Carbonylation Reactions at Carbon-Centered Radicals with an Adjacent Heteroatom.

Heteroatoms are essential to living organisms and present in almost all molecules with medicinal usage. The catalytic functionalization at the carbon-centered radical with an adjacent heteroatom provides an effective way to value added moiety while retaining the unique physicochemical and pharmacological properties of heteroatoms, which can promote the development of pharmaceutical and fine chemical production. Carbonylative transformation was discovered nearly a century ago which is an efficient method for the synthesis of carbonyl-containing molecules with potent applications in both industry and academia. Despite numerous advances in new reaction development, carbonylative transformation involving adjacent heteroatom carbon radical remain a subject that deserves to be discussed. In this minireview, we systematically summarized and discussed the recent advances in carbonylative transformations involving carbon-centered radicals with an adjacent heteroatom, including oxygen (O), nitrogen (N), phosphorus (P), silicon (Si), sulfur (S), boron (B), fluorine (F), and chlorine (Cl). The related reaction mechanism was also discussed.

Visible light induced cooperative carbonylation and (hetero)aryl migration: synthesis of multi-carbonyl compounds.

Carbonylative transformation represents one of the most straightforward procedures for the synthesis of carbonyl-containing compounds. However, the carbonylative procedure toward 1,4-diketones is still limited which are key moieties with potent applications in various areas. Herein, we report a new strategy for the synthesis of multi-carbonyl compounds containing a 1,4-diketone skeleton through remote heteroaryl migration of traditionally restricted 1,3-migratory substrates utilizing carbon monoxide (CO) as the C1 synthon and diazonium compounds as the starting material.

Photoredox-catalyzed carbonylative acylation of styrenes with Hantzsch esters.

Ketones exist widely in naturally occurring products and are indispensable building blocks in organic synthesis. Carbonylation represents one of the most straightforward methods for ketone preparation and has become an attractive field in modern organic chemistry as well. Among the strategies, photocatalytic carbonylation is also worthy of further exploration. Herein, we developed a three-component carbonylation that provides a new method for the synthesis of ketones from Hantzsch esters, CO and styrenes. The reaction was performed under a blue light environment and yields a series of ketones with moderate to good yields.

Iron-Catalyzed Aminoalkylative Carbonylative Cyclization of Alkenes toward α-Tetralones.

Carbonylative multifunctionalization of alkenes is an efficient approach to introduce multiple functional groups into one molecule from easily available materials. Herein, we developed an iron-catalyzed radical relay carbonylative cyclization of alkenes with acetamides. Various α-tetralones can be constructed in moderate yields from readily available substrates with an earth-abundant iron salt as the catalyst.

The Association Between Short-Acting ß2-Agonist Over-Prescription, and Patient-Reported Acquisition and Use on Asthma Control and Exacerbations: Data from Australia.

INTRODUCTION: In Australia, short-acting ß2-agonists (SABA) are available both over the counter (OTC) and on prescription. This ease of access may impact SABA use in the Australian population. Our aim was to assess patterns and outcome associations of prescribed, acquired OTC and reported use of SABA by Australians with asthma. METHODS: This was a cross-sectional study, using data derived from primary care electronic medical records (EMRs) and patient completed questionnaires within Optimum Patient Care Research Database Australia (OPCRDA). A total of 720 individuals aged ≥ 12 years with an asthma diagnosis in their EMRs and receiving asthma therapy were included. The annual number of SABA inhalers authorised on prescription, acquired OTC and reported, and the association with self-reported exacerbations and asthma control were investigated. RESULTS: 92.9% (n = 380/409) of individuals issued with SABA prescription were authorised ≥ 3 inhalers annually, although this differed from self-reported usage. Of individuals reporting SABA use (n = 546) in the last 12 months, 37.0% reported using ≥ 3 inhalers. These patients who reported SABA overuse experienced 2.52 (95% confidence interval [CI] 1.73-3.70) times more severe exacerbations and were 4.51 times (95% CI 3.13-6.55) more likely to have poor asthma control than those who reported using 1-2 SABA inhalers. Patients who did not receive SABA on prescription (43.2%; n = 311/720) also experienced 2.71 (95% CI 1.07-7.26) times more severe exacerbations than those prescribed 1-2 inhalers. Of these patients, 38.9% reported using OTC SABA and other prescription medications, 26.4% reported using SABA OTC as their only asthma medication, 13.2% were prescribed other therapies but not SABA OTC and 14.5% were not using any medication. CONCLUSION: Both self-reported SABA overuse and zero SABA prescriptions were associated with poor asthma outcomes. The disconnect between prescribing authorisation, OTC availability and actual use, make it difficult for clinicians to quantify SABA use.

Effects of selenium-cadmium co-enriched Cardamine hupingshanensis on bone damage in mice.

Selenium (Se) and cadmium (Cd) usually co-existed in soils, especially in areas with Se-rich soils in China. The potential health consequences for the local populations consuming foods rich in Se and Cd are unknown. Cardamine hupingshanensis (HUP) is Se and Cd hyperaccumulator plant that could be an ideal natural product to assess the protective effects of endogenous Se against endogenous Cd-caused bone damage. Male C57BL/6 mice were fed 5.22 mg/kg cadmium chloride (CdCl2) (Cd 3.2 mg/kg body weight (BW)), or HUP solutions containing Cd 3.2 mg/kg BW and Se 0.15, 0.29 or 0.50 mg/kg BW (corresponding to the HUP0, HUP1 and HUP2 groups) interventions. Se-enriched HUP1 and HUP2 significantly decreased Cd-induced femur microstructure damage and regulated serum bone osteoclastic marker levels and osteogenesis-related genes. In addition, endogenous Se significantly decreased kidney fibroblast growth factor 23 (FGF23) protein expression and serum parathyroid hormone (PTH) levels, and raised serum calcitriol (1,25(OH)2D3). Furthermore, Se also regulated gut microbiota involved in skeletal metabolism disorder. In conclusion, endogenous Se, especially with higher doses (the HUP2 group), positively affects bone formation and resorption by mitigating the damaging effects of endogenous Cd via the modulation of renal FGF23 expression, circulating 1,25(OH)2D3 and PTH and gut microbiota composition.

Analysis of Individualized Silicone Rubber Bolus Using Fan Beam Computed Tomography in Postmastectomy Radiotherapy: A Dosimetric Evaluation and Skin Acute Radiation Dermatitis Survey.

Objective: To investigate the dosimetric effects of using individualized silicone rubber (SR) bolus on the target area and organs at risk (OARs) during postmastectomy radiotherapy (PMRT), as well as evaluate skin acute radiation dermatitis (ARD). Methods: A retrospective study was performed on 30 patients with breast cancer. Each patient was prepared with an individualized SR bolus of 3 mm thickness. Fan-beam computed tomography (FBCT) was performed at the first and second fractions, and then once a week for a total of 5 times. Dosimetric metrics such as homogeneity index (HI), conformity index (CI), skin dose (SD), and OARs including the heart, lungs, and spinal cord were compared between the original plan and the FBCTs. The acute side effects were recorded. Results: In targets' dosimetric metrics, there were no significant differences in Dmean and V105% between planning computed tomography (CT) and actual treatments (P > .05), while the differences in D95%, V95%, HI, and CI were statistically significant (P < .05). In OARs, there were no significant differences between the Dmean, V5, and V20 of the affected lung, V5 of the heart and Dmax of the spinal cord (P > .05) except the V30 of affected lung, which was slightly lower than the planning CT (P < .05). In SD, both Dmax and Dmean in actual treatments were increased than plan A, and the difference was statistically significant (P < .05), while the skin-V20 and skin-V30 has no difference. Among the 30 patients, only one patient had no skin ARD, and 5 patients developed ARD of grade 2, while the remaining 24 patients were grade 1. Conclusion: The OR bolus showed good anastomoses and high interfraction reproducibility with the chest wall, and did not cause deformation during irradiation. It ensured accurate dose delivery of the target and OARs during the treatment, which may increase SD by over 101%. In this study, no cases of grade 3 skin ARD were observed. However, the potential of using OR bolus to reduce grade 1 and 2 skin ARD warrants further investigation with a larger sample size.

Cobalt-catalyzed aminoalkylative carbonylation of alkenes toward direct synthesis of γ-amino acid derivatives and peptides.

γ-Amino acids and peptides analogues are common constituents of building blocks for numerous biologically active molecules, pharmaceuticals, and natural products. In particular, γ-amino acids are providing with better metabolic stability than α-amino acids. Herein we report a multicomponent carbonylation technology that combines readily available amides, alkenes, and the feedstock gas carbon monoxide to build architecturally complex and functionally diverse γ-amino acid derivatives in a single step by the implementation of radical relay catalysis. This transformation can also be used as a late-stage functionalization strategy to deliver complex, advanced γ-amino acid products for pharmaceutical and other areas.

Cobalt-Catalyzed Carbonylative Synthesis of 4-Oxobutanoates from Formamide and Ethylene.

The direct concurrent installation of amide and ester groups across olefin motifs represents a powerful and promising functionalization tool in organic chemistry. Herein, a ligand-free cobalt-catalyzed four-component radical relay carbonylative difunctionalization of ethylene for the synthesis of 4-oxobutanoates has been developed. Valuable C4 building blocks were produced in a highly atom-economical fashion.

Site-selective carbonylation of arenes via C(sp2)-H thianthrenation: direct access to 1,2-diarylethanones.

Herein, a new reaction for the site-selective carbonylation of arenes via C(sp2)-H thianthrenation under mild conditions has been developed. With low loadings of palladium catalysts, various desired 1,2-diarylethanones are produced in good yields. This strategy also enables the late-stage modification of complex molecules, which was previously challenging with similar carbonylative Negishi-type reactions.

Copper-Catalyzed Direct Carbonylation of Carbenes toward the Synthesis of Propanedioic Acid Derivatives.

Carbenes are highly active reaction intermediates, which can be used as reaction precursors to modify organisms, drugs, and material molecules. In this work, we realized a new cheap metal-catalyzed carbonylation of carbene to give propanedioic acid derivatives. With copper salt as the catalyst, synthetically important malonates and related compounds were produced in good yields under mild reaction conditions.

Green solvent processing: Effect of type of solvent on extraction and quality of protein from dairy and non-dairy expired milk products.

The present study was designed to study the effect of green solvent processing in two folds, (i) to extract valuable protein from dairy and non-dairy expired milk products and (ii) to compare extraction efficiency and quality of extracted protein using conventional (CS) and green solvents (GS). Ethyl acetate, ethanol, isopropanol, n-heptane and cyclopentyl methyl ether (CPME) were selected as the GS for the possible substitution of hexane and ethyl ether. For each respective solvent, protein recovery, structural and functional modifications were studied. Protein yield was extracted most effectively by GS n-heptane in dairy milk (5.33 ± 0.01%) with a protein purity of 39.73 ± 0.90%. Non-dairy milk and product had similar protein yield when treated with CS and GS. Total mean of extraction efficiency, structural and functional modifications across all samples showed GS solvents were statistically more effective than CS.

Impact of cavitation on the structure and functional quality of extracted protein from food sources - An overview.

Increasing protein demands directly require additional resources to those presently and recurrently available. Emerging green technologies have witnessed an escalating interest in "Cavitation Processing" (CP) to ensure a non-invasive, non-ionizing and non-polluting extraction. The main intent of this review is to present an integrated summary of cavitation extraction methods specifically applied to food protein sources. Along with a comparative assessment carried out for each type of cavitation model, protein extraction yield and implications on the extracted protein's structural and functional properties. The basic principle of cavitation is due to the pressure shift in the liquid flow within milliseconds. Hence, cavitation emerges similar to boiling; however, unlike boiling (temperature change), cavitation occurs due to pressure change. Characterization and classification of sample type is also a prime candidate when considering the applications of cavitation models in food processing. Generally, acoustic and hydrodynamic cavitation is applied in food applications including extraction, brewing, microbial cell disruption, dairy processing, emulsification, fermentation, waste processing, crystallisation, mass transfer and production of bioactive peptides. Micro structural studies indicate that shear stress causes disintegration of hydrogen bonds and Van der Waals interactions result in the unfolding of the protein's secondary and/or tertiary structures. A change in the structure is not targeted but rather holistic and affects the physicochemical, functional, and nutritional properties. Cavitation assisted extraction of protein is typically studied at a laboratory scale. This highlights limitations against the application at an industrial scale to obtain potential commercial gains.

Non-Noble Metal-Catalyzed Carbonylative Multi-Component Reactions.

Carbonylative multi-component reactions (CMCR), having four or more kinds of starting materials, provide an efficient strategy for the preparation of polyfunctional carbonylated compounds. Diverse CMCR utilizing non-noble transition-metal catalysts have been developed. This review summarized and discussed the recent advances in non-noble metal-catalyzed carbonylative multi-component reactions.

Clinical evaluation of deep learning-based clinical target volume three-channel auto-segmentation algorithm for adaptive radiotherapy in cervical cancer.

OBJECTIVES: Accurate contouring of the clinical target volume (CTV) is a key element of radiotherapy in cervical cancer. We validated a novel deep learning (DL)-based auto-segmentation algorithm for CTVs in cervical cancer called the three-channel adaptive auto-segmentation network (TCAS). METHODS: A total of 107 cases were collected and contoured by senior radiation oncologists (ROs). Each case consisted of the following: (1) contrast-enhanced CT scan for positioning, (2) the related CTV, (3) multiple plain CT scans during treatment and (4) the related CTV. After registration between (1) and (3) for the same patient, the aligned image and CTV were generated. Method 1 is rigid registration, method 2 is deformable registration, and the aligned CTV is seen as the result. Method 3 is rigid registration and TCAS, method 4 is deformable registration and TCAS, and the result is generated by a DL-based method. RESULTS: From the 107 cases, 15 pairs were selected as the test set. The dice similarity coefficient (DSC) of method 1 was 0.8155 ± 0.0368; the DSC of method 2 was 0.8277 ± 0.0315; the DSCs of method 3 and 4 were 0.8914 ± 0.0294 and 0.8921 ± 0.0231, respectively. The mean surface distance and Hausdorff distance of methods 3 and 4 were markedly better than those of method 1 and 2. CONCLUSIONS: The TCAS achieved comparable accuracy to the manual delineation performed by senior ROs and was significantly better than direct registration.

Efficacy and Safety of Apatinib plus Neoadjuvant Chemotherapy for Locally Advanced Esophageal Squamous Cancer: A Phase II Trial.

Evidence for neoadjuvant chemotherapy combined with targeted therapy for locally advanced esophageal squamous cancer (ESCC) is inadequate. We conducted a single-arm phase II trial to evaluate the efficacy and safety of apatinib combined with taxol and cisplatin (ATP) for locally advanced ESCC. All patients were cT3-4aN0-3 M0 (IIIb-IVa) stage, which were confirmed by histopathology. Apatinib was taken orally (425 mg/d) for two cycles, followed by one cycle of rest. Taxol was administered at 135 mg/m2 intravenously on day 1, and cisplatin was administered at 20 mg/m2 intravenously on day 1 to day 3. Radical ESCC resection was performed 4 weeks after ATP. The primary endpoint was pathological response rate (pCR). Secondary endpoints were pathologic response rate (MPR), disease-free survival (DFS), overall survival (OS), R0 resection rate, and safety profile. This trial was registered. We evaluated 41 patients for screening from Oct 2018 to July 2020, of whom 39 were enrolled in the study, with a median age of 65 years (range 49-75 years), and 29 (74.4%) were male. Among the 39 patients, 1 was considered unresectable by the multidisciplinary team due to tumor progression, and 38 patients underwent surgery eventually. The median follow-up was 22 months (range 5-29 months), and the follow-up rate was 100%. The 1-year and 2-year OS was 95% and 95%, and the 1-year and 2-year DFS was 85% and 82%, respectively. Thirty-eight (97.3%) successfully underwent R0 resection. Of the 38 evaluable patients, 9 (23.6%) were pCR, and 15 (39.5%) were MPR. The most common ATP-related AEs were nausea (76.9%), leucopenia (53.8%), neutropenia (51.2%) and vomit (51.2%), anemia (41.0%), and hypertension (25.6%). The most frequent grade 3-4 events included leucopenia (15.3%), neutropenia (15.3%), nausea (12.8%), vomit (12.8%), and hypertension (10.2%). No treatment-related death occurred. Neoadjuvant apatinib combined with taxol and cisplatin for locally advanced ESCC showed favorable activity and manageable safety.

Nickel-Catalyzed Four-Component Carbonylation of Ethers and Olefins: Direct Access to γ-Oxy Esters and Amides.

Multi-component carbonylation of olefins, a reaction that installs both a carbon-carbon(heteroatom) bond and a carbonyl group across the double bond, is an attractive strategy for alkene functionalization. Herein, we developed a novel nickel-catalyzed four-component carbonylation of olefins with ethers under low CO gas pressure. Using alcohols and amines as the reaction partner, diverse γ-oxy-substituted esters and amides were produced in good yields with excellent functional group tolerance. Notably, Naftidrofuryl, a medicine for the treatment of cerebrovascular disease (CVD), can be synthesized by this process straightforwardly.

Palladium-Catalyzed Desulfonative Carbonylation of Thiosulfonates: Elimination of SO2 and Insertion of CO.

A palladium-catalyzed desulfonative carbonylation of thiosulfonates has been explored. Without any additive, a series of S-aryl/alkyl benzenesulfonothioates were successfully transformed to thioesters in moderate to excellent yields by SO2 extrusion and CO insertion under the pressure of 1 bar of CO. The solvent dimethylacetamide (DMAc) facilitated this desulfonative carbonylation due to its high absorbing ability of SO2.

Controllable access to trifluoromethyl-containing indoles and indolines: palladium-catalyzed regioselective functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides.

The synthesis of diverse products from the same starting materials is always attractive in organic chemistry. Here, a palladium-catalyzed substrate-controlled regioselective functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides has been developed, which provides a direct but controllable access to a variety of structurally diverse trifluoromethyl-containing indoles and indolines. In more detail, with respect to γ,δ-alkenes, 1,1-geminal difunctionalization of unactivated alkenes with trifluoroacetimidoyl chloride enables the [4 + 1] annulation to produce indoles; as for ß,γ-alkenes, a [3 + 2] heteroannulation with the hydrolysis product of trifluoroacetimidoyl chloride through 1,2-vicinal difunctionalization of alkenes occurs to deliver indoline products. The structure of alkene substrates differentiates the regioselectivity of the reaction.

Cobalt-Catalyzed Direct Aminocarbonylation of Ethers: Efficient Access to α-Amide Substituted Ether Derivatives.

Ethers are of central importance in the fields of biomass, energy, and organic chemistry. Herein, a novel cobalt-catalyzed carbonylative coupling of ethers with amines to construct α-carbonylated ethers has been achieved. Remarkably, Alfuzosin, a medicine for treatment of benign prostatic hyperplasia (BPH), can be synthesized by this process straightforwardly. Notably, this protocol presents the first example on the direct carbonylative reaction of ethers.