Deoxygenative Functionalizations of Aldehydes, Ketones and Carboxylic Acids.

The simple and efficient conversion of carbonyl compounds into functionalized alkanes via deoxygenation is highly enabling in chemical synthesis. This Review covers the recent methodology development in carbonyl and carboxyl deoxygenative functionalizations, highlighting some representative and significant contributions in this field. These advances are categorized based on the reactivity patterns of some oxygenated feedstock compounds, including aldehydes, ketones and carboxylic acids. Four types of reactive intermediates arising from aldehydes and ketones during the deoxygenation, namely, bis-electrophiles, carbenoids, bis-nucleophiles and alkyl radical equivalents, are presented, while the carboxylic acids mainly behave as tris-electrophiles when deoxygenated. In each subcategory, selected examples are organized according to the type of bond formation and discussed from a generalized mechanistic perspective.

Metal-Free Direct Deoxygenative Borylation of Aldehydes and Ketones.

Direct conversion of aldehydes and ketones into alkylboronic esters via deoxygenative borylation represents an unknown yet highly desirable transformation. Herein, we present a one-step and metal-free method for carbonyl deoxy-borylation under mild conditions. A wide range of aromatic aldehydes and ketones are tolerated and successfully converted into the corresponding benzylboronates. By the same deoxygenation manifold with aliphatic aldehydes and ketones, we also enable a concise synthesis of 1,1,2-tris(boronates), a family of compounds that currently lack efficient synthetic methods. Given its simplicity and versatility, we expect that this novel borylation approach could show great promise in organoboron synthesis and inspire more carbonyl deoxygenative transformations in both academic and industrial settings.

Aromatic Chemistry in the Excited State: Facilitating Metal-Free Substitutions and Cross-Couplings.

Transition-metal-catalyzed cross-couplings between aromatic electrophiles and nucleophiles have revolutionized modern chemical syntheses. Nevertheless, transition-metal-free approaches are preferable, considering the various issues caused by metal catalysts. This Minireview summarizes the recent progress in the light-enabled transition-metal-free formation of carbon-carbon and carbon-heteroatom bonds in aromatics, which opens a new avenue in aromatic reactions. From the mechanistic perspective, it classifies different reaction types of aryl electrophiles in an excited state with various nucleophiles. We believe this will provide more rationales for metal-free aromatic substitutions and cross-couplings with light, and guide the development of novel transformations of aromatic compounds facilitated by light.

En Route to Intermolecular Cross-Dehydrogenative Coupling Reactions.

Cross-coupling reaction between two C-H bonds has become a fundamental strategy in synthetic organic chemistry. With its increasing importance in green chemistry, atom economy, and step economy, its development has sky-rocketed within the last 20 years, with the term "cross-dehydrogenative coupling (CDC)" popularized and progressed by the group of Li and others to describe direct Y-Z bond formations from Y-H and Z-H bonds under oxidative conditions. Among all types of CDC reactions, the C-C bond formations are of prime importance in building up the molecular complexity but their categorization currently remains disarray due to a wide diversity, resulting in frequent display in separate topics. In this Perspective, a contemporary categorization via C-H activation strategies is presented herein, which could be vital for future CDC designs. With this mechanism-based categorization and discussion, we wish that this minireview will help more synthetic chemists gain insight into the design of CDC reactions and inspires more ideas on this topic.

Synthesis of Benzopyridoindolone Derivatives via a One-Pot Copper Catalyzed Tandem Reaction of 2-Iodobenzamide Derivatives and 2-Iodobenzylcyanides.

An efficient approach for the synthesis of benzo-fused pyridoindolone derivatives via a one-pot copper catalyzed tandem reaction of 2-iodobenzamides with 2-iodobenzylcyanides has been developed. Using this protocol, benzo-fused pyridoindolone derivatives are obtained in high yields in a relatively short period of time under mild reaction conditions. To the best of our knowledge, this is the first approach where one can synthesize free indole N-H benzo-fused pyridoindolones. Also, both indole and pyridone cores are constructed during the course of the reaction. The methodology shows good functional group tolerance and allows synthesis of thiophene-fused pyridoindolones and fused indolobenzonaphthyridone derivatives.

Synthesis of Biologically Active Indenoisoquinoline Derivatives via a One-Pot Copper(II)-Catalyzed Tandem Reaction.

A concise route for the synthesis of indenoisoquinoline derivatives from 2-iodobenzamide and 1,3-indanedione derivatives in the presence of copper(II) chloride and cesium carbonate in acetonitrile solvent is reported. A wide variety of 2-iodobenzamide derivatives and indandiones could be used to synthesize indenoisoquinoline derivatives and other fused indenoisoquinoline in moderate to good yields. This methodology was adapted for the one-step synthesis of a series of clinically active topoisomerase I inhibitors such as NSC 314622, LMP-400, LMP-776.

Syntheses of 4-Indolylquinoline Derivatives via Reductive Cyclization of Indolylnitrochalcone Derivatives by Fe/HCl.

An easy and efficient procedure for the synthesis of 4-indolylquinoline derivatives is described. This process involves two steps, the first of which is the Michael addition of indole to nitrochalcones promoted by sulfamic acid under solvent free conditions and the second step is a reductive cyclization of the indolylnitrochalcone intermediates to 4-indolylquinoline derivatives by Fe/HCl in ethanol. In both steps, the reactions are clean and the yields of products are high.

Synthesis of Bicyclic Isoxazoles and Isoxazolines via Intramolecular Nitrile Oxide Cycloaddition.

An efficient and straight forward procedure for the syntheses of bicyclic isoxazole/isoxazoline derivatives from the corresponding dimethyl-2-(2-nitro-1-aryl/alkyl)-2-(prop-2-yn-1yl)malonates or dimethyl 2-allyl-2-(2-nitro-1-aryl/alkyl ethyl)malonate is described. High yields and simple operations are important features of this methodology.

Novel antifungal drug discovery based on targeting pathways regulating the fungus-conserved Upc2 transcription factor.

Infections by Candida albicans and related fungal pathogens pose a serious health problem for immunocompromised patients. Azole drugs, the most common agents used to combat infections, target the sterol biosynthetic pathway. Adaptation to azole therapy develops as drug-stressed cells compensate by upregulating several genes in the pathway, a process mediated in part by the Upc2 transcription factor. We have implemented a cell-based high-throughput screen to identify small-molecule inhibitors of Upc2-dependent induction of sterol gene expression in response to azole drug treatment. The assay is designed to identify not only Upc2 DNA binding inhibitors but also compounds impeding the activation of gene expression by Upc2. An AlphaScreen assay was developed to determine whether the compounds identified interact directly with Upc2 and inhibit DNA binding. Three compounds identified by the cell-based assay inhibited Upc2 protein level and UPC2-LacZ gene expression in response to a block in sterol biosynthesis. The compounds were growth inhibitory and attenuated antifungal-induced sterol gene expression in vivo. They did so by reducing the level of Upc2 protein and Upc2 DNA binding in the presence of drug. The mechanism by which the compounds restrict Upc2 DNA binding is not through a direct interaction, as demonstrated by a lack of DNA binding inhibitory activity using the AlphaScreen assay. Rather, they likely inhibit a novel pathway activating Upc2 in response to a block in sterol biosynthesis. We suggest that the compounds identified represent potential precursors for the synthesis of novel antifungal drugs.

Effect of acupuncture on ischaemic stroke in patients with rheumatoid arthritis: a nationwide propensity score-matched study.

OBJECTIVE: To demonstrate that acupuncture is beneficial for decreasing the risk of ischaemic stroke in patients with rheumatoid arthritis (RA). DESIGN: A propensity score-matched cohort study. SETTING: A nationwide population-based study. PARTICIPANTS: Patients with RA diagnosed between 1 January 1997 and 31 December 2010, through the National Health Insurance Research Database in Taiwan. INTERVENTIONS: Patients who were administered acupuncture therapy from the initial date of RA diagnosis to 31 December 2010 were included in the acupuncture cohort. Patients who did not receive acupuncture treatment during the same time interval constituted the no-acupuncture cohort. PRIMARY OUTCOME MEASURES: A Cox regression model was used to adjust for age, sex, comorbidities, and types of drugs used. We compared the subhazard ratios (SHRs) of ischaemic stroke between these two cohorts through competing-risks regression models. RESULTS: After 1:1 propensity score matching, a total of 23 226 patients with newly diagnosed RA were equally subgrouped into acupuncture cohort or no-acupuncture cohort according to their use of acupuncture. The basic characteristics of these patients were similar. A lower cumulative incidence of ischaemic stroke was found in the acupuncture cohort (log-rank test, p<0.001; immortal time (period from initial diagnosis of RA to index date) 1065 days; mean number of acupuncture visits 9.83. In the end, 341 patients in the acupuncture cohort (5.95 per 1000 person-years) and 605 patients in the no-acupuncture cohort (12.4 per 1000 person-years) experienced ischaemic stroke (adjusted SHR 0.57, 95% CI 0.50 to 0.65). The advantage of lowering ischaemic stroke incidence through acupuncture therapy in RA patients was independent of sex, age, types of drugs used, and comorbidities. CONCLUSIONS: This study showed the beneficial effect of acupuncture in reducing the incidence of ischaemic stroke in patients with RA.

The Association between Acupuncture Therapy and the Risk of Disability Development in Dementia Patients: A Nationwide Cohort Study.

Purpose: Disability is the comorbidity of dementia for which there is no available preventive measure. The aim of this study was to investigate the association between acupuncture treatment and the risk of disability development in dementia patients. Patients and Methods: A cohort study was performed using a nationwide health database in Taiwan. The included dementia patients were divided into acupuncture and non-acupuncture cohorts based on whether they received acupuncture treatment during the follow-up period. The variables in the two cohorts were controlled by 1:1 propensity-score matching. The difference in disability development in dementia patients between the acupuncture and non-acupuncture cohorts was also analyzed. Subgroup analyses were performed using socioeconomic variables, comorbidities and anti-dementia agents (donepezil, rivastigmine, galantamine and memantine) used for dementia treatment. Results: A total of 9,760 dementia patients met our inclusion criteria, and patients were divided into an equal number (n=2,422) of acupuncture and non-acupuncture groups, respectively, after 1:1 propensity-score matching. The dementia patients had a lower risk of disability development after acupuncture treatment than those who did not receive acupuncture treatment (adjusted hazard ratio 0.65, 95% confidence interval 0.60-0.70, p < 0.001). The results were independent of basic variables or comorbidities in the two cohorts. Patients who did not use anti-dementia agents had a lower risk of developing disability after receiving acupuncture intervention than those who used anti-dementia agents. Conclusion: Our results revealed the relationship between acupuncture intervention and decreased risk of developing disability in dementia patients. The results are useful for dementia treatment, trial design and further planning of care programs.

A novel TREX1 inhibitor, VB-85680, upregulates cellular interferon responses.

Activation of the cGAS-STING pathway plays a key role in the innate immune response to cancer through Type-1 Interferon (IFN) production and T cell priming. Accumulation of cytosolic double-stranded DNA (dsDNA) within tumor cells and dying cells is recognized by the DNA sensor cyclic GMP-AMP synthase (cGAS) to create the secondary messenger cGAMP, which in turn activates STING (STimulator of INterferon Genes), resulting in the subsequent expression of IFN-related genes. This process is regulated by Three-prime Repair EXonuclease 1 (TREX1), a 3' → 5' exonuclease that degrades cytosolic dsDNA, thereby dampening activation of the cGAS-STING pathway, which in turn diminishes immunostimulatory IFN secretion. Here, we characterize the activity of VB-85680, a potent small-molecule inhibitor of TREX1. We first demonstrate that VB-85680 inhibits TREX1 exonuclease activity in vitro in lysates from both human and mouse cell lines. We then show that treatment of intact cells with VB-85680 results in activation of downstream STING signaling, and activation of IFN-stimulated genes (ISGs). THP1-Dual™ cells cultured under low-serum conditions exhibited an enhanced ISG response when treated with VB-85680 in combination with exogenous DNA. Collectively, these findings suggest the potential of a TREX1 exonuclease inhibitor to work in combination with agents that generate cytosolic DNA to enhance the acquisition of the anti-tumor immunity widely associated with STING pathway activation.

Effect of Acupoint Stimulation on Controlling Pain from Heel Lance in Neonates: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

To evaluate the effect of acupoint stimulation compared to other interventions on pain control in neonates who underwent heel lance, we searched for randomized controlled trials across six databases (CINAHL, Cochrane Library, EMBASE, Medline, PubMed, and Web of Science) published up to January 2023. Studies comparing acupoint stimulation and other interventions for controlling heel lance pain in neonates were included. These reports measured at least one of the following variables: pain score, crying time, oxygenation saturation, heart rate, respiration rate, and duration of the procedure. The data were independently extracted by two authors, and the PRISMA guidelines for study selection were followed. A total of 79 articles were screened, and 10 studies, with results on 813 neonates, were included in the final selection. The pain scores recorded during the heel lance procedure were not significantly different between the acupoint stimulation cohort and the control cohort (SMD of -0.26, 95% confidence interval (CI) from -0.52 to 0.01; p = 0.06; I2 = 68%). After processing the subgroup analyses, significant differences were found in the comparisons of acupuncture vs. usual care (SMD of -1.25, 95% CI from -2.23 to 0.27) and acupressure vs. usual care (SMD of -0.62, 95% CI from -0.96 to -0.28); nonsignificant differences were found in other comparisons. Our results demonstrate that acupoint stimulation may improve pain score during the heel lance procedure.

Trends in Coprescription Among Taiwanese Children from 2002 to 2012.

Purpose: Coprescription means that patients use different prescription medications at the same time, which can lead to polypharmacy and subsequent complications. In Taiwan, prescriptions can be ordered by Western physicians, traditional Chinese physicians and dentists. It is essential to disclose the trends in coprescription to prevent possible polypharmacy among children. Patients and Methods: We used the Longitudinal Health Insurance Database 2000 in Taiwan. Children <18 years old who had coprescription from 2002 to 2012 are included. The odds ratio and 95% confidence interval are estimated by a logistic regression model to evaluate the correlation between basic characteristics and coprescription. Results: A total of 44,801 children are included in the analysis. The numbers of children with coprescription and the numbers of coprescriptions ordered for children increased with calendar years. Children aged 3-5 year and 6-8 years constituted the majority of coprescriptions, while those aged <3 years constituted the minority of coprescriptions. Compared to those in the Western medication-alone group, aged 3-5 years and children who lived in central and southern Taiwan are more likely to have coprescription. Conclusion: Coprescription among Taiwanese children is not uncommon. Healthcare providers, policymakers and parents should be aware of the real coprescription situation among the children.

The association between acupuncture therapy and the risk of reduced pressure ulcers in dementia patients: A retrospective matched cohort study.

Background: The pressure ulcer is a complication developed from dementia. The aim of this study is to study the association between the development of pressure ulcers and the use of acupuncture therapy in patients with dementia. Methods: We performed a retrospective 1:1 propensity score-matched cohort study to investigate the association between acupuncture therapy and the risk of pressure ulcers in patients with dementia. Results: A total of 8,994 patients were identified, 237 patients in the acupuncture cohort and 362 patients in the no-acupuncture cohort developed pressure ulcers. A reduced cumulative incidence of pressure ulcers was observed in the acupuncture cohort (P<0.001). The association between acupuncture and reducing the incidence of pressure ulcers was not affected by sex, age, residence, income, or comorbidities. The variables of etiologies to cause dementia did not change the final result. In the subgroups analyses, the patients without medication for dementia control had a significantly lower rate of pressure ulcers development when they had accepted acupuncture therapy (log-rank test, P<0.001). Conclusion: Our results revealed the association between acupuncture therapy and a reduced incidence of pressure ulcer development in patients with dementia. This finding offers important ideas for further research.

Acceptorless cross-dehydrogenative coupling for C(sp3)-H heteroarylation mediated by a heterogeneous GaN/ketone photocatalyst/photosensitizer system.

Alkanes are naturally abundant chemical building blocks that contain plentiful C(sp3)-H bonds. While inert, the activation of C(sp3)-H via hydrogen atom abstraction (HAT) stages an appealing approach to generate alkyl radicals. However, prevailing shortcomings include the excessive use of oxidants and alkanes that impede scope. We herein show the use of gallium nitride (GaN) as a non-toxic, recyclable, heterogeneous photocatalyst to enable alkyl C(sp3)-H in conjunction with the catalytic use of simple photosensitizer, benzophenone, to promote the desired alkyl radical generation. The dual photocatalytic cycle enables cross-dehydrogenative Minisci alkylation under mild and chemical oxidant-free conditions.

Dextromethorphan reduces prenatal lipopolysaccharide exposure-induced dopaminergic neuronal loss and cytokine changes in offspring.

Maternal infection during pregnancy may affect fetal brain development and increase the risk of developing neurological and mental disorders later in life in offspring. In this study, we used low-dose lipopolysaccharide (LPS) injection to mimic mild maternal infection at a critical time window for fetal dopamine (DA) and serotonin (5-HT) neuron development. The affected offspring exhibited reduction of dopaminergic and serotonergic neurons and anxiety- and depression-related behaviors in adulthood. In the current study, we evaluated whether dextromethorphan (DM, 30 mg/kg), an over-the-counter antitussive drug with anti-inflammatory and neuroprotective properties, could reduce the adverse effects of maternal infection mimicked by LPS exposure. We discovered that DM application did not change the baseline serum interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) levels in the LPS-exposed offspring. However, DM treatment could reduce the heightened immune responses induced by a postnatal LPS challenge test in prenatal LPS-exposed offspring. The neuroprotective effect of DM was only seen in DA neurons but not in 5-HT neurons. We concluded that DM treatment can partially protect the offspring against the adverse effects of LPS-induced maternal immune activation. The reduction in heightened immune responses and dopaminergic neuronal loss in LPS-exposed offspring could potentially reduce the risk of DA-related neurological and psychiatric disorders later in life.

A ligand-enabled metallaphotoredox protocol for Suzuki-Miyaura cross-couplings for the synthesis of diarylmethanes.

Here, we present a ligand-enabled metallaphotoredox Suzuki-Miyaura cross-coupling protocol for the facile synthesis of diarylmethanes. Specifically, we describe the preparation of a unique class of ligands, 2,4-diarylquinolines, and demonstrate their application in nickel-catalyzed fragment couplings between alkyltrifluoroborates and haloarenes. We detail the synthesis of the most enabling ligand, PPQN2,4-di-OMe, on a gram scale via sequential Grignard reaction and Friedländer condensation. We also outline how coupling reactions are performed without external photocatalysts under violet light irradiation. For complete details on the use and execution of this protocol, please refer to Li et al. (2022b).