wide range of substrates, excellent atom economy, high chemical discrimination and the use of a ligand-free catalytic system. Reactions were performed at room temperature in water providing alcohols in high yields and purity.

Association of composite dietary antioxidant index with mortality in adults with hypertension: evidence from NHANES.

Objective: The objective of this study is to assess the correlation between composite dietary antioxidant index (CDAI) with all-cause mortality and cause-specific mortality in adults with hypertension. Methods: The cohort study comprised adult participants with hypertension from the NHANES database, spanning 9 cycles from 2001 to 2018. Follow-up was conducted until December 31, 2019. Multi-variable Cox regression analysis was utilized to ascertain hazard ratios (HR) and their corresponding 95% confidence intervals, evaluating the relationship between CDAI and the risks of all-cause and cause-specific mortality. To further investigate the association between CDAI and mortality rates in adults with hypertension, Kaplan-Meier survival curves, restricted cubic splines (RCS), subgroup analyses and sensitivity analyses were employed. Results: The analysis included 16,713 adults with hypertension (mean age 56.93 ± 0.23 years, 8,327 [49.61%] male). During the mean follow-up time 102.11 ± 1.22 months, with 3,908 (18.08%) all-cause mortality occurred, 1,082 (4.84%) cardiovascular mortality and 833 (3.80%) cancer mortality. Compared to the lowest quartile of CDAI, the weighted multivariate hazard ratios of participants in the highest quartile was 0.77 (95% CI, 0.68-0.87) for all-cause mortality, 0.83 (95% CI, 0.67-1.04) for cardiovascular mortality, and 0.64 (95% CI, 0.50-0.82) for cancer mortality. RCS analysis demonstrated a nonlinear association of CDAI with all-cause and cancer mortality, and a linear association between CDAI and cardiovascular mortality. The results were robust in subgroup analyses and sensitivity analyses. Conclusion: Higher CDAI is associated with reduced all-cause mortality, cardiovascular mortality, and cancer mortality in hypertensive adults. Our findings highlight the importance of an antioxidant diet in improving outcomes in adults with hypertension.

A mild protocol for efficient preparation of functional molecules containing triazole.

The construction of a class of novel triazole molecules containing sulfonyl fluoride functionalities was achieved through Cu-catalyzed click chemistry in good to excellent yields. The sulfonyl fluoride moieties were cleaved completely under base conditions to produce N-unsubstituted triazoles quantitatively, which provides a strategy to combine SuFEx click chemistry with Cu-catalyzed click chemistry ingeniously.

One-Pot Three-Component Synthesis of Indolyl-4H-chromene-3-sulfonyl Fluoride: A Class of Important Pharmacophore.

A one-pot, sequential three-component reaction between salicylaldehyde, indole, and 2-bromoprop-2-ene-1-sulfonyl fluoride (BPESF) has been demonstrated for the synthesis of sulfonyl fluoride substituted 4H-chromene derivatives in moderate to excellent yields (45%-94%). This one-pot sequential method features easily available starting materials, wide substrate scope, mild conditions, and great efficiency.

A novel ADAMTSL4 compound heterozygous mutation in isolated ectopia lentis: a case report and review of the literature.

BACKGROUND: Congenital ectopia lentis is characterized by dislocation of the lens caused by partial or complete abnormalities in the zonular fibers. It can be caused by either systemic diseases or isolated ocular diseases. Gene detection techniques can provide valuable information when an etiological diagnosis is challenging. Herein, we report the case of a six-year-old girl with a confirmed diagnosis of isolated ectopia lentis caused by a compound heterozygous ADAMTSL4 gene mutation. CASE PRESENTATION: The patient was a 6-year-old Chinese Han girl with strabismus in the right eye. Slit lamp examination revealed that the lens in the right eye was opacified and dislocated, without an ectopic pupil. Gene detection demonstrated the presence of a compound heterozygous mutation in the ADAMTSL4 gene [c. 2270dupG (p.Gly758Trpfs *59) and c. 2110A > G (p.Ser704Gly)], and the diagnosis of isolated ectopia lentis was confirmed. She underwent lens extraction, and a sutured scleral-fixated posterior chamber intraocular lens (IOL) was placed in the right eye. The best-corrected visual acuity was 0.1 one month postoperatively. CONCLUSION: Gene detection plays a crucial role in diagnosing disorders with similar symptoms, such as isolated ectopia lentis and Marfan syndrome. In this study, we used whole exons sequencing to diagnose isolated ectopia lentis and identified the variant c.2110A > G (p.Ser704Gly), which may be associated with the development of ectopia lentis and early-onset cataract in the patient. These pathogenic gene mutations have significant implications for the genetic diagnosis of congenital ectopia lentis, treatment, surveillance, and hereditary and prenatal counseling for the patient and their family members.

Microtiter plate-based chemistry and in situ screening: SuFEx-enabled lead discovery of selective AChE inhibitors.

Sulphur fluoride exchange (SuFEx) is a category of click chemistry that enables covalent linking of modular units through sulphur connective hubs. Here, we reported an efficient synthesis and in situ screening method for building a library of sulphonamides on the picomolar scale by SuFEx reaction between a sulphonyl fluoride (RSO2F) core and primary or secondary amines. This biocompatible SuFEx reaction would allow us to rapidly synthesise sulphonamide molecules, and evaluate their ChE inhibitory activity. Compound T14-A24 was identified as a reversible, competitive, and selective AChE inhibitor (Ki = 22 nM). The drug-like evaluation showed that T14-A24 had benign BBB penetration, remarkable neuroprotective effect, and safe toxicological profile. In vivo behavioural study showed that T14-A24 treatment improved the Aß1 - 42-induced cognitive impairment, significantly prevented the effects of Aß1 - 42 toxicity. Therefore, this SuFEx click reaction can accelerate the discovery of lead compounds.

Synthesis of aliphatic nitriles from cyclobutanone oxime mediated by sulfuryl fluoride (SO2F2).

A SO2F2-mediated ring-opening cross-coupling of cyclobutanone oxime derivatives with alkenes was developed for the construction of a range of δ-olefin-containing aliphatic nitriles with (E)-configuration selectivity. This new method features wide substrate scope, mild conditions, and direct N-O activation.

Green and efficient synthesis of pure ß-sulfonyl aliphatic sulfonyl fluorides through simple filtration in aqueous media.

A green and efficient method for the synthesis of ß-sulfonyl aliphatic sulfonyl fluorides was developed. This reaction works in aqueous media under mild and environmentally benign conditions without any ligand or additive. The efficiency of this method is demonstrated by isolating the desired products obtained through simple filtration.

Synthesis and biological evaluation of novel ß-lactam-metallo ß-lactamase inhibitors.

ß-lactamases are enzymes that deactivate ß-lactam antibiotics through a hydrolysis mechanism. There are two known types of ß-lactamases: serine ß-lactamases (SBLs) and metallo ß-lactamases (MBLs). The two existing strategies to overcome ß-lactamase-mediated resistance are (a) to develop novel ß-lactam antibiotics that are not susceptible to hydrolysis by these enzymes; or (b) to develop ß-lactamase inhibitors that deactivate the enzyme and thereby restore the efficacy of the co-administered antibiotics. Many commercially available SBL inhibitors are used in combination therapy with antibiotics to treat antimicrobial resistant infections; however, there are only a handful of MBL inhibitors undergoing clinical trials. In this study, we present 11 novel potential MBL inhibitors (via multi-step chemical synthesis), that have shown to completely restore the efficacy of meropenem (≤2 mg L-1) against New Delhi metallo-ß-lactamase (NDM) producing Klebsiella pneumoniae in vitro. These compounds contain a cyclic amino acid zinc chelator conjugated to various commercially available ß-lactam antibiotic scaffolds with the aim to improve the overall drug transport, lipophilicity, and pharmacokinetic/pharmacodynamic properties as compared to the chelator alone. Biological evaluation of compounds 24b and 24c has further highlighted the downstream application of these MBLs, since they are non-toxic at the selected doses. Time-kill assays indicate that compounds 24b and 24c exhibit sterilizing activity towards NDM producing Klebsiella pneumoniae in vitro using minimal concentrations of meropenem. Furthermore, 24b and 24c proved to be promising inhibitors of VIM-2 (Ki = 0.85 and 1.87, respectively). This study has revealed a novel series of ß-lactam MBLIs that are potent, efficacious, and safe leads with the potential to develop into therapeutic MBLIs.

Complex Interplay Between Metabolism and CD4+ T-Cell Activation, Differentiation, and Function: a Novel Perspective for Atherosclerosis Immunotherapy.

Atherosclerosis is a complex pathological process that results from the chronic inflammatory reaction of the blood vessel wall and involves various immune cells and cytokines. An imbalance in the proportion and function of the effector CD4+ T-cell (Teff) and regulatory T-cell (Treg) subsets is an important cause of the occurrence and development of atherosclerotic plaques. Teff cells depend on glycolytic metabolism and glutamine catabolic metabolism for energy, while Treg cells mainly rely on fatty acid oxidation (FAO), which is crucial for determining the fate of CD4+ T cells during differentiation and maintaining their respective immune functions. Here, we review recent research achievements in the field of immunometabolism related to CD4+ T cells, focusing on the cellular metabolic pathways and metabolic reprogramming involved in the activation, proliferation, and differentiation of CD4+ T cells. Subsequently, we discuss the important roles of mTOR and AMPK signaling in regulating CD4+ T-cell differentiation. Finally, we evaluated the links between CD4+ T-cell metabolism and atherosclerosis, highlighting the potential of targeted modulation of CD4+ T-cell metabolism in the prevention and treatment of atherosclerosis in the future.

Regulatory T Cells in Pathological Cardiac Hypertrophy: Mechanisms and Therapeutic Potential.

BACKGROUND: Pathological cardiac hypertrophy is linked to immune-inflammatory injury, and regulatory T cells (Tregs) play a crucial role in suppressing immune-inflammatory responses. However, the precise role of Tregs in pathological cardiac hypertrophy remains unclear. OBJECTIVE: To summarize the current knowledge on the role and mechanisms of Tregs in pathological cardiac hypertrophy and explore their perspectives and challenges as a new therapeutic approach. RESULTS: Treg cells may play an important protective role in pressure overload (hypertension, aortic stenosis), myocardial infarction, metabolic disorders (diabetes, obesity), acute myocarditis, cardiomyopathy (hypertrophic cardiomyopathy, storage diseases), and chronic obstructive pulmonary disease-related pathological cardiac hypertrophy. Although some challenges remain, the safety and efficacy of Treg-based therapies have been confirmed in some clinical trials, and engineered antigen-specific Treg cells may have better clinical application prospects due to stronger immunosuppressive function and stability. CONCLUSION: Targeting the immune-inflammatory response via Treg-based therapies might provide a promising and novel future approach to the prevention and treatment of pathological cardiac hypertrophy.

Sulfur-fluoride exchange (SuFEx)-enabled lead discovery of AChE inhibitors by fragment linking strategies.

SuFEx click chemistry has been a method for the rapid synthesis of functional molecules with desirable properties. Here, we demonstrated a workflow that allows for in situ synthesis of sulfonamide inhibitors based on SuFEx reaction for high-throughput testing of their cholinesterase activity. According to fragment-based drug discovery (FBDD), sulfonyl fluorides [R-SO2F] with moderate activity were identified as fragment hits, rapidly diversified into 102 analogs in SuFEx reactions, and the sulfonamides were directly screened to yield drug-like inhibitors with 70-fold higher potency (IC50 = 94 nM). Moreover, the improved molecule J8-A34 can ameliorate cognitive function in Aß1-42-induced mouse model. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, this methodology can accelerate the development of robust biological probes and drug candidates.

Synthesis of Pyrazolo[1,5-a]pyridinyl, Pyrazolo[1,5-a]quinolinyl, and Pyrazolo[5,1-a]isoquinolinyl Sulfonyl Fluorides via a [3 + 2] Annulation.

A [3 + 2] cycloaddition reaction of N-aminopyridines, N-aminoquinolines, and N-aminoisoquinolines with 1-bromoethene-1-sulfonyl fluoride (BESF) was performed to obtain optimum yields of various useful pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]quinolinyl, and pyrazolo[5,1-a]isoquinolinyl sulfonyl fluorides (43-90% yield). The transformation process showed broad substrate specificity, mild reaction conditions, and operational simplicity. Therefore, the reaction has great applicable value in the field of medicinal chemistry and other disciplines.

Discovery of (E)-2-Methoxyethene-1-sulfonyl Fluoride for the Construction of Enaminyl Sulfonyl Fluoride.

A new sulfonyl fluoride reagent (E)-2-methoxyethene-1-sulfonyl fluoride (MeO-ESF) was developed and successfully applied for the construction of enaminyl sulfonyl fluoride (N-ESF). This protocol provides highly atom-economical access to diverse N-ESF and produces CH3OH as the sole byproduct under mild and environmentally benign conditions.

Arterial remodeling: the role of mitochondrial metabolism in vascular smooth muscle cells.

Arterial remodeling is a common pathological basis of cardiovascular diseases such as atherosclerosis, vascular restenosis, hypertension, pulmonary hypertension, aortic dissection, and aneurysm. Vascular smooth muscle cells (VSMCs) are not only the main cellular components in the middle layer of the arterial wall but also the main cells involved in arterial remodeling. Dedifferentiated VSMCs lose their contractile properties and are converted to a synthetic, secretory, proliferative, and migratory phenotype, playing key roles in the pathogenesis of arterial remodeling. As mitochondria are the main site of biological oxidation and energy transformation in eukaryotic cells, mitochondrial numbers and function are very important in maintaining the metabolic processes in VSMCs. Mitochondrial dysfunction and oxidative stress are novel triggers of the phenotypic transformation of VSMCs, leading to the onset and development of arterial remodeling. Therefore, pharmacological measures that alleviate mitochondrial dysfunction reverse arterial remodeling by ameliorating VSMCs metabolic dysfunction and phenotypic transformation, providing new options for the treatment of cardiovascular diseases related to arterial remodeling. This review summarizes the relationship between mitochondrial dysfunction and cardiovascular diseases associated with arterial remodeling and then discusses the potential mechanism by which mitochondrial dysfunction participates in pathological arterial remodeling. Furthermore, maintaining or improving mitochondrial function may be a new intervention strategy to prevent the progression of arterial remodeling.

Chemical and biology of sulfur fluoride exchange (SuFEx) click chemistry for drug discovery.

Compounds containing an SF bond have garnered intense interest in the chemical and biological literature. In particular, sulfonyl fluorides (RSO2F) are commonly used as covalent protein inhibitors and biological probes. The introduction of the fluorine atom into drugs often leads to significantly promoted medicinal properties, which revolutionized the development of pharmaceuticals and gained attention because of the beneficial properties of these small and highly electro-negative halogens. The sulfonyl fluoride functional group has also been widely adopted throughout the field of chemical biology due to its unique balance between reactivity and stability under physiological conditions. This comprehensive review highlights the recent developments of sulfonyl fluorides based compounds in a massive range of therapeutic applications. We believe this review article will be helpful to inspire new ideas for structural design and developments of less toxic and potent Sulfur based drugs against the numerous death-causing diseases.

A General Procedure for the Construction of 2-Alkyl-Substituted Vinyl Sulfonyl Fluoride.

A series of compact and multifunctional 2-alkyl-substituted vinyl sulfonyl fluorides were efficiently prepared from the corresponding alkyl iodides and 2-chloroprop-2-ene-1-sulfonyl fluoride (CESF). This Giese-type radical approach provided new and general access to alkenyl sulfonyl fluorides, including structures that would otherwise be challenging to synthesize with previously established methods. A correspondingly large collection of derivatization reactions was also demonstrated on the alkenyl sulfonyl fluorides.

A reductive dehalogenative process for chemo- and stereoselective synthesis of 1,3-dienylsulfonyl fluorides.

A method for the mild and efficient synthesis of 1,3-dienylsulfonyl fluorides was developed via dehalogenation of α-halo-1,3-dienylsulfonyl fluorides in the presence of zinc powder and acetic acid, achieving exclusive chemo- and stereoselectivities. This protocol was successfully applied to the synthesis of heterocyclic dienylsulfonyl fluorides and polyene sulfonyl fluoride.

Fluorosulfate-containing pyrazole heterocycles as selective BuChE inhibitors: structure-activity relationship and biological evaluation for the treatment of Alzheimer's disease.

Novel scaffolds are expected to treat Alzheimer's disease, pyrazole-5-fluorosulfates were found as selective BuChE inhibitors. Compounds K1-K26 were assayed for ChE inhibitory activity, amongst them, compound K3 showed potent BuChE and hBuChE inhibition (IC50 = 0.79 µM and 6.59 µM). SAR analysis showed that 1-, 3-, 4-subtituent and 5-fluorosulfate of pyrazole ring affected BuChE inhibitory activity. Molecular docking showed that the fluorosulfate increased the binding affinity of hBuChE through π-sulphur interaction. Compound K3 was a reversible, mixed and non-competitive BuChE inhibitor (Ki = 0.77 µM) and showed remarkable neuroprotection, safe toxicological profile and BBB penetration. In vivo behavioural study showed that K3 treatment improved the Aß1 - 42-induced cognitive impairment, and significantly prevented the effects of Aß1 - 42 toxicity. Therefore, selective BuChE inhibitor K3 has potential to be further developed as AD therapeutics.

A regio- and stereoselective Heck-Matsuda process for construction of γ-aryl allylsulfonyl fluorides.

A highly efficient regio- and stereoselective Heck-Matsuda method was developed employing aryl diazoniums and allylsulfonyl fluorides for the construction of a class of novel γ-aryl allylsulfonyl fluorides in the presence of Pd(OAc)2 and PPh3. The method features excellent regio- and stereoselectivity (up to 100% E-selectivity), broad substrate scope and mild reaction conditions. Further application of γ-aryl allylsulfonyl fluoride in SuFEx reactions was achieved to provide their corresponding sulfonates and sulfonamides in excellent yields.