Cyclo[2]pyridine[8]pyrrole: An Expanded Porphyrinoid with Three Closed-Shell Oxidation States.

We report here an expanded porphyrinoid, cyclo[2]pyridine[8]pyrrole, 1, that can exist at three closed-shell oxidation levels. Macrocycle 1 was synthesized via the oxidative coupling of two open chain precursors and fully characterized by means of NMR and UV-vis spectroscopies, MS, and X-ray crystallography. Reduction of the fully oxidized form (1, blue) with NaBH4 produced either the half-oxidized (2, teal) or fully reduced forms (3, pale yellow), depending on the amount of reducing agent used and the presence or absence of air. Reduced products 2 or 3 can be oxidized to 1 by various oxidants (quinones, FeCl3, and AgPF6). Macrocycle 1 also undergoes proton-coupled reductions with I-, Br-, Cl-, SO32-, or S2O32- in the presence of an acid. Certain thiol-containing compounds likewise reduce 1 to 2 or 3. This conversion is accompanied by a readily discernible color change, making cyclo[2]pyridine[8]pyrrole 1 able to differentiate biothiols, such as cysteine (Cys), homocysteine (Hcy), and glutathione (GSH).

GLP-1R activation attenuates the progression of pulmonary fibrosis via disrupting NLRP3 inflammasome/PFKFB3-driven glycolysis interaction and histone lactylation.

BACKGROUND: Pulmonary fibrosis is a serious interstitial lung disease with no viable treatment except for lung transplantation. Glucagon-like peptide-1 receptor (GLP-1R), commonly regarded as an antidiabetic target, exerts antifibrotic effects on various types of organ fibrosis. However, whether GLP-1R modulates the development and progression of pulmonary fibrosis remains unclear. In this study, we investigated the antifibrotic effect of GLP-1R using in vitro and in vivo models of pulmonary fibrosis. METHODS: A silica-induced pulmonary fibrosis mouse model was established to evaluate the protective effects of activating GLP-1R with liraglutide in vivo. Primary cultured lung fibroblasts treated with TGF-ß1 combined with IL-1ß (TGF-ß1 + IL-1ß) were used to explore the specific effects of liraglutide, MCC950, and 3PO on fibroblast activation in vitro. Cell metabolism assay was performed to determine the glycolytic rate and mitochondrial respiration. RNA sequencing was utilized to analyse the underlying molecular mechanisms by which liraglutide affects fibroblast activation. ChIP‒qPCR was used to evaluate histone lactylation at the promoters of profibrotic genes in TGF-ß1 + IL-1ß- or exogenous lactate-stimulated lung fibroblasts. RESULTS: Activating GLP-1R with liraglutide attenuated pulmonary inflammation and fibrosis in mice exposed to silica. Pharmacological inhibition of the NLRP3 inflammasome suppressed PFKFB3-driven glycolysis and vice versa, resulting in decreased lactate production in TGF-ß1 + IL-1ß-stimulated lung fibroblasts. Activating GLP-1R inhibited TGF-ß1 + IL-1ß-induced fibroblast activation by disrupting the interaction between the NLRP3 inflammasome and PFKFB3-driven glycolysis and subsequently prevented lactate-mediated histone lactylation to reduce pro-fibrotic gene expression. In addition, activating GLP-1R protected mitochondria against the TGF-ß1 + IL-1ß-induced increase in oxidative phosphorylation in fibroblasts. In exogenous lactate-treated lung fibroblasts, activating GLP-1R not only repressed NLRP3 inflammasome activation but also alleviated p300-mediated histone lactylation. Finally, GLP-1R activation blocked silica-treated macrophage-conditioned media-induced lung fibroblast activation. CONCLUSIONS: The antifibrotic effects of GLP-1R activation on pulmonary fibrosis could be attributed to the inhibition of the interaction between NLRP3 inflammasome and PFKFB3-driven glycolysis, and histone lactylation in lung fibroblasts. Thus, GLP-1R is a specific therapeutic target for the treatment of pulmonary fibrosis.

Liquidambaric acid inhibits the proliferation of hepatocellular carcinoma cells by targeting PPARα-RXRα to down-regulate fatty acid metabolism.

Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver. As the global obesity rate rises, non-alcoholic fatty liver disease (NAFLD) has emerged as the most rapidly increasing cause of HCC. Consequently, the regulation of lipid metabolism has become a crucial target for the prevention and treatment of HCC. Liquidambaric acid (LDA), a pentacyclic triterpenoid compound derived from various plants, exhibits diverse biological activities. We found that LDA could inhibit HCC cell proliferation by arresting cell cycle and prompting apoptosis. Additionally, LDA can augment the therapeutic efficacy of Regorafenib in HCC in vitro and vivo. Our study utilized transcriptome analysis, luciferase reporter assays, and co-immunocoprecipitation experiments to elucidate the anti-HCC mechanism of LDA. We discovered that LDA disrupts the formation of the PPARα-RXRα heterodimer, leading to the down-regulation of the ACSL4 gene and subsequently impacting the fatty acid metabolism of HCC cells, ultimately inhibiting HCC proliferation. Our research contributes to the identification of novel therapeutic agents and targets for the treatment of HCC.

Isopimaric acid, an ion channel regulator, regulates calcium and oxidative phosphorylation pathways to inhibit breast cancer proliferation and metastasis.

Breast cancer is the globally most common malignant tumor and the biggest threat to women. Even though the diagnosis and treatment of breast cancer are progressing continually, a large number of breast cancer patients eventually develop a metastatic tumor, especially triple-negative breast cancer (TNBC). Recently, metal ion homeostasis and ion signaling pathway have become important targets for cancer therapy. In this study, We analyzed the effects and mechanisms of isopimaric acid (IPA), an ion channel regulator, on the proliferation and metastasis of breast cancer cells (4 T1, MDA-MB-231and MCF-7) by cell functional assay, flow cytometry, western blot, proteomics and other techniques in vitro and in vivo. Results found that IPA significantly inhibited the proliferation and metastasis of breast cancer cells (especially 4 T1). Further studies on the anti-tumor mechanism of IPA suggested that IPA might affect EMT and Wnt signaling pathways by targeting mitochondria oxidative phosphorylation and Ca2+ signaling pathways, and then inducing breast cancer cell cycle arrest and apoptosis. Our research reveals the therapeutic value of IPA in breast cancer and provides a theoretical basis for the new treatment of breast cancer.

LncRNA CYP4A22-AS1 promotes the progression of lung adenocarcinoma through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes.

OBJECTIVES: Lung adenocarcinoma (LUAD) exhibits a higher fatality rate among all cancer types worldwide, yet the precise mechanisms underlying its initiation and progression remain unknown. Mounting evidence suggests that long non-coding RNAs (lncRNAs) exert significant regulatory roles in cancer development and progression. Nevertheless, the precise involvement of lncRNA CYP4A22-AS1 in LUAD remains incompletely comprehended. METHODS: Bioinformatics analyses evaluated the expression level of CYP4A22-AS1 in lung adenocarcinoma and paracancer. The LUAD cell line with a high expression of CYP4A22-AS1 was constructed to evaluate the role of CYP4A22-AS1 in the proliferation and metastasis of LUAD by CCK8, scratch healing, transwell assays, and animal experiments. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. Luciferase reporter gene analyses, west-blotting, and qRT-PCR were carried out to reveal the interaction between CYP4A22-AS1, miR-205-5p/EREG, and miR-34c-5p/BCL-2 axes. RESULTS: CYP4A22-AS1 expression was significantly higher in LUAD tissues than in the adjacent tissues. Furthermore, we constructed a LUAD cell line with a high expression of CYP4A22-AS1 and noted that the high expression of CYP4A22-AS1 significantly enhanced the proliferation and metastasis of LUAD. We applied transcriptome and microRNA sequencing to examine the mechanism of CYP4A22-AS1 enhancing the proliferation and metastasis of LUAD. CYP4A22-AS1 increased the expression of EREG and BCL-2 by reducing the expression of miR-205-5p and miR-34-5p and activating the downstream signaling pathway of EGFR and the anti-apoptotic signaling pathway of BCL-2, thereby triggering the proliferation and metastasis of LUAD. The transfection of miR-205-5p and miR-34-5p mimics inhibited the role of CYP4A22-AS1 in enhancing tumor progression. CONCLUSION: This study elucidates the molecular mechanism whereby CYP4A22-AS1 overexpression promotes LUAD progression through the miR-205-5p/EREG and miR-34c-5p/BCL-2 axes.

Role of the EM clustering method in determining the geochemical background of As and Cr in soils: a case study in the north of Changchun, China.

Determining the geochemical background for heavy metals is vital in soil management activities. Although many statistical methods for geochemical background determination have been proposed, the multi-population problem of geochemical data, primarily regional ones, derived mainly from mixing multiple populations belonging to various geological sources or processes, needs to be better addressed. In this study, the Expectation-Maximization (EM) algorithm was employed to separate multiple populations in a 1:250,000 scale regional geochemical data set of soils in a lithologically complex region in the north of Changchun, China. The data set included 3746 surface soil samples analyzed for SiO2, K2O, Al2O3, CaO, La, Rb, Y, Ti, Ce, V, Cr, and As. The potential high-risk areas of As and Cr were determined before and after the separation of multiple populations. The comparison results show that the EM clustering method can efficiently separate multiple populations and determine soil geochemical background more reasonably, thus eliminating false contamination that is easily misidentified and better revealing concealed contamination that is challenging to detect.

Effects of dietary stachyose levels on caecal skatole concentration, hepatic cytochrome P450 mRNA expressions and enzymatic activities in broilers.

Effects of dietary supplemental stachyose on caecal skatole concentration, hepatic cytochrome P450 (CYP450, CYP) mRNA expressions and enzymatic activities in broilers were evaluated. Arbor Acre commercial mixed male and female chicks were assigned randomly into six treatments. The positive control (PC) diet was based on maize-soyabean meal, and the negative control (NC) diet was based on maize-non-soyabean meal. The NC diet was then supplemented with 4, 5, 6 and 7 g/kg stachyose to create experimental diets, named S-4, S-5, S-6 and S-7, respectively. Each diet was fed to six replicates of ten birds from days 1 to 49. On day 49, the caecal skatole concentrations in the PC, S-4, S-5, S-6 and S-7 groups were lower than those in the NC group by 42·28, 23·68, 46·09, 15·31 and 45·14 % (P < 0·01), respectively. The lowest pH value was observed in the S-5 group (P < 0·05). The stachyose-fed groups of broilers had higher caecal acetate and propionate levels compared with control groups, and propionate levels in the S-6 and S-7 groups were higher than those in the S-4 and S-5 groups (P < 0·001). The highest CYP3A4 expression was found in the S-7 group (P < 0·05), but this was not different from PC, S-4, S-5 and S-6 treatments. There was no significant difference in CYP450 (1A2, 2D6 and 3A4) enzymatic activities among the groups (P > 0·05). In conclusion, caecal skatole levels can be influenced by dietary stachyose levels, and 5 g/kg of stachyose in the diet was suggested.

Fasudil inhibits neutrophil-endothelial cell interactions by regulating the expressions of GRP78 and BMPR2.

Regulation of leukocyte-endothelial cell interactions and of vascular permeability plays a critical role in the maintenance of functional pulmonary microvascular barriers. Little is yet known about the effect of the Rho-associated protein kinase (ROCK) inhibitor fasudil on leukocyte-endothelial cell interactions or the underlying mechanism. In the present study, as evaluated using co-culture systems of neutrophils and human pulmonary microvascular endothelial cells (HPMECs), fasudil dose-dependently suppressed neutrophil chemotaxis by decreasing the production of chemotactic factors in lipopolysaccharide (LPS)-treated HPMECs. The inhibitory role of fasudil in neutrophil chemotaxis was mediated by down-regulation of the chaperone glucose-regulated protein 78 (GRP78), since the inhibition was abolished by 4-phenyl butyric acid (a chemical chaperone mimicking GRP78). In addition, fasudil inhibited LPS-induced neutrophil-endothelial adhesion by reducing the expression of intercellular adhesion molecule (ICAM)-1. By use of lentiviral transfection in HPMECs, bone morphogenic protein receptor 2 (BMPR2) overexpression suppressed the LPS-induced increase of both ICAM-1 expression and neutrophil-endothelial adhesion, whereas knocking down BMPR2 abolished the inhibitory role of fasudil in both ICAM-1 expression and neutrophil-endothelial adhesion. Moreover, fasudil alleviated LPS-induced hyperpermeability of HPMEC monolayers by leading to the recovery of intercellular junctions, thereafter reduced neutrophil transendothelial cell migration. Therefore, fasudil inhibited leukocyte-endothelial cell interactions and vascular hyperpermeability through modulation of GRP78 and BMPR2 expression, suggesting a potential role for ROCK as a switch for inhibiting leukocyte-endothelial cell interactions.

Pulmonary Fungal Diseases in Immunocompetent Hosts: A Single-Center Retrospective Analysis of 35 Subjects.

BACKGROUND: Pulmonary fungal disease is an emerging issue in immunocompetent patients, for whom the characteristics are only partially understood. METHODS: We conducted a single-center retrospective study of histologically verified pulmonary fungal disease in Eastern China from 2006 to 2014 to understand the demographics, clinical manifestations, therapeutic approaches, and factors associated with prognosis in this population. All cases were diagnosed according to the 2008 European Organization for the Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infection Diseases Mycoses Study Group definition criteria. RESULTS: A total of 112 cases of pulmonary fungal diseases were enrolled (35 proven, 16 probable, 61 possible), and we analyzed the 35 patients with histologically proven pulmonary fungal diseases in this study. The main fungal species identified were Aspergillus (51.4 %), Cryptococcus (22.9 %), and Mucor (2.4 %). Treatment consisted of antifungal therapeutic agents (54.3 %), surgery and postsurgical agents (25.7 %), or surgery alone (14.3 %). The overall crude mortality rate was 14.3 %, and the mortality due to pulmonary fungal infections was 2.9 %. Significant predictors of mortality by univariate analysis were hypoalbuminemia (P = 0.005), cancer (P = 0.008), and positive culture (P = 0.044). Additionally, hypoalbuminemia was the only risk factor for mortality by multivariate analysis (RR = 7.56, 95 % CI 1.38-41.46). CONCLUSION: Pulmonary fungal disease in immunocompetent patients, with Aspergillus as the most common identified species, had a prognosis that was influenced by the level of serum albumin.

[Analysis of pathogenic spectrum and risk factors in 165 non-transplant patients with invasive fungal disease].

OBJECTIVE: To describe the clinical characteristics of and risk factors for invasive fungal disease, and therefore to improve the early diagnosis and treatment of fungal infections. METHODS: The clinical data of invasive fungal disease in 165 patients without transplantation from 2006 to 2012 in the First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed. The diagnosis was based on the following guidelines: diagnosis and treatment guidelines of critically ill patients with invasive fungal infection (2007), diagnostic criteria and treatment principle of invasive fungal infection in patients with hematopathy/malignant tumors (fourth edition, 2013), diagnostic criteria and treatment principle of invasive pulmonary fungal infection (draft, 2006). RESULTS: Invasive fungal disease was mostly diagnosed in the respiratory department (31.5%). The major pathogens were cryptococcus (48.3%), aspergillus (31.7%) and followed by mucor (5.9%). The most common symptoms included cough, haemoptysis, and fever. Radiological Findings were non-specific, nodules or opacities being more common as compared to classical aspergilloma, halo sign, and crescent sign. The most common underlying diseases were diabetes (15.8%), chronic obstructive pulmonary disease (13.3%), and malignant hematological disease (10.3%). Moreover, 66.1% cases of invasive fungal disease were accompanied by one or more risk factors (eg. administration of antibiotics more than 7 days, invasive operations, and therapy with long-term glucocorticoids or immunosuppressant drugs). The mortality of invasive fungal disease with more than 2 risk factors was 10.6%. CONCLUSIONS: The most common pathogens of invasive fungal disease in non-transplant patients were cryptococcus, aspergillus and mucor. The lung and the brain were the mostly involved organs. Compared to cryptococcus, invasive fungal disease caused by other fungal pathogens mainly occurred in patients with serious underlying diseases and risk factors.

Unraveling the allosteric mechanisms of prolyl endopeptidases for celiac disease therapy: Insights from molecular dynamics simulations.

Prolyl endopeptidases (PEP) from Sphingomonas capsulata (sc) and Myxococcus xanthus (mx) selectively degrade gluten peptides in vitro, offering a potential therapeutic strategy for celiac disease. However, the mechanisms governing the interaction of these enzymes with their substrates remain unclear. In this study, conventional molecular dynamics simulations with a microsecond timescale and targeted molecular dynamics simulations were performed to investigate the native states of mxPEP and scPEP enzymes, as well as their allosteric binding with a representative substrate, namely, Z-Ala-Pro-p-nitroanilide (pNA). The simulations reveal that the native scPEP is in an open state, while the native mxPEP is in a closed state. When pNA approaches a closed mxPEP, it binds to an allosteric pocket located at the first and second ß-sheet of the ß-propeller domain, inducing the opening of this enzyme. Neither enzyme is active in the open or partly-open states. Enzymatic activity is enabled only when the catalytic pocket in the closed state fully accommodates the substrates. The internal capacity of the catalytic pocket of PEP in the closed state determines the maximum size of the gluten peptides that the enzymes can catalyze. The present work provides essential molecular dynamics information for the redesign or engineering of PEP enzymes.

Application of the partial least square regression method in determining the natural background of soil heavy metals: A case study in the Songhua River basin, China.

The "background" is an essential index for identifying anthropogenic inputs and potential ecological risks of soil heavy metals. However, the lithology of bedrock can cause significant spatial variation in the natural background of soil elements, posing considerable difficulties in estimating background values. In this study, an attempt was made to calculate the natural background through regression analysis of soil chemical composition, and reasonably evaluate the impact of lithology. A total of 1771 surface soil samples were collected from the Songhua River Basin, China, for chemical composition analysis, and the partial least square regression (PLSR) method was employed to establish the relationship between heavy metals (As, Hg, Cr, Cd, Pb, Cu, Zn, and Ni) and soil chemical composition/environmental parameters (SiO2, Al2O3, TFe2O3, MgO, CaO, K2O, Na2O, La, Y, Zr, V, Sc, Sr, Li and pH). The result shows that As, Cr, Pb, Cu, Zn, and Ni have significant linear relationships with soil chemical composition. Each of these six heavy metals obtained 1771 regression background values; some were higher than the uniform background value obtained from the boxplot, while others were lower. The regression background values recognized not only subtle anthropogenic inputs and potential ecological risks in low-background regions but also spurious contamination in high-background areas. All these indicate that the PLSR method can effectively improve the determination accuracy of the natural background of soil heavy metals. More attention should be paid to the serious anthropogenic inputs appearing in some places of the study area.

Spinosad blocks CHRNA5 mediated EGFR signaling pathway activation to inhibit lung adenocarcinoma proliferation.

Lung adenocarcinoma (LUAD) is the leading cause of cancer death worldwide, with high incidence and low survival rates. Nicotinic acetylcholine receptors play an important role in the progression of LUAD. In this study, a screening of 17 nicotinic acetylcholine receptor allosteric agents revealed that spinosad effectively suppressed the proliferation of LUAD cells. The experiments demonstrated that spinosad induced cell cycle arrest in the G1 phase and stimulated apoptosis, thereby impeding the growth of LUAD and enhancing the responsiveness to gefitinib in vitro and vivo. Mechanistic insights obtained through transcriptome sequencing, Co-IP, and protein immunoblots indicated that spinosad disrupted the interaction between CHRNA5 and EGFR, thereby inhibiting the formation of downstream complexes and activation of the EGFR signaling pathway. The supplementation of exogenous acetylcholine showed to mitigate the inhibition of LUAD cell proliferation induced by spinosad. This study elucidates the therapeutic effects and mechanisms of spinosad in LUAD, and offers a theoretical and experimental foundation for novel LUAD treatments.

Environmental contamination and health risk assessment of potentially toxic trace metal elements in soils near gold mines - A global meta-analysis.

Gold mining is the most important anthropogenic source of heavy metal emissions into the environment. Researchers have been aware of the environmental impacts of gold mining activities and have conducted studies in recent years, but they have only selected one gold mining site and collected soil samples in its vicinity for analysis, which does not reflect the combined impact of all gold mining activities on the concentration of potentially toxic trace elements (PTES) in nearby soils at a global scale. In this study, 77 research papers from 24 countries were collected from 2001 to 2022, and a new dataset was developed to provide a comprehensive study of the distribution characteristics, contamination characteristics, and risk assessment of 10 PTEs (As, Cd, Cr, Co, Cu, Hg, Mn, Ni, Pb, and Zn) in soils near the deposits. The results show that the average levels of all 10 elements are higher than the global background values and are at different levels of contamination, with As, Cd, and Hg at strong contamination levels and serious ecological risks. As and Hg contribute to a greater non-carcinogenic risk to both children and adults in the vicinity of the gold mine, and the carcinogenic risks of As, Cd, and Cu are beyond the acceptable range. Gold mining on a global scale has already caused serious impacts on nearby soils and should be given adequate attention. Timely heavy metal treatment and landscape restoration of extracted gold mines and environmentally friendly approaches such as bio-mining of unexplored gold mines where adequate protection is available are of great significance.

Novel human mPGES-1 inhibitors identified through structure-based virtual screening.

Microsomal prostaglandin E synthase-1 (mPGES-1) is an inducible prostaglandin E synthase after exposure to pro-inflammatory stimuli and, therefore, represents a novel target for therapeutic treatment of acute and chronic inflammatory disorders. It is essential to identify mPGES-1 inhibitors with novel scaffolds as new leads or hits for the purpose of drug design and discovery that aim to develop the next-generation anti-inflammatory drugs. Herein we report novel mPGES-1 inhibitors identified through a combination of large-scale structure-based virtual screening, flexible docking, molecular dynamics simulations, binding free energy calculations, and in vitro assays on the actual inhibitory activity of the computationally selected compounds. The computational studies are based on our recently developed three-dimensional (3D) structural model of mPGES-1 in its open state. The combined computational and experimental studies have led to identification of new mPGES-1 inhibitors with new scaffolds. In particular, (Z)-5-benzylidene-2-iminothiazolidin-4-one is a promising novel scaffold for the further rational design and discovery of new mPGES-1 inhibitors. To our best knowledge, this is the first time a 3D structural model of the open state mPGES-1 is used in structure-based virtual screening of a large library of available compounds for the mPGES-1 inhibitor identification. The positive experimental results suggest that our recently modeled trimeric structure of mPGES-1 in its open state is ready for the structure-based drug design and discovery.

Pyridazine-bridged expanded rosarin and semi-rosarinogen.

The synthesis of the pyridazine-bridged expanded rosarin 1 and a reduced precursor, semi-rosarinogen 2, is reported. A single crystal X-ray diffraction analysis of 1 and theoretical calculations show that both 1 and 2 have distorted structures. Expanded rosarin 1 and its precursor 2 can differentiate various thiols in organic solvents by means of species-specific colour changes and reaction times.

Primary pulmonary extranodal NK/T-cell lymphoma: a case report and literature review.

Extranodal natural killer/T-cell lymphoma (ENKTL) is rare lymphoma subtype with a very poor prognosis. ENKTL in the lung is strongly associated with Epstein-Barr virus (EBV) and is extremely rare; only a few cases have been reported. In the present study, we report a case that a 40-year-old male who presented with cough, sputum and intermittent fever for one month. Chest radiograph revealed progressive multiple nodules in both lungs with ground-glass opacities and bilateral pleural effusion. Based on clinical characteristics and computed tomography (CT) findings, he was initially treated with empirical antibiotics. As there was no significant improvement, bone marrow puncture, left axillary mass biopsy and CT- guided percutaneous lung biopsy were conducted. Therefore, a diagnosis of primary pulmonary ENKTL was confirmed by pathology as cells are positive for CD2, cytoplasmic CD3e, CD56. In situ hybridization for EBV-encoded ribonucleic acid (EBER) was positive. Next generation sequencing (NGS) was used to determine potential therapeutic targets, and the missense mutation of signal transducer and activator of transcription 3 (STAT3) was found. However, the patient demonstrated rapid deterioration and refused chemotherapy. He died shortly following diagnosis. In conclusion: A diagnosis of ENKTL should be considered when patients present with fever and expansive consolidation of the lung, which do not respond to antibiotics. To our knowledge, our patient was the first to undergo NGS for primary pulmonary ENKTL.

Correlation between the pKa and nuclear shielding of α-hydrogen of ketones.

The α-H acidity is an important chemical property of ketones that has attracted much research interest. Theoretical prediction of pKa for ketone α-H is significant. In this work, we theoretically studied the nuclear shielding of various α-Hs in a set of ketones and that of the corresponding enolic hydroxyl Hs in tautomeric enol forms. It has been demonstrated through linear regression analyses that the pKa values of these ketones correlate with both sets of the calculated nuclear shielding values. The correlation coefficient R2 of the linear correlation relationship is 0.90. The present work has provided a new approach to computationally evaluating the acidity of α-Hs in ketones, enabling us to semi-empirically predict the ketone α-H acidity from the calculated nuclear shielding values. Graphical AbstractExperimental pKa values in DMSO vs predicted pKa values calculated from 1H nuclear shielding for the hydroxyl hydrogens in the enol forms and for the α-Hs in the keto forms. The surrounding solvent effects were modelled by keto/enol-DMSO clusters and SMD solvent models.

Correlations between the 1H NMR chemical shieldings and the pKa values of organic acids and amines.

The acid dissociation constants and 1H NMR chemical shieldings of organic compounds are important properties that have attracted much research interest. However, few studies have explored the relationship between these two properties. In this work, we theoretically studied the NMR chemical shifts of a series of carboxylic acids and amines in the gas phase and in aqueous solution. It was found that the negative logarithms of the experimental acid dissociation constants (i.e., the pKa values) of the organic acids and amines in aqueous solution correlate almost linearly with the corresponding calculated NMR chemical shieldings. Key factors that affect the theoretically predicted pKa values are discussed in this paper. The present work provides a new way to predict the pKa values of organic/biochemical compounds. Graphical abstract The chemical shielding values of organic acids and amines correlate near linearly with their corresponding pKa values.