Design, Synthesis, and Antifungal Activities of Phenylpyrrole Analogues Based on Alkaloid Lycogalic Acid.

Plant diseases caused by pathogenic fungi seriously affect the yield and quality of crops, cause huge economic losses, and pose a considerable threat to global food security. Phenylpyrrole analogues were designed and synthesized based on alkaloid lycogalic acid. All target compounds were characterized by 1H NMR, 13C NMR, and HRMS. Their antifungal activities against seven kinds of phytopathogenic fungi were evaluated. The results revealed that most compounds had broad-spectrum fungicidal activities at 50 µg/mL; 14 compounds displayed more than 60% fungicidal activities against Rhizoctonia cerealis and Sclerotinia sclerotiorum, and in particular, the fungicidal activities of compounds 8g and 8h against Rhizoctonia cerealis were more than 90%, which could be further developed as lead agents for water-soluble fungicides. The molecular docking results indicate that compounds 8g and 8h can interact with 14α-demethylase (RcCYP51) through hydrogen bonding with strong affinity.

Photoredox Nickel-Catalysed Stille Cross-Coupling Reactions.

The Stille cross-coupling reaction is one of the most common strategies for the construction of C-C bonds. Despite notable strides in the advancement of the Stille reaction, persistent challenges persist in hindering its greener evolution. These challenges encompass multiple facets, such as the high cost of precious metals and ligands, the demand for various additives, and the slow reaction rate. In comparison to the dominant palladium-catalysed Stille reactions, cost-effective nickel-catalysed systems lag behind, and enantioconvergent Stille reactions of racemic stannanes remain undeveloped. Herein, we present a pioneering instance of nickel-catalysed enantioconvergent Stille cross-coupling reactions of racemic stannane reagents, resulting in the formation of C-C bonds in good to high yields with excellent stereoselectivity. This strategy provides a practical, scalable, and operationally straightforward method for the synthesis of C(sp3 )-C(sp3 ), C(sp3 )-C(sp2 ), and C(sp3 )-C(sp) bonds under exceptionally mild conditions (without additives and bases, ambient temperature). The innovative use of synergistic photoredox/nickel catalysis enables a novel single-electron transmetalation process of stannane reagents, providing a new research paradigm of Stille reactions.

Stereoselective alkyl C-glycosylation of glycosyl esters via anomeric C-O bond homolysis: efficient access to C-glycosyl amino acids and C-glycosyl peptides.

C-Glycosyl peptides possess excellent metabolic stability and therapeutic properties and thus play critical roles in biological studies as well as drug discoveries. However, the limited accessibility of C-glycosyl amino acids has significantly hindered the broader research of their structural features and mode of action. Herein, for the first time we disclose a novel visible-light-driven radical conjugate addition of 1,4-dihydropyridine (DHP)-derived glycosyl esters with dehydroalanine derivatives, generating C-glycosyl amino acids and C-glycosyl peptides in good yields with excellent stereoselectivities. Redox-active glycosyl esters, as readily accessible and bench-stable radical precursors, could be easily converted to glycosyl radicals via anomeric C(sp3)-O bond homolysis under mild conditions. Importantly, the generality and practicality of this transformation were fully demonstrated in >40 examples including 2-dexosugars, oligosaccharides, oligopeptides, and complex drug molecules. Given its mild reaction conditions, robust sugar scope, and high anomeric control and diastereoselectivity, the method presented herein could find widespread utility in the preparation of C(sp3)-linked sugar-based peptidomimetics.

Self-supervised learning enables 3D digital subtraction angiography reconstruction from ultra-sparse 2D projection views: A multicenter study.

3D digital subtraction angiography (DSA) reconstruction from rotational 2D projection X-ray angiography is an important basis for diagnosis and treatment of intracranial aneurysms (IAs). The gold standard requires approximately 133 different projection views for 3D reconstruction. A method to significantly reduce the radiation dosage while ensuring the reconstruction quality is yet to be developed. We propose a self-supervised learning method to realize 3D-DSA reconstruction using ultra-sparse 2D projections. 202 cases (100 from one hospital for training and testing, 102 from two other hospitals for external validation) suspected to be suffering from IAs were conducted to analyze the reconstructed images. Two radiologists scored the reconstructed images from internal and external datasets using eight projections and identified all 82 lesions with high diagnostic confidence. The radiation dosages are approximately 1/16.7 compared with the gold standard method. Our proposed method can help develop a revolutionary 3D-DSA reconstruction method for use in clinic.

Iodine-mediated electrochemical C(sp3)-H cyclization: the synthesis of quinazolinone-fused N-heterocycles.

An efficient iodine-mediated electrochemical C(sp3)-H cyclization was developed under mild conditions. A variety of functionalized quinazolinone-fused N-heterocycles can be obtained with good to excellent yields by virtue of this method. The reaction features a broad substrate scope and scalability, and is metal-free and chemical oxidant-free.

Electrosynthesis of Quinazolines and Quinazolinones via an Anodic Direct Oxidation C(sp3)-H Amination/C-N Cleavage of Tertiary Amine in Aqueous Medium.

An electrochemical synthesis for quinazolines and quinazolinones was developed via a C(sp3)-H amination/C-N cleavage by virtue of the anodic oxidation. The reaction can be carried out in aqueous media under mild conditions to afford the desired products with high yields. The reaction mechanism was proposed after detailed investigation.

Electrosynthesis of 2-(1,3,4-Oxadiazol-2-yl)aniline Derivatives with Isatins as Amino-Attached C1 Sources.

An intramolecular decarboxylative coupling reaction for the construction of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives was developed from readily available isatins and hydrazides by virtue of electrochemistry. In this reaction, isatins were employed as amino-attached C1 sources, providing a variety of 2-(1,3,4-oxadiazol-2-yl)aniline derivatives with moderate to good yields.

Iodine-Mediated Electrochemical C(sp2)-H Amination: Switchable Synthesis of Indolines and Indoles.

A metal-free electrochemical intramolecular C(sp2)-H amination using iodine as a mediator was developed. This method enables a switchable synthesis of indoline and indole derivatives, respectively, from easily available 2-vinyl anilines.

3-Nitro-3,4-dihydrocoumarins: valuable precursors for the synthesis of enantiomerically enriched masked quaternary α-amino acid derivatives with a 3,4-dihydrocoumarin scaffold.

A bifunctional squaramide catalyzed enantioselective formal [2 + 4] annulation reaction with 3-nitro-3,4-dihydrocoumarins and ortho-quinone methide has been developed. Novel chiral masked quaternary α-amino acid derivatives with a 3,4-dihydrocoumarin scaffold are obtained in a highly stereocontrolled manner. Representative transformation of the annulation product to a biologically important quaternary α-amino acid derivative is achieved without any appreciable loss in the diastereo- and enantioselectivity.

Electrocatalytic Three-Component Reaction: Synthesis of Cyanide-Functionalization Imidazo-Fused N-Heterocycles.

An electrochemical three-component cyclization was developed under metal-free conditions, which provides a novel and facile approach for the construction of cyanide-functionalization imidazo-fused N-heterocycles. A variety of cyanide-functionalization imidazo-fused N-heterocycles can be obtained from easily available methyl N-heteroaromatics, primary alkylamines, and trimethylsilyl cyanide with good to excellent yields. The reaction features a broad scope of substrates, scalability, and mild conditions.

Electrocatalytic Tandem Synthesis of 1,3-Disubstituted Imidazo[1,5- a]quinolines via Sequential Dual Oxidative C(sp3)-H Amination in Aqueous Medium.

An NH4I-mediated tandem electrosynthesis of 1,3-disubstituted imidazo[1,5- a]quinolines was developed from readily available starting materials in aqueous medium, affording a variety of 1,3-disubstituted imidazo[1,5- a]quinolines with good to excellent yields.

Application of Entropy Spectral Method for Streamflow Forecasting in Northwest China.

Streamflow forecasting is vital for reservoir operation, flood control, power generation, river ecological restoration, irrigation and navigation. Although monthly streamflow time series are statistic, they also exhibit seasonal and periodic patterns. Using maximum Burg entropy, maximum configurational entropy and minimum relative entropy, the forecasting models for monthly streamflow series were constructed for five hydrological stations in northwest China. The evaluation criteria of average relative error (RE), root mean square error (RMSE), correlation coefficient (R) and determination coefficient (DC) were selected as performance metrics. Results indicated that the RESA model had the highest forecasting accuracy, followed by the CESA model. However, the BESA model had the highest forecasting accuracy in a low-flow period, and the prediction accuracies of RESA and CESA models in the flood season were relatively higher. In future research, these entropy spectral analysis methods can further be applied to other rivers to verify the applicability in the forecasting of monthly streamflow in China.

Electrocatalytic Intermolecular C(sp3)-H/N-H Coupling of Methyl N-Heteroaromatics with Amines and Amino Acids: Access to Imidazo-Fused N-Heterocycles.

An efficient NH4I-mediated intermolecular annulation of methyl N-heteroaromatics with amines/amino acids was developed by virtue of anodic oxidation, providing a variety of functionalized imidazo-fused N-heterocycles with good to excellent yields. The practicality of this protocol was demonstrated by the readily available starting materials, broad substrate scope, water tolerance, scalability, and the diverse transformations of the electrolysis product.

Asymmetric Formal [4 + 2] Annulation of o-Quinone Methides with ß-Keto Acylpyrazoles: A General Approach to Optically Active trans-3,4-Dihydrocoumarins.

An asymmetric cascade reaction between ß-keto acylpyrazoles and o-quinone methides in a formal [4 + 2] fashion to access potentially pharmacological active trans-3,4-dihydrocoumarins has been achieved efficiently by using a quinine-based chiral squaramide as the catalyst. The desired products were obtained in high yields with excellent diastereo- and enantioselectivities (up to 96% yield, >19/1 dr and 96% ee) under mild reaction conditions.

Autologous Bone Marrow-Derived Stem Cells for Treating Diabetic Neuropathy in Metabolic Syndrome.

Diabetic neuropathy is one of the most common and serious complications of diabetes mellitus and metabolic syndrome. The current therapy strategies, including glucose control and pain management, are not effective for most patients. Growing evidence suggests that infiltration of inflammation factors and deficiency of local neurotrophic and angiogenic factors contribute significantly to the pathologies of diabetic neuropathy. Experimental and clinical studies have shown that bone marrow-derived stem cells (BMCs) therapy represents a novel and promising strategy for tissue repair through paracrine secretion of multiple cytokines, which has a potential to inhibit inflammation and promote angiogenesis and neurotrophy in diabetic neuropathy. In this review, we discuss the clinical practice in diabetic neuropathy and the therapeutic effect of BMC. We subsequently illustrate the functional impairment of autologous BMCs due to the interrupted bone marrow niche in diabetic neuropathy. We anticipate that the functional restoration of BMCs could improve their therapeutic effect and enable their wide applications in diabetic neuropathy.

Chemical Synthesis of K34-Ubiquitylated H2B for Nucleosome Reconstitution and Single-Particle Cryo-Electron Microscopy Structural Analysis.

Post-translational modifications (e.g., ubiquitylation) of histones play important roles in dynamic regulation of chromatin. Histone ubiquitylation has been speculated to directly influence the structure and dynamics of nucleosomes. However, structural information for ubiquitylated nucleosomes is still lacking. Here we report an alternative strategy for total chemical synthesis of homogenous histone H2B-K34-ubiquitylation (H2B-K34Ub) by using acid-cleavable auxiliary-mediated ligation of peptide hydrazides for site-specific ubiquitylation. Synthetic H2B-K34Ub was efficiently incorporated into nucleosomes and further used for single-particle cryo-electron microscopy (cryo-EM) imaging. The cryo-EM structure of the nucleosome containing H2B-K34Ub suggests that two flexible ubiquitin domains protrude between the DNA chains of the nucleosomes. The DNA chains around the H2B-K34 sites shift and provide more space for ubiquitin to protrude. These analyses indicated local and slight structural influences on the nucleosome with ubiquitylation at the H2B-K34 site.

Organocatalyzed Asymmetric Michael Addition of 1-Acetylindolin-3-ones to ß,γ-Unsaturated α-Ketoesters: An Access to Chiral Indolin-3-ones with Two Adjacent Tertiary Stereogenic Centers.

Asymmetric Michael addition of 1-acetylindolin-3-ones to ß,γ-unsaturated α-ketoesters was investigated for the synthesis of chiral indolin-3-ones with two adjacent tertiary stereogenic centers. Under the catalysis of a chiral bifunctional squaramide derived from l-tert-leucine, a wide range of 1-acetylindolin-3-ones and ß,γ-unsaturated α-ketoesters were well-tolerated in this transformation to provide the corresponding novel densely functionalized chiral indolin-3-one derivatives in high yield with excellent diastereo- and enantioselectivity under mild reaction conditions.

Stereocontrolled Construction of Tetrahydropyrano[2,3-c]pyrazole Scaffold via an Organocatalyzed Formal [3 + 3] Annulation.

A bifunctional squaramide catalyzed enantioselective formal [3 + 3] annulation reaction with pyrazolin-5-ones and nitroallylic acetates has been developed. Densely substituted tetrahydropyrano[2,3-c]pyrazoles with two adjacent stereogenic centers are obtained in a highly stereocontrolled manner. Representative transformation of the annulation product to a biologically important fused dihydroisoquinoline is achieved without any appreciable loss in the diastereo- and enantioselectivity.

Organocatalytic multicomponent synthesis of polysubstituted pyrroles from 1,2-diones, aldehydes and arylamines.

We have developed an organocatalyzed three-component reaction of 1,2-diones, aldehydes and arylamines, which provides an efficient approach to access polysubstituted pyrroles. In the catalysis of 4-methylbenzenesulfonic acid monohydrate, the reactions of a wide range of 1,2-diones, arylamines and aldehydes took place smoothly to generate the corresponding polysubstituted pyrroles in acceptable to good yields under mild reaction conditions.

Application of "Hydrogen-Bonding Interaction" in Drug Design. Part 2: Design, Synthesis, and Structure-Activity Relationships of Thiophosphoramide Derivatives as Novel Antiviral and Antifungal Agents.

On the basis of the structure of natural product harmine, lead compound 18, and the structure of compounds in part 1, a series of thiophosphoramide derivatives 1-17 were designed and synthesized from various amines in one step. Their antiviral and antifungal activities were evaluated. Most of the compounds showed significantly higher antiviral activity against tobacco mosaic virus (TMV) than commercial virucide ribavirin. Compound (R,R)-17 showed the best anti-TMV activity in vitro (70%/500 µg/mL and 33%/100 µg/mL) and in vivo (inactivation effect, 68%/500 µg/mL and 30%/100 µg/mL; curative effect, 64%/500 µg/mL and 31%/100 µg/mL; protection effect, 66%/500 µg/mL and 31%/100 µg/mL), which is higher than that of ningnanmycin and lead compound 18. The antiviral activity of (R,R)-17·HCl is about similar to that of (R,R)-17. However, the antifungal activity of (R,R)-17·HCl against Puccinia sorghi is slightly lower than that of (R,R)-17. The systematic study provides compelling evidence that these simple thiophosphoramide compounds could become efficient antiviral and antifungal agents.