Visible-Light-Triggered Difluoroacetylation/Cyclization of Chromone-Tethered Alkenes Enabling Synthesis of Tetrahydroxanthones.

Hydroxanthones have attracted considerable attention due to their significance in organic and biological chemistry, yet their synthesis remains a great challenge. In this study, a series of chromone-tethered alkenes are designed, and a radical cyclization reaction of these chromone derivatives has been achieved under photoredox conditions. The reaction uses bromodifluoroacetamides or bromodifluoroacetates as coupling partners, affording a broad range of functionalized tetrahydroxanthone products with up to 85% yields. The reaction is triggered via the generation of difluoroacetate radicals or alkene radical cations with fac-Ir(ppy)3 or 2,3,5,6-tetrakis(carbazol-9-yl)-1,4-dicyanobenzene as a photocatalyst. This approach offers access to various tetrahydroxanthone derivatives from readily available starting materials and enriches the research content of heteroarene-tethered alkenes.

The Duration of Hardware Retention After Radiologic Union of Surgically Treated Femoral Neck Fractures in Children May Predict the Aggravation or Occurrence of Avascular Necrosis of the Femoral Head or Neck After Hardware Removal.

BACKGROUND: The incidence of aggravation or occurrence of avascular necrosis (AVN) following hardware removal in surgically treated pediatric femoral neck fractures who achieved radiologic consolidation is unknown. This study aimed to investigate the risk factors for this complication. METHODS: Seventy-one pediatric (mean age: 9.8±3.9 y) were retrospectively analyzed. Risk factors (age, sex, laterality, severity of initial displacement, type of fracture, time from trauma to reduction, reduction and fixation method, quality of reduction, time required to achieve radiologic union, duration of hardware retention, presence of AVN before hardware removal and follow-up time) were recorded. The severity of AVN was assessed based on radiographs with Ratliff's classification. RESULTS: Following hardware removal, the aggravation/occurrence of AVN was detected in 11 hips (15.5%). Among the 5 hips (7%) with aggravation of AVN, 1 (1.4%) with type II AVN and 3 (4.2%) with type III AVN exhibited aggravation of type I AVN, while the remaining hip (1.4%; type I) showed enlargement of the involved AVN area. Six hips (8.5%) developed AVN following hardware removal: 2 (2.8%) were classified as type I and 4 (5.6%) as type III. Receiver operating characteristic curve analysis indicated that hardware retention >7 months after union is associated with a decreased rate of aggravation or occurrence of AVN of the femoral neck or head following hardware removal. CONCLUSIONS: The incidence of aggravation or occurrence of AVN following hardware removal in surgically treated pediatric femoral neck fractures is 15.5%; hardware retention >7 months after radiologic union may reduce the risk of aggravation or occurrence of AVN of the femoral neck or head postimplant removal. LEVEL OF EVIDENCE: Level III.

Step-cut osteotomy for cubitus varus deformity with application of patient-specific instrument in children: a preliminary report.

PURPOSE: The step-cut osteotomy has been recognized as a valuable approach for addressing cubitus varus deformity, albeit one that necessitates technical proficiency. This study aims to evaluate the efficacy of the modified step-cut osteotomy technique in conjunction with patient-specific instruments by clinical and radiological assessment. METHODS: We conducted a retrospective review of patients who underwent modified step-cut osteotomy with the use of patient-specific instruments in conjunction with Kirschner wires fixation for the correction of cubitus varus deformity between April 2016 and April 2022. Follow-up was performed for a minimum of two years, during which pre-operative and post-operative clinical and radiological parameters were compared. RESULTS: Fifteen patients were enrolled in this study. The mean pre-operative humeral-elbow-wrist (HEW) of the affected side was -21.7° (ranging from -14° to -34°), while the normal side was 9.4° (ranging from 5° to 15°). The post-operation HEW of affected side was 9° (ranging from 4° to 16°). There was no significant difference between the normal side and affected side after operation (p = 0.74). Pre-operative range of motion in the affected side was 130°, while the post-operative range of motion was 132°. Fourteen patients (93.3%) were pleased with the overall appearance of their elbow. None lazy-S deformity was observed in these cases. There were no major complications. CONCLUSION: The modified step-cut osteotomy technique, utilizing patient-specific instrument in conjunction with Kirschner wires fixation was found to be a safe, reliable, and technically easy procedure for correcting cubitus varus deformity.

Copper-catalyzed multicomponent reaction of ß-trifluoromethyl ß-diazo esters enabling the synthesis of ß-trifluoromethyl N,N-diacyl-ß-amino esters.

An efficient multicomponent reaction of newly designed ß-trifluoromethyl ß-diazo esters, acetonitrile, and carboxylic acids via an interrupted esterification process under copper-catalyzed conditions has been developed, which affords various unsymmetrical ß-trifluoromethyl N,N-diacyl-ß-amino esters in good to excellent yields. The reaction features mild conditions, a wide scope of ß-amino esters and carboxylic acids, and also applicability to large-scale synthesis, thus providing an efficient way for the synthesis of ß-trifluoromethyl ß-diacylamino esters. Furthermore, this reaction represents the first example of a Mumm rearrangement of ß-trifluoromethyl ß-diazo esters.

Cascade Detrifluoroacetylation, C-S Bond Cleavage, and SN2' Reaction of α,α-Difluorinated Gem-Diols with MBH Esters.

A new SN2' reaction type of Morita-Baylis-Hillman (MBH) ester with sulfonyl anion, generated in situ via detrifluoroacetylation as a nucleophile is developed. Experimental results and DFT calculations disclose that the reaction proceeds via C-C bond cleavage to generate a PhSO2CF2 anion, C-S bond cleavage to generate a sulfonyl anion with the release of CF2 carbene, and an SN2' reaction with the MBH ester. The reaction features operational simplicity, wide substrate scope, high yields, and excellent stereoselectivity, which represents a new reaction mode of fluorinated gem-diols and also provides an efficient way to obtain ß,γ-unsaturated sulfones.

Electrochemical Annulation of Indole-Tethered Alkynes Enabling Synthesis of Exocyclic Alkenyl Tetrahydrocarbazoles.

An electrochemical sulfonylation-triggered cyclization reaction of indole-tethered terminal alkynes with sulfinates as sulfonyl sources has been developed, which affords exocyclic alkenyl tetrahydrocarbazoles in good chemical yields. This reaction features convenient operation and tolerates a wide scope of substrates with a variety of electronically and sterically diverse substituents. Furthermore, high E-stereoselectivity is observed for this reaction, which provides an efficient method for the preparation of functionalized tetrahydrocarbazole derivatives.

A Cu-promoted reaction of ß-keto trifluoromethyl amines enabling stereoselective synthesis of trifluoromethylated aziridines.

An efficient Cu(I) complex-promoted intramolecular cyclization reaction of ß-keto trifluoromethyl amines has been developed, providing access to a series of unprotected trifluoromethylated aziridines with good chemical yields and excellent stereoselectivity (trans : cis > 99 : 1). The reaction can be carried out under mild conditions and tolerates a wide range of substrates with diverse functional groups, representing a straightforward method for the preparation of trifluoromethylated aziridines from readily available starting materials.

Chemical Aspects of Human and Environmental Overload with Fluorine.

Over the last 100-120 years, due to the ever-increasing importance of fluorine-containing compounds in modern technology and daily life, the explosive development of the fluorochemical industry led to an enormous increase of emission of fluoride ions into the biosphere. This made it more and more important to understand the biological activities, metabolism, degradation, and possible environmental hazards of such substances. This comprehensive and critical review focuses on the effects of fluoride ions and organofluorine compounds (mainly pharmaceuticals and agrochemicals) on human health and the environment. To give a better overview, various connected topics are also discussed: reasons and trends of the advance of fluorine-containing pharmaceuticals and agrochemicals, metabolism of fluorinated drugs, withdrawn fluorinated drugs, natural sources of organic and inorganic fluorine compounds in the environment (including the biosphere), sources of fluoride intake, and finally biomarkers of fluoride exposure.

Research on anterior minimally invasive approach in the treatment of children with developmental dysplasia of the hip.

OBJECTIVES: To investigate the clinical efficacy and safety of open reduction through anterior minimally invasive approach in the treatment of children with developmental dysplasia of the hip. METHOD: A total of 23 patients (25 hips) less than 2 years with developmental dysplasia of the hip treated by open reduction through anterior minimally invasive approach were treated in our hospital from August 2016 to March 2019. Through the anterior minimally invasive approach, we enter from the gap between sartorius muscle and tensor fasciae lata without cutting off rectus femoris muscle, which can effectively expose the joint capsule and reduce the damage to medial blood vessels and nerves. The operation time, incision length, intraoperative bleeding, hospital stay and surgical complications were observed. The progression of developmental dysplasia of the hip and avascular necrosis of the femoral head were evaluated by imaging examination. RESULT: All patients were performed with follow-up visit for an average of 22 months. The average incision length was 2.5 cm, the average operation time was 26 min, the average intraoperative bleeding was 12ml, and the average hospital stay was 4.9 days. All patients received concentric reduction immediately after operation, and no re-dislocation occurred. At the last follow-up visit, the acetabular index was (25.8 ± 6.4°). During the follow-up visit, X-ray showed avascular necrosis of the femoral head in 4 hips (16%). CONCLUSION: open reduction through anterior minimally invasive approach can achieve good clinical effect in the treatment of infantile developmental dysplasia of the hip.

The effectiveness of physeal bar resection with or without Hemi-Epiphysiodesis to treat partial growth arrest.

PURPOSE: To evaluate the outcomes of distal femoral, proximal tibial, and distal tibial physeal bar resection combined with or without the Hemi-Epiphysiodesis procedure and provide a better understanding of the application of physeal bar resection combined with Hemi-Epiphysiodesis procedure in the treatment of physeal bar growth arrest. METHODS: We retrospectively reviewed the patients who suffered physeal bar and underwent physeal bar resection with or without the Hemi-Epiphysiodesis technique during 2010-2020. All were followed up for at least 2 years or to maturity. A modified mapping method was used to determine the area of a physeal bar by CT data. The aLDFA, aMPTA, aLDTA, MAD, and LLD were measured to assess the deformity of the lower limb. RESULTS: In total, 19 patients were included in this study. The average age was 8.9 years (range 4.4 to 13.3 years old). During the follow-up, 4 (21.1%) patients had an angular change < 5°; 12 (63.2%) patients had angular deformity improvement > 5° averaging 10.0° (range 5.3° to 23.2°), and 3 (15.8%) patients had improvement of the angular deformity averaging 16.8° (range 7.4° to 27.1°). Eleven patients (57.9%) had significant MAD improvement. After surgery, we found that 7 (36.8%) patients had an LLD change of < 5 mm and were considered unchanged. Only 2 (15%) patients had an LLD improvement > 5 mm averaging 1.0 cm (range 0.7 to 1.3 cm), and 7 (36.8%) patients had increasing of LLD > 5 mm averaging 1.3 cm (range 0.5 to 2.5 cm). There were no postoperative fractures, infections, or intraoperative complications such as neurovascular injury. CONCLUSION: Physeal bar resection combined with Hemi-epiphysiodesis is helpful for partial epiphysis growth arrest. Without statistically verifying, we still believe that patients with limited growth ability could benefit more from physeal bar resection combined with Hemi-epiphysiodesis.

Is there an alternative to the Delbet-Colonna classification? Introduction and reliability assessment of a new classification system for paediatric femoral neck fractures: preliminary results.

PURPOSE: The purpose of this study was to introduce a new classification system for paediatric femoral neck fractures (PFNFs) and to evaluate its reliability. METHODS: Two hundred and eight unilateral PFNFs (mean patient age: 9.0 ± 4.8 years) were included. Based on preoperative radiographs, the new classification system distinguished PFNFs without anterior or posterior translation (Type I), PFNFs with anterior (Type II) or posterior (Type III) translation, PFNFs with a comminuted medial or posterior column (Type IV), and subtrochanteric femoral fractures (SFFs; Type V). Radiographs were evaluated twice with an interval of two weeks by 19 raters with different specialties, experiences and geographical origins. The results were compared with a selection of 50 patient age-matched unilateral PFNFs and SFFs (mean patient age: 9.1 ± 4.9 years). These were graded twice by the same graders according to the Delbet-Colonna (D-C) classification. RESULTS: Four radiologists and 15 paediatric orthopaedic surgeons from Europe and Asia graded the radiographs. Fair agreement was found between radiologists (κ = 0.296 ± 0.01) and surgeons (κ = 0.3 ± 0.005) (P = 0.17), although more experienced surgeons performed better than less experienced ones; a similar fair assessment was found for raters from Europe (κ = 0.309 ± 0.021) and Asia (κ = 0.3 ± 0.006) and for type II, III and IV fractures; the κ value in the first evaluation (0.309) was similar to that in the second evaluation (0.298). The overall κ value of the D-C classification subtypes was significantly higher (0.599 ± 0.217) than that of the new classification, 0.326 ± 0.162 (t = 3.190 P = 0.005). CONCLUSIONS: The new classification system showed fair reliability relative to the D-C classification. The reliability of the new classification system was not affected by the specialty or geographic origin of the rater or the evaluation round, only by rater experience level. The concordance was worse for PFNFs with anterior or posterior translation or with a comminuted medial or posterior columns.

New Approved Drugs Appearing in the Pharmaceutical Market in 2022 Featuring Fragments of Tailor-Made Amino Acids and Fluorine.

The strategic fluorination of oxidatively vulnerable sites in bioactive compounds is a relatively recent, widely used approach allowing us to modulate the stability, bio-absorption, and overall efficiency of pharmaceutical drugs. On the other hand, natural and tailor-made amino acids are traditionally used as basic scaffolds for the development of bioactive molecules. The main goal of this review article is to emphasize these general trends featured in recently approved pharmaceutical drugs.

Synthesis of Aminoalkyl Sclareolide Derivatives and Antifungal Activity Studies.

Sclareolide was developed as an efficient C-nucleophilic reagent for an asymmetric Mannich addition reaction with a series of N-tert-butylsulfinyl aldimines. The Mannich reaction was carried out under mild conditions, affording the corresponding aminoalkyl sclareolide derivatives with up to 98% yield and 98:2:0:0 diastereoselectivity. Furthermore, the reaction could be performed on a gram scale without any reduction in yield and diastereoselectivity. Additionally, deprotection of the obtained Mannich addition products to give the target sclareolide derivatives bearing a free N-H group was demonstrated. In addition, target compounds 4-6 were subjected to an antifungal assay in vitro, which showed considerable antifungal activity against forest pathogenic fungi.

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups.

A synthetic route to the bench-stable fluorinated masked carbene reagent diethyl 2-diazo-1,1,3,3,3-pentafluoropropylphosphonate, bearing a trifluoromethyl and a difluoromethyl group is reported for the first time. Its application in CuI-catalyzed cyclopropanation reactions with aromatic and aliphatic terminal alkenes under mild reaction conditions is demonstrated. In total, sixteen new cyclopropanes were synthesized in good to very good yields.

Case series of congenital pseudarthrosis of the tibia unfulfilling neurofibromatosis type 1 diagnosis: 21% with somatic NF1 haploinsufficiency in the periosteum.

Up to 84% of patients with congenital pseudarthrosis of the tibia (CPT) present with neurofibromatosis type 1 (NF1) (NF1-CPT). However, the etiology of CPT not fulfilling the NIH diagnostic criteria for NF1 (non-NF1-CPT) is not well understood. Here, we collected the periosteum tissue from the pseudarthrosis (PA) site of 43 non-NF1-CPT patients and six patients with NF1-CPT, together with the blood or oral specimen of trios (probands and unaffected parents). Whole-exome plus copy number variation sequencing, multiplex ligation-dependent probe amplification (MLPA), ultra-high amplicon sequencing, and Sanger sequencing were employed to identify pathogenic variants. The result showed that nine tissues of 43 non-NF1-CPT patients (21%) had somatic mono-allelic NF1 inactivation, and five of six NF1-CPT patients (83.3%) had bi-allelic NF1 inactivation in tissues. However, previous literature involving genetic testing did not reveal somatic mosaicism in non-NF1-CPT patients so far. In NF1-CPT patients, when the results from earlier reports and the present study were combined, 66.7% of them showed somatic NF1 inactivation in PA tissues other than germline inactivation. Furthermore, no diagnostic variants from other known genes (GNAS, AKT1, PDGFRB, and NOTCH3) related to skeletal dysplasia were identified in the nine NF1 positive non-NF1-CPT patients and six NF1-CPT patients. In conclusion, we detected evident somatic mono-allelic NF1 inactivation in the non-NF1-CPT. Thus, for pediatric patients without NF1 diagnosis, somatic mutations in NF1 are important.

MECOM-related disorder: Radioulnar synostosis without hematological aberration due to unique variants.

PURPOSE: The etiology for a considerable proportion of patients with congenital radioulnar synostosis (RUS) remains unclear. This study aimed to investigate the genetic cause of RUS without a known cause. METHODS: Patients with RUS were investigated. Exome sequencing and/or Sanger sequencing was performed. Bioinformatics analysis was also performed. Pathogenicity was evaluated for variants of interest. RESULTS: We identified unique missense variants in MECOM (encodes EVI1) associated with RUS in 8 families. Of them, 6 families had variants in residue R781, including 3 families with R781C (c.2341C>T), 2 families with R781H (c.2342G>A), and 1 family with R781L (c.2342G>T). Another 2 variants included I783T (c.2348T>C) in 1 family and Q777E (c.2329C>G) in 1 family. All these variants were clustered within the ninth zinc finger motif of EVI1. Phenotype evaluation identified that most of these patients with RUS harboring mutant MECOM had finger malformations, but none of them had identifiable hematological abnormalities. Functional experiments showed that MECOM R781C led to alterations in TGF-ß-mediated transcriptional responses. CONCLUSION: This study examined MECOM variants by focusing on RUS instead of hematological abnormalities. The R781 residue in EVI1 is a hotspot for human RUS variants. Mutant MECOM is the second most common cause for familial RUS.

Carboxylic Acid O-H Insertion Reaction of ß-Ester Diazos Enabling Synthesis of ß-Acyloxy Esters.

Generation of non-stabilized ß-ester diazos and their applications in carboxylic acid O-H insertion reactions have been reported, which afford ß-acyloxy esters in excellent yield. Varieties of aryl- and alkyl-substituted diazos are well tolerated in this insertion reaction under mild and convenient conditions. Moreover, structural modification of the natural product and molecular drug can also be achieved in this reaction. This protocol not only realizes the reaction involving unstable ß-ester diazos but also provides an efficient strategy for the synthesis of ß-acyloxy esters.

Arylsulfonylation-Triggered Cyclization of 3-Alkenyl Indoles Enabling Synthesis of Tetrahydro-γ-carboline.

A visible-light promoted cyclization reaction of 3-alkenyl indole derivatives with arylsulfonyl chlorides as coupling partners has been developed, which afforded functionalized tetrahydro-γ-carbolines in good chemical yields. The reaction used 3-alkenyl indoles as radical acceptors and proceeded via the sequence of sulfonylation and intramolecular cyclization. The reaction was carried out under mild conditions and tolerated a wide range of substrates, which provides an efficient strategy for the synthesis of tetrahydro-γ-carboline derivatives.

CircPVT1 promotes the tumorigenesis and metastasis of osteosarcoma via mediation of miR-26b-5p/CCNB1 axis.

INTRODUCTION: Osteosarcoma (OS) is the most aggressive malignancy among the bone tumors in the world. Circular RNAs (circRNAs) have been reported to be participated in multiple cancers, including OS. Meanwhile, circPVT1 has been proved to be upregulated in OS. However, the mechanism by which circPVT1 mediates the tumorigenesis of OS remains to be further explored. MATERIALS AND METHODS: Protein and gene expressions in OS cells were measured by western blot and RT-qPCR, respectively. Cell growth was assessed by flow cytometry and colony formation, respectively. In addition, cell migration was assessed by wound healing, and invasion was evaluated by Transwell assay. Meanwhile, the correlation among circPVT1, miR-26b-5p and CCNB1 was explored by RNA pull-down and dual luciferase assay. Finally, in vivo model was established to explore the role of circPVT1 in OS in vivo. RESULTS: CircPVT1 and CCNB1 were significantly upregulated in OS cells, while miR-26b-5p was downregulated. Knockdown of circPVT1 notably inhibited proliferation and induced apoptosis of OS cells. CircPVT1 shRNA significantly suppressed the OS cell invasion and migration. Meanwhile, circPVT1 sponged miR-26b-5p and CCNB1 was found to be the direct target of miR-26b-5p. Furthermore, silencing of circPVT1 inhibited the growth and metastasis of OS in vivo. CONCLUSION: Silencing of circPVT1 notably suppressed the tumorigenesis and metastasis of OS via miR-26b-5p/CCNB1 axis. Therefore, circPVT1 might be used as a target for OS treatment.

New insights into pathogenesis of congenital pseudarthrosis of tibia in children using periosteum proteomics analysis.

RATIONALE: The exact etiology and pathogenesis of congenital pseudarthrosis of tibia (CPT) are not clear. Quantitative proteomics analysis plays a vital role in disease pathology research. Tandem mass tag (TMT)-based proteomics techniques were employed to identify and analyze the differentially expressed proteins (DEP) in the tibia periosteum tissues of CPT patients. METHODS: The samples were divided into three groups: CPT with NF1 group, CPT without NF1 group (non-NF1-CPT), and control group (patients with open tibial fracture). A fold change ≥1.5 or ≤0.66 and P-value <0.05 were used as the thresholds to screen DEPs. Subsequently, bioinformatics resources such as online tools DAVID and String were used to generate gene ontology (GO) annotation, KEGG pathways enrichment, and protein-protein interaction (PPI) network for these DEPs. RESULTS: The results show that a total of 347 proteins were differentially expressed in NF1-CPT groups, 212 of which were upregulated and 135 were downregulated. There were more DEPs in non-NF1-CPT groups; we identified 467 DEPs, including 281 upregulated and 186 downregulated. Among them, NF1-CPT groups and non-NF1-CPT groups shared 231 DEPs, and the remaining 230 DEPs showed the same expression trend in the two disease groups, with 117 upregulated and 113 downregulated. In particular, 116 proteins were altered only in NF1-CPT groups (94 were upregulated and 22 were downregulated), whereas 236 proteins were altered only in non-NF1-CPT groups (164 were upregulated and 72 were downregulated). Finally, compared with non-NF1-CPT groups, 47 proteins changed 1.5-fold and P-value < 0.05 in NF1-CPT groups. CONCLUSIONS: To sum up, we found that common DEPS in periosteum of NF1-CPT and non-NF1-CPT groups are mainly involved in cell matrix assembly, cell adhesion, AKT-PI3K signal pathway activation, and vascular agglutination, which indicate that these are the pathological characteristics of CPT. The osteogenic ability is weak, the osteoclastic ability is strong, the vascular lumen is narrow, the invasive growth and the proliferation of fibroblasts are enhanced in CPT patients.