bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct Functionalization of Unactivated C(sp
3
)H Bonds via Photocatalyzed Hydrogen Atom Transfer
Authors: Gong Lei , Lin Yu‐Mei
Published: October 2022

The direct and selective functionalization of unactivated C(sp
3
)H bonds is one of the most attractive goals in synthetic chemistry. While the radical‐mediated hydrogen atom transfer (HAT) process has shown considerable potential in such reactions, it faces fundamental problems associated with reactivity and selectivity. This chapter describes the strategies of indirect HAT (
i
‐HAT) and direct HAT (
d
‐HAT) photocatalysis developed for C(sp
3
)H functionalization in unactivated aliphatic hydrocarbons and remote C(sp
3
)H feedstocks. A number of examples demonstrate the advantages of HAT photocatalysis for the initiation of radical processes in a mild and controllable manner, which can help to achieve useful chemo‐, site‐, and stereoselectivity. Combination of such reactions with asymmetric catalysis, offering appealing opportunities to furnish chiral products from the most abundant starting materials, is discussed. Such advances in this methodology will stimulate further progress in diversity‐oriented synthesis, catalysis, pharmaceutics, and material science.
Mechanistic Insights into Nickel‐Catalyzed CH Functionalization Reactions
Authors: Shu Xing‐Zhong , Pang Xiaobo , Wei Xiao‐Xue
Published: October 2022

In this article, we summarize the four mechanisms according to the experimental and theoretical basis in chronological order. These include the oxidative addition process, base‐assisted nickelation of CH bonds, the ligand‐to‐ligand hydrogen transfer (LLHT) process, and σ‐bond metathesis. Meanwhile, the representative efforts in nickel‐catalyzed CH functionalization in the past two decades are also summarized. These reactions typically involve (i) the hydrocarbonation of unsaturated CC bonds; (ii) the coupling reactions of CH with carbon electrophiles and nucleophiles; (iii) the oxidative CH and CH coupling reactions; and (iv) the construction of carbon–hetero bonds.
Transition‐Metal‐Catalyzed Stereo‐ and Chemo‐Selective Alkenyl CH Functionalizations
Authors: Zhang Jian , Zhong Guofu
Published: October 2022

Alkenyl CH bond functionalization represents one step‐/atom economic access to alkene derivatives; however, regio‐ and stereoselectivity controlling remains a challenging goal. Although many attentions have been made on the site‐selective aromatic CH functionalizations, there have been much less examples on selective alkenyl CH functionalizations presumably due to the reaction lability and conformation flexibility. Group‐directed CH functionalizations lead to site‐ and stereo‐selective formations of CC and CX bonds. This article focuses on transition‐metal‐catalyzed vicinal‐ and geminal‐group‐directed alkenyl CH functionalizations, such as alkenylation, alkylation, allylation, arylation, halogenation, alkynylation, silylation, and cyanation to be proceeded by the formation of exo‐/endo‐metallocycles.
Innate Directing Group‐Guided Transition Metal‐Catalyzed C(sp
2
)H Activation: Functionalization of Biosignificant Heterocyclic Scaffolds
Authors: Seth Kapileswar
Published: October 2022

The transition metal‐catalyzed CH activation is a fundamentally important organic transformation. The Lewis basic coordinating atoms, which typically function as directing control, have set the stage for efficient transition metal‐catalyzed CH functionalizations in a site‐ and regioselective fashion. Frequently, the directing atom(s) is a preexisting intrinsic part of the molecular entity naturally and remains unperturbed to the skeleton at the end of the desired CH functionalizations. This has been the case with several heterocycles and can be classified as innate directing group (DG). Different types of CC bond formation via innate DG‐assisted CH activation of selected biosignificant heterocyclic scaffolds have been presented; in particular, the functionalizations of C(sp
2
)H bond have been covered.
Gold‐Catalyzed CH Activation/Functionalization Reactions
Authors: Hu Chao , Hashmi A. Stephen K.
Published: October 2022

Gold catalysis has exhibited significant potential in CH activation/functionalization; a broad array of versatile synthetic methods have been developed; and various new reactions have been established. This article discusses a selection of recent seminal advances and conceptual breakthroughs of gold‐catalyzed CH bond functionalization of alkynes, arenes, and alkanes, aiming to provide the reader with an overview of the progress and potential in this rapidly growing research field.
Visible‐Light‐Promoted Fluorine‐Containing Functionalization of C(sp
3
)H Bonds
Authors: Zhao Chuan‐Gang , Wang Chenkun , Li Weipeng , Zhu Chengjian , Xie Jin
Published: October 2022

image

This article provides a general overview of the visible‐light‐mediated conversion of C(sp
3
)H bonds to fluorine‐containing functional groups. We summarized different types of CH fluorine‐containing functionalization reactions, including the reactive C(sp
3
)H bond of carbonyl compounds, relatively weak C(sp
3
)H bonds such as α‐C(sp
3
)H adjacent to heteroatoms and benzylic CH bonds as well as the nonactivated C(sp
3
)H bonds of aliphatic alkanes. A wide range of fluorine‐containing functionalization of C(sp
3
)H bonds are discussed, such as trifluoromethylation, fluoroalkenylation, perfluoralkylation, trifluoromethylthiolation, and fluorination.
Recent Advances in Boron‐Mediated CH Functionalization
Authors: Zhang Zhenguo , Ji Liang , Liu Xiaoxiao , Jia Zhenhua
Published: October 2022

The CH functionalization of organic molecules has become an efficient approach to access diverse bioactive compounds and functional materials. In recent years, transition metal catalysts dominated the field of CH functionalization, such as Rh, Pd, Ir, and Ru. The main group‐centered complexes, especially organoboron reagents, emerged as an alternative option to mediate CH functionalization and received lots of attention in the pharmaceutical and agricultural industries due to their metal‐free feature avoiding to remove metal residues from the final products. In this article, we summarize the recent advances in boron‐mediated CH functionalization, such as CH borylation, CH silylation, CH insertion, CH alkylation, CH hydroxylation, CH deuteration, and other transformations involving CH activation.
Iridium‐Catalyzed C(sp
2
)H Bond Functionalization
Authors: Machado Luana A. , Jardim Guilherme A. M. , Bozzi Ícaro A. O. , Pedrosa Leandro F. , Wood James M. , da Silva Júnior Eufrânio N.
Published: October 2022

Over the last two decades, iridium catalysis has emerged as a reliable tool for the functionalization of C(sp
2
)H bonds, enabling the development of catalytic methods for the construction of complex molecular scaffolds from simple building blocks. The unique reactivity of iridium complexes has enabled breakthroughs in fundamental and applied CH bond activation chemistry, unlocking several types of reactions. Herein, general aspects and key concepts regarding the reactivity of iridium catalysts toward a variety of C(sp
2
)H bonds are discussed. Relevant iridium‐catalyzed CH functionalization methodologies are also highlighted, featuring arene and heterocyclic substrates, as well as more challenging vinylic substrates and examples of distal CH activation reactions.
Heterocycles Synthesis by (Cross)‐Dehydrogenative Coupling
Authors: Mondal Rakesh , Guin Amit K. , Paul Nanda D.
Published: October 2022

Heterocyclic compounds are ubiquitous in nature and constitute the backbone of many naturally occurring and synthetic organic compounds having a broad spectrum of biological and pharmacological activities. Due to the importance of this class of compounds, the development of straightforward, efficient, atom‐economical, and eco‐friendly synthesis of various heterocyclic compounds has always drawn considerable attention. Among the different available synthetic methodologies, the cross‐dehydrogenative coupling (CDC) reactions represent one of the most efficient and straightforward approaches, which do not require the time‐consuming multistep prefunctionalization of starting precursors. In this article, we concentrated on various CDC approaches for the synthesis of different heterocyclic compounds. Both transition metal‐catalyzed and ‐free methodologies developed over the past decades have been summarized.
Recent Advances of Unactivated C(sp3)H Functionalization via Radical Pathway
Authors: Zhou Liejin , Zhang Zuxiao
Published: October 2022

Radical C(sp3H) functionalization has been experienced a rapid growth with the renaissance of radical chemistry. The newly developed radical generation and radical trap methods enabled numerous regio, chemo, and enantioselective CH functionalization which offered a distinct and complementary strategy for CH functionalization compared with traditional CH activations. In this article, we summarized the recent advances of radical C(sp3)H functionalization reactions which involved the generation of carbon radical from CH bonds. Representative examples were selected to explain the factors affecting the selectivity of HAT. In addition, the methods to trap carbon radicals to install various functional groups are discussed as well.
CH Carboxylation with CO
2
Authors: Hu Xin‐Long , Jiang Yuan‐Xu , Song Lei , Yu Da‐Gang
Published: October 2022

In this article, we outline the development of using CO
2
as the carboxyl source in CH bond functionalization. As the main products of CO
2
‐involving organic synthesis, carboxylic acids and their derivatives are highly important and widely used. Among the numerous methods to generate carboxylic acids, the direct carboxylation of CH bonds with CO
2
is the most efficient in an atom‐economical way. The development of the direct carboxylation of different CH bonds with CO
2
is summarized separately. A summary and outlook of this area are presented.
Transition Metal‐Catalyzed CH Bond Functionalization Involving Metal Migration
Authors: Ju Cheng‐Wei , Zhao Dongbing
Published: October 2022

Transition metal‐catalyzed CH functionalization has become a pivotal organic transformation in the past decades. Numerous methodologies involving transition metal migrations have evolved into novel and significant synthetic tools for the introduction of metallic moiety into positions that have challenged traditional methods. The metal migration process is accompanied by concurrent migration of a hydrogen atom in the direction opposite to that of the metal migration. The current article provides an overview of catalytic CH functionalization involving 1,4‐ and 1,5‐metal‐migration processes with a focus on Pd‐ and Rh‐catalyzed reactions to demonstrate the synthetic power of such strategies.
Copper‐Mediated Free‐Radical C(sp
3
)H Activation
Authors: Kumar Nivesh , Liu Shuai , Robert Frédéric , Landais Yannick
Published: October 2022

The availability, low cost, and toxicity of copper as compared to other transition metals have led to an increasing interest in organic synthesis. This article describes recent advances in the field of Cu‐mediated C(sp
3
)H activation and the formation of new CO, CC, CN, CX, and CS bonds. Here, we describe the role of copper in the generation of hydrogen atom transfer agents and its involvement in the subsequent formation of new bonds from unactivated CH bonds. Many examples are provided which illustrate the versatility of the methodology in the synthesis of ethers, esters, amines, thioethers, and the possibility of late‐stage functionalization of complex molecules starting from simple hydrocarbon precursors. Mechanisms are discussed, which have allowed a rapid development of this operationally simple strategy leading to high‐value substrates.
The Functionalization of Amino Acids, Peptides, and Derivatives by Cross‐Dehydrogenative Coupling
Authors: Phillips Ana M. Faisca , Pombeiro Armando J.L.
Published: October 2022

Modified or unnatural amino acids and peptides are required for a number of applications, which include drug development, diagnostics, to study protein function, for vaccine development, and also for synthetic building blocks and catalysts. By joining two native CH bonds directly, cross‐dehydrogenative coupling provides an efficient, atom‐economical, and environmentally friendly methodology for the α‐functionalization of these substances. Many oxidants, including air, may be utilized to facilitate the loss of hydrogen, and several types of catalysts, metal or organocatalysts and even light, are now known that activate CH bonds for a variety of applications. Site‐selective peptide functionalization is possible in some cases, compatible with the presence of many functional groups in the molecules, and also asymmetric synthesis. This article revises the literature available on this topic, covering at the same time the reaction mechanisms involved and studies performed to elucidate them, aiming to interest the reader in potential future applications.
CH Functionalization Using Carboxylic Acids and Carboxylic Acid Derivatives as Electrophiles under Redox‐Neutral Conditions
Authors: Gao Pengcheng , Meng Guangrong , Hammadi Batoul , Szostak Michal
Published: October 2022

The article provides a summary of the recent developments in using carboxylic acids and derivatives as aryl, alkenyl, and alkyl electrophiles for CH functionalization. This manifold exploits ubiquitous carboxylic acids as electrophiles after oxidative addition and decarbonylation in the absence of external oxidants under Rh, Pd, Ni, and Ir catalysis. Mechanistically, acyl RC(O)X bond oxidative addition to low valent metals is followed by decarbonylation, resulting in a net generation of R[M] electrophiles for a broad range of CH functionalization processes. The article covers aroyl chlorides, aroyl fluorides, anhydrides, carboxylic acids, esters and amides, and other related acyl derivatives.
Iron‐Catalyzed Nitrene Insertion of CH Bonds
Authors: Zhong Dayou , Zheng Yu‐Qing , Liu Wen‐Bo
Published: October 2022

Nitrene insertion of CH bonds represents a powerful synthetic method to form nitrogen‐containing organic compounds. This article summarized recent development of iron‐catalyzed nitrene insertion of CH bonds for the construction of CN bonds and organized by the types of nitrene precursors, including iminoiodanes, organic azides, hydroxylamine derivatives, sulfonamides, etc. Important examples and breakthroughs in this field are highlighted, and the current mechanistic understandings of the formation of iron‐nitrenoid species and the catalytic cycles are discussed. Additionally, the synthetic application of this chemistry is also included.
Applications of Palladacycles Toward Medicinal Chemistry
Authors: Tareque Raysa K. , Neto Brenno , Spencer John
Published: October 2022

Selected recent examples of the use of palladacycles as anticancer agents or as catalysts to enable the synthesis of biologically relevant molecules are presented.
CH Functionalization Reactions Promoted by First‐Row Transition Metals with Redox‐Active Ligands. Nature Did it First
Authors: Wu Tong , Hebert David D. , Puri Ankita , Garcia‐Bosch Isaac
Published: October 2022

Some natural metalloenzymes carry out challenging organic transformations utilizing 3d metals (e.g. Fe and Cu) in combination with redox‐active moieties. Based on the exquisite reactivity of these natural catalysts, we compiled the most relevant examples of CH functionalization reactions promoted by 3d metals that cooperate with redox‐active supporting ligands, oxidants, and substrates.
Inner‐Sphere CH Bond Activation
Authors: Mahato Rina , Sharma Pragya , Hazra Chinmoy K.
Published: October 2022

Transition metal‐catalyzed inert C(sp2)H and C(sp3)H bond activation is an emerging approach for introducing desired functionality to a specific location. This article describes the regioselective functionalization of aryl/alkyl moieties for the synthesis of useful compounds and molecular materials. A wide range of directing‐group assisted CH activation reactions, and some of the most well‐known regio‐controlled reactions via noncovalent interactions have been addressed. This distance‐ and geometry‐based differentiation technique for regioselective distant CH activation not only led to the desired site but also reduces the reaction time and waste. Additionally, more challenging distal gamma and delta C(sp3)H bond functionalization is another striking feature appearing in this enclosed article.
CH Functionalization via Chalcogen and Pnictogen Salts
Authors: Kelly Christopher B. , Padilla‐Salinas Rosaura
Published: October 2022

CH functionalization is an enabling technology for medicinal chemistry efforts, allowing a greater chemical landscape to be assayed in a shorter time frame from non‐pre‐functionalized materials. Part of an elite class of the so‐called late‐stage functionalization (LSF) reactions, CH functionalization can take many forms, with one emerging form involving the intermediacy of chalcogen and pnictogen salts. Although canonical boronate esters or halides are the “go‐to” species for CH functionalization, three unrelated cationic groups (phosphonium, pyridinium, and thianthrenium) have emerged as viable alternatives with rich avenues for diversification. Despite being a two‐step process to achieve the net desired CH transformation, the ease of entry and the unusual regiochemical selectivity of salt formation make these chalcogen and pnictogen indispensable assets to LSF efforts. This article details the fundamentals of using these salts for CH functionalization, with an emphasis on how they can be enabling technologies for medicinal chemistry.
Oxidative C(sp3)H Bond Functionalization with Hydride Abstractor‐Type Oxidants
Authors: Lohmann Niklas , Mancheño Olga García
Published: October 2022

This article deals with oxidative C(sp3)H bond functionalization reactions mediated by hydride abstractor‐type oxidants. An overview of the state‐of‐the‐art in this area is provided, sorted primarily by hydride abstractor type and reaction category. Although the number of examples implying hydride abstractor‐mediated CH bond functionalization reactions is still relatively limited, the methods described in this article display a variety of advantageous alternatives from an atom and step economic point of view to classical transition‐metal‐catalyzed cross‐coupling reactions. Hence, the use of oxoammonium salts as mild oxidants has been furthermost explored and their applications in dehydrogenative cross‐coupling, including nucleophilic addition, cyclization, or tandem reactions, are discussed first. In the following, CH bond functionalization reactions with other types of hydride abstractors such trityl salts, tropylium salts, and DDQ mediated processes are presented.
HFIP‐Mediated CH Functionalization
Authors: Solyev Pavel N.
Published: October 2022

1,1,1,3,3,3‐Hexafluoroisopropanol (HFIP) is a solvent with properties in the extreme. Being used in specific scopes for more than half a century, nowadays, it has become a hot topic in complex organic transformations. The application of HFIP is gaining wide perspectives not only in synthetic chemistry but in biology and chemical physics. This article discloses the unusual nature of HFIP and its extraordinary solvation effects upon different classes of molecules and on CH functionalization reactions in general. The structure and coordinating modes of the solvent make it possible to infer the impact of HFIP on the reagents activation, intermediates stabilization, and products outcome in CH functionalization reactions.
CH Functionalization Reactions Following a Single‐Electron Transfer and Radical Pathway
Authors: Bains Amreen K. , Adhikari Debashis
Published: October 2022

The CH functionalization reactions are of utmost importance in synthetic chemistry and multiple approaches have been adopted to discover easy and mild processes. This article focuses on CH functionalization reactions that are predominantly promoted by radical species. Many prior processes often rely on prefunctionalization of a particular CH bond, hence a direct method without such prior activation would be very much appreciable. In a radical‐driven CH functionalization process, an alkyl or aryl radical can be generated from an appropriate precursor by single electron transfer event. Beyond that, a significant effort is devoted to discover new precursor molecules from which a variety of alkyl and aryl radicals will be efficiently generated. The mildness of the process is often demonstrated by the chemoselectivity, and a wide functional group tolerance. The applicability of the radical‐mediated CH functionalization processes stretches further to the realm of medicinally and pharmaceutically important molecules. Additionally, many photochemical processes are recent addition to the repertoire of radical generation that facilitate the methods without any heating. Intriguing mechanistic scenarios for radical generation and further reactions toward CH functionalization is described and discussed.
Direct CH (Het)arylation of 1,2‐Heteroazoles, Heterodiazoles, and Triazoles
Authors: Koyioni Maria , Koutentis Panayiotis A.
Published: October 2022

Recent developments in the direct CH (het)arylation of 1,2‐heteroazoles, heterodiazoles, and triazoles are reviewed, i.e. pyrazoles, isoxazoles, isothiadiazoles, triazoles oxadiazoles, thiadiazoles, and their arene‐fused analogs. Reaction scope and mechanistic considerations are reported. The direct arylation of “unactivated” CH bonds avoids procedures that require prefunctionalization of the substrate, making such synthesis more cost‐effective and atom economic as well as avoiding the generation of stoichiometric amounts of toxic waste. As such, this synthetically valuable strategy has been applied to a broad array of (het)arenes. This article covers the direct CH (het)arylation of less common, heteroatom‐rich azoles from 1982, the first reported reaction, to the present day.
Copper in CH Functionalization: Mechanistic Insights into CH to CC/N/O Transformations
Authors: Gayathri K. , Kundu Subrata
Published: October 2022

This article illustrates a diverse array of copper‐mediated CH to CX (X = C/N/O) transformations. Moreover, the examples are discussed to underscore the possible copper‐containing intermediates by emphasizing the routes for the generation of the catalytically viable intermediates and their reactivity trends relevant to CH to CX transformations. In contrast to the organometallic pathways commonly preferred by the 2nd and 3rd row transition metal‐catalyzed CH to CX (X = C/N/O) transforming routes, the routes involving copper sites have been illustrated to involve both organometallic as well as outer sphere mechanisms. Consequently, the copper‐mediated CH functionalization routes utilize a combination of both 1e‐ and 2e‐ steps. Thus, a detailed understanding of the mechanism is critical for the rational design of the catalyst as well as the methods.
Electrochemical Oxidative CH Functionalization: A Metal‐Free Approach
Authors: Ghosh Adrija , Bera Atanu , Bera Sourajit , Banerjee Debasis
Published: October 2022

Electrochemical CH bond functionalization of organic molecules has emerged as one of the most powerful tools for the synthesis of carbon–carbon and carbon–heteroatom bonds. In past decades, metal‐catalyzed CH activation has attracted significant attention owing to the drawbacks of the conventional methods. At the same time, classical approaches suffer from serious limitations such as the use of expensive catalytic systems, toxic reagents, harsh reaction conditions, and additional waste generation. This has highlighted the need for a sustainable and atom‐efficient solution in the form of various modern‐day techniques. Metal‐ and oxidant‐free electrochemical CH functionalization has proved to be an efficient alternative in terms of efficacy as well as atom economy. Herein, we have discussed about the contribution of metal‐free oxidative electrochemical CH activation in the construction of challenging CC and C–heteroatom (CN, CO, CS, C–halogen) bonds. Detailed mechanistic descriptions and applications toward synthesis of bio‐active drug molecules are also considered till April 2021.
Structurally Defined Molecular Bismuth Compounds in CH Activation
Authors: Oberdorf Kai , Lichtenberg Crispin
Published: October 2022

With their low costs, ready availability, and relatively low toxicity, bismuth and its compounds offer interesting properties for the use as reagents in synthetic chemistry. Furthermore, bismuth is a heavy metal with a large covalent and ionic radius and a range of accessible coordination geometries and oxidation states, which allows for careful complex design in order to address desired reactivity patterns. The scientific efforts toward the exploitation of bismuth compounds for unusual CH activation reactions are summarized in this contribution with a focus on the different types of synthetic strategies that have been elaborated.
Directing Group‐Assisted CH Bond Functionalization on the Naphthalene
Authors: Ghosh Subhash Chandra
Published: October 2022

The direct functionalization of CH bonds is now considered an attractive, powerful, and step‐economical tool in organic synthesis. Regioselective CH functionalization of arenes implies the installation of a functional group on the desired position of the ring of mono‐substituted arenes. Naphthalene is a privileged aromatic compound that is widely presented in numerous pharmaceuticals, agrochemicals, dyes, and functional materials. Consequently, a lot of research has been carried out in the past decade to develop new methodologies to install a functional group on every possible position of the naphthalene nucleus. In this article, we have summarized the regioselective functionalization of mono‐substituted naphthalene via directing group assistance strategy.
Late‐Stage CH Functionalizations Directed by Nickel Catalysis and Its Implications on Total Synthesis of Natural Products
Authors: Kokkonda Praveen , Deb Arghya
Published: October 2022

The predominant existence of CH bonds in plethora of natural products influence the synthetic chemist to develop reactions by utilizing CH functionalization for directly generating valuable products from simple feedstock. Due to low cost, easy availability and unique reactivity profiles, tremendous advancement in the field of CH functionalization has been achieved by first‐row transition metals and been recognized as the potential alternative to noble transition metals. Among these, nickel has drawn considerable attentions as due to it's potential in diverse mechanistically different reactions, entrapping both the classical organometallic and radical‐based intermediates. This book chapter focuses on Ni‐catalyzed CH functionalization reactions by which challenging late stage functionalization and a number of total synthesis of natural products were achieved.
Electrophotocatalytic CH Bonds Functionalization
Authors: Wang Kui , Wang Hong , Wang Aihua , Liu Siyuan , Ma Li , Gao Wei , Chen Jianbin
Published: October 2022

Synthetic photoelectrochemistry (PEC), the fusion of photoredox catalysis (PRC), and synthetic organic electrochemistry (SOE) provide a powerful way for the selective C(sp
2
)/C(sp
3
)H functionalization via single‐electron transfer (SET). Compared with PRC and SOE, PEC shows stronger redox ability under mild conditions and significant atomic and energy economy. The combination of PEC with hydrogen atom transfer (HAT) makes the inert CH activation possible. Herein, the corresponding work is reviewed by the classification of the formation of CO, CC, CN, and CP bonds.
Ru‐Catalyzed C(sp
3
)H Functionalization
Authors: Murugesh V. , Sahoo Apurba Ranjan , Achard Mathieu , Suresh Surisetti
Published: October 2022

Selective C(sp
3
)H activation/functionalization is one of the most challenging transformations in the modern synthetic organic chemistry. A number of ruthenium(0) and ruthenium(II) complexes have shown remarkable efficiency in this regard. This article aims to concentrate on the notable advancements in this field of ruthenium‐induced C(sp
3
)H activation of amines, alcohols, ketones, and alkanes.
Ru‐Catalyzed CH Functionalization of Heterocycles
Authors: Bai Ruopeng , Shan Chunhui , Lan Yu
Published: October 2022

Heterocycles are key structural motifs in a variety of organic functional compounds, which are widely used in organic chemistry, pharmaceutical sciences, optoelectronics, and material science. In recent years, direct CH bond activation/functionalization has become a promising and attractive synthetic strategy and has been widely applied to construct new CC and Cheteroatom bonds. This article focuses on recent progress in ruthenium‐catalyzed‐directed CH functionalization of heterocycles, including CH alkylation, alkenylation, and alkynylation. In addition, due to the importance and rapid progress in photocatalysis, pioneering work was also summarized in the field of photoredox CH heterocycles functionalization employing ruthenium as photocatalyst.
Comparison of plasma and CSF biomarkers in predicting cognitive decline
Authors: Aschenbrenner Andrew J. , Li Yan , Henson Rachel L. , Volluz Katherine , Hassenstab Jason , Verghese Philip , West Tim , Meyer Matthew R. , Kirmess Kristopher M. , Fagan Anne M. , Xiong Chengjie , Holtzman David , Morris John C. , Bateman Randall J. , Schindler Suzanne E.
Published: October 2022

Objectives

Concentrations of amyloid‐β peptides (Aβ42/Aβ40) and neurofilament light (NfL) can be measured in plasma or cerebrospinal fluid (CSF) and are associated with Alzheimer’s disease brain pathology and cognitive impairment. This study directly compared plasma and CSF measures of Aβ42/Aβ40 and NfL as predictors of cognitive decline.

Methods

Participants were 65 years or older and cognitively normal at baseline with at least one follow‐up cognitive assessment. Analytes were measured with the following types of assays: plasma Aβ42/Aβ40, immunoprecipitation‐mass spectrometry; plasma NfL, Simoa; CSF Aβ42/Aβ40, automated immunoassay; CSF NfL plate‐based immunoassay. Mixed effects models evaluated the global cognitive composite score over a maximum of 6 years as predicted by the fluid biomarkers.

Results

Analyses included 371 cognitively normal participants, aged 72.7 ± 5.2 years (mean ± standard deviation) with an average length of follow‐up of 3.9 ± 1.6 years. Standardized concentrations of biomarkers were associated with annualized cognitive change: plasma Aβ42/Aβ40, 0.014 standard deviations (95% confidence intervals 0.002 to 0.026); CSF Aβ42/Aβ40, 0.020 (0.008 to 0.032); plasma Nfl, −0.018 (−0.030 to −0.005); and CSF NfL, −0.024 (−0.036 to −0.012). Power analyses estimated that 266 individuals in each treatment arm would be needed to detect a 50% slowing of decline if identified by abnormal plasma measures versus 229 for CSF measures.

Interpretation

Both plasma and CSF measures of Aβ42/Aβ40 and NfL predicted cognitive decline. A clinical trial that enrolled individuals based on abnormal plasma Aβ42/Aβ40 and NfL levels would require only a marginally larger cohort than if CSF measures were used.
Bioinspired and Inflammation‐Modulatory Glycopeptide Hydrogels for Radiation‐Induced Chronic Skin Injury Repair
Authors: Feng Zujian , Zhang Yumin , Yang Chunfang , Liu Xiang , Huangfu Yini , Zhang Chuangnian , Huang Pingsheng , Dong Anjie , Liu Jinjian , Liu Jianfeng , Kong Deling , Wang Weiwei
Published: October 2022

Clinical wound management of radiation‐induced skin injury (RSI) remains a great challenge due to acute injuries induced by excessive reactive oxygen species (ROS), and the concomitant repetitive inflammatory microenvironment caused by an imbalance in macrophage homeostasis. Herein, a cutaneous extracellular matrix (ECM)‐inspired glycopeptide hydrogel (GK@TAgel) is rationally designed for accelerating wound healing through modulating the chronic inflammation in RSI. The glycopeptide hydrogel not only replicates ECM‐like glycoprotein components and nanofibrous architecture, but also displays effective ROS scavenging and radioprotective capability that can reduce the acute injuries after exposure to irradiation. Importantly, the mannose receptor (MR) in GK@TAgel exhibits high affinity and bioactivity to drive the M2 macrophage polarization, thereby overcoming the persistent inflammatory microenvironment in chronic RSI. The repair of RSI in mice demonstrates that GK@TAgel significantly reduces the hyperplasia of epithelial, promotes appendage regeneration and angiogenesis, and decreased the proinflammatory cytokine expression, which is superior to the treatment of commercial radioprotective drug amifostine. Collectively, the ECM‐mimetic hydrogel dressing can protect the tissue from irradiation and heal the chronic wound in RSI, holding great potential in clinical wound management and tissue regeneration.
A Conductive Hydrogel Microneedle‐Based Assay Integrating PEDOT:PSS and Ag‐Pt Nanoparticles for Real‐Time, Enzyme‐Less, and Electrochemical Sensing of Glucose
Authors: GhavamiNejad Peyman , GhavamiNejad Amin , Zheng Hanjia , Dhingra Karan , Samarikhalaj Melisa , Poudineh Mahla
Published: October 2022

Continuous glucose meters (CGMs) have tremendously boosted diabetes care by emancipating millions of diabetic patients’ need for repeated self‐testing by pricking their fingers every few hours. However, CGMs still suffer from major deficiencies regarding accuracy, precision, and stability. This is mainly due to their dependency on an enzymatic detection mechanism. Here a low‐cost hydrogel microneedle (HMN)‐CGM assay fabricated using swellable dopamine (DA)‐hyaluronic acid (HA) hydrogel for glucose interrogation in dermal interstitial fluid (ISF) is introduced. Platinum and silver nanoparticles are synthesized within the 3D porous hydrogel scaffolds for nonenzymatic electrochemical sensing of the glucose. Incorporation of a highly water dispersible conductive polymer, poly(3,4‐ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) enhances the electrical properties of HMN array, making the patch suitable as the working electrode of the sensor. The in vitro and ex vivo characterization of this newly developed HMN patch is fully studied. The performance of the HMN‐CGM for real‐time measurement of glucose is also shown using a rat model of type 1 diabetes. The device introduces the first HMN‐based assay for tracking important disease biomarkers and expect to pave the way for next generation of polymeric‐based sensors.
Multi‐walled carbon nanotubes/carbon fiber fabric multiscale hybrid materials for improving the mechanical and tribological properties of phenolic resin composites
Authors: Wang Beibei , Fu Qiangang , Liu Yue , Lu Zhenyuan , Lu Yaru , Cao Sheng
Published: October 2022

Multi‐walled carbon nanotubes (MWCNT)/carbon fiber fabric multiscale hybrid materials were prepared by grafting MWCNT on carbon fabric surface via heating grafted method to improve the mechanical and tribological properties of phenolic resin composites. Field emission scanning electron microscopy, Raman spectrometer, and X‐ray photoelectron spectroscopy were used to analyze the surface properties of carbon fiber. The results shown that the tensile strength of composites modified by 0.15 wt% MWCNT was 38% higher than that of unmodified composites. The wear rates decreased from 3.31 × 10−14 m3 (N·m)−1 for unmodified composites to 0.68 × 10−14 m3 (N·m)−1 for 0.15 wt% MWCNT reinforced composites. The reason was that the uniformly distributed MWCNT could increase interface interaction and mechanical interlocking between carbon fiber fabric and resin matrix.
Examining the relationship between cognitive inflexibility and internalizing and externalizing symptoms in autistic children and adolescents: A systematic review and meta‐analysis
Authors: Lei Jiedi , Charman Tony , Leigh Eleanor , Russell Ailsa , Mohamed Zameer , Hollocks Matthew J.
Published: October 2022

Compared to neurotypical peers, autistic adolescents show greater cognitive inflexibility (CI) which manifests at the behavioral and cognitive level and potentially increases vulnerability for the development of internalizing (INT) and externalizing (EXT) symptoms. This systematic review and meta‐analysis explored the association between CI and INT/EXT in autistic adolescents. PubMed, EMBASE, MEDLINE, PsycINFO and Web of Science databases were searched to identify relevant studies until April 2022 (PROSPERO protocol: CRD42021277294). Systematic review included 21 studies (n = 1608) of CI and INT, and 15 studies (n = 1115) of CI and EXT. A pooled effect size using Pearson's correlation between CI and INT/EXT was calculated and the moderating effects of age, sex, IQ and study quality were investigated using meta‐regressions. Sensitivity analyses were completed to investigate the impact of measure variance for CI and co‐occurring ADHD on the overall effects. Greater CI is associated with increased INT (nine studies; n = 833; r = 0.39 (moderate effect), 95% confidence interval [0.32, 0.46]) and EXT (six studies; n = 295; r = 0.48 (large effect), 95% confidence interval [0.38, 0.58]). Results withheld when only using parental reports of CI and excluding autistic adolescents with co‐occurring ADHD. Increased CI may be a transdiagnostic vulnerability factor that can increase autistic adolescents' rigid or perseverative patterns of unhelpful cognition and behaviors and reduce their ability to access psychological interventions. Addressing CI may improve autistic children and adolescents' engagement with psychological therapy for co‐occurring mental health difficulties.
Origin, production and molecular determinants of macrophages for their therapeutic targeting
Authors: Chowdhury Sangita , Trivedi Arun K.
Published: October 2022

Macrophages, the most heterogeneous cells of the hematopoietic system and the giant eaters of the immune system that present either as tissue‐resident cells or infiltrated immune cells, eliminate foreign pathogens and microbes and also play different physiological roles to maintain the body's immune response. In this review, we basically provide a broad overview of macrophages from their origin, functional diversity to M1‐M2 polarization, specialized markers, and their role as important therapeutic targets in different diseases based on the current research and evidence. Apart from this, we have precisely discussed about tumor‐associated macrophages (TAMs) and their role in tumor progression and newly discovered lesser‐known markers of TAMs that could be used as potential therapeutic targets to treat life‐threatening diseases. It is really very important to understand the diversity of macrophages to develop TAM‐modulating strategies to activate our own immune system against diseases and to overcome immune resistance.
The effect of mesenchymal stem cells and imatinib on macrophage polarization in rat model of liver fibrosis
Authors: Malmir Ali , Farivar Shirin , Rezaei Ramazan , Tokhanbigli Samaneh , Hatami Behzad , Mazhari Sogol , Baghaei Kaveh
Published: October 2022

Liver fibrosis is a disorder in which inflammatory reactions play an important role, and central to the progression and pathogenesis of this disease are the immune‐specific cells known as macrophages. Macrophage types are distinguished from each other by the expression of a series of surface markers. STAT6 and Arg1 play an important role in the polarization of macrophages, so these two factors are downstream of interleukin 4 (IL‐4) and IL‐13 cytokines and cause to differentiate M2. Therefore, this study aimed to compare the independent effects of imatinib and mesenchymal cell treatment on the polarization of macrophages in rat models of liver fibrosis. The liver fibrosis was induced by the injection of CCL4 for 6 weeks in Sprague–Dawley rats. Then, rats were divided into four different groups, and the effects of imatinib and mesenchymal cells on the expression of Arg1, Ly6c, and STAT6 were evaluated. Histopathology experiments considered the amelioration effect of treatments. Our results showed that Arg1 expression was significantly increased in the groups treated with mesenchymal cells and imatinib compared to the control group. On the other hand, expression of STAT6 was significantly increased in the imatinib‐treated mice compared to mesenchymal and control groups. Moreover, the expression of LY6C significantly decreased in imatinib and mesenchymal treated groups compared to the control group. Therefore, our data showed that mesenchymal stem cells and imatinib significantly modulate the fibrotic process in rat models of fibrosis, probably by polarizing macrophages towards an anti‐inflammatory profile and increasing the frequency of these cells in liver tissue.
Retinoic acid receptor gamma is required for proliferation of pancreatic cancer cells
Authors: Ji Kaiyuan , Dou Wenlong , Zhang Ningfang , Wen Bolun , Zhong Mingyan , Zhang Qianbing , Xu Shuxiang , Zhou Jianlong , Liu Jingfeng
Published: October 2022

Despite the expectation that retinoic acid receptor could be the potential therapeutic targets for pancreatic cancers, there has been the lack of information about the role and the impact of retinoic acid receptor gamma (RARγ, RARG) on pancreatic cancer, unlike other two RARs. Herein, we applied TCGA and GEO database to show that the expression and prognosis of RARG is closely related to pancreatic cancer, which demonstrates that RARG is commonly overexpressed in human pancreatic cancer and is an independent diagnostic marker predicting the poor prognosis of pancreatic cancer patients. In addition, we demonstrated that the reduction in the expression of RARG in human pancreatic cancer cells dramatically suppress their proliferation and tumor growth in vivo, partially attributable to the downregulation of tumor‐supporting biological processes such as cell proliferation, antiapoptosis and metabolism and the decreased expression of various oncogenes like MYC and STAT3. Mechanistically, RARG binds on the promoters of MYC, STAT3, and SLC2A1 which is distinguished from well‐known conventional Retinotic acid response elements (RAREs) and that the binding is likely to be responsible for the epigenetic activation in the level of chromatin, assessed by the measurement of deposition of the gene activation marker histone H3 K27 acetylation (H3K27ac) using ChIP‐qPCR. In this study, we reveal that RARG plays important role in the tumorigenesis of pancreatic cancer and represents new therapeutic targets for human pancreatic cancer.
Diagnostic ultrasound‐mediated microbubble cavitation dose‐dependently improves diabetic cardiomyopathy through angiogenesis
Authors: Zhou Nan‐Qian , Song Yu‐Ting , Liu Wei‐Zhen , Yue Rui‐Zhu , Tian Xin‐Qiao , Yang Shi‐Chang , Yin Ya‐Ling , Li Peng
Published: October 2022

Ultrasound‐mediated microbubble cavitation (UMMC) induces therapeutic angiogenesis to treat ischemic diseases. This study aimed to investigate whether diagnostic UMMC alleviates diabetic cardiomyopathy (DCM) and, if so, through which mechanisms. DCM model was established by injecting streptozocin into rats to induce hyperglycemia, followed by a high‐fat diet. The combined therapy of cation microbubble with low‐intensity diagnostic ultrasound (frequency = 4 MHz), with a pulse frequency of 20 Hz and pulse length (PL) of 8, 18, 26, or 36 cycles, was given to rats twice a week for 8 consecutive weeks. Diagnostic UMMC therapy with PL at 8, 18, and 26 cycles, but not 36 cycles, dramatically prevented myocardial fibrosis, improved heart functions, and increased angiogenesis, accompanied by increased levels of PI3K, Akt, and eNOS proteins in the DCM model of rats. In cultured endothelial cells, low‐intensity UMMC treatment (PL = 3 cycles, sound pressure level = 50%, mechanical index = 0.82) increased cell viability and activated PI3K‐Akt‐eNOS signaling. The combination of diagnostic ultrasound with microbubble destruction dose‐dependently promoted angiogenesis, thus improving heart function through PI3K‐Akt‐eNOS signaling in diabetes. Accordingly, diagnostic UMMC therapy should be considered to protect the heart in patients with diabetes.
The diagnostic and prognostic value of pseudogene SIGLEC17P in lung adenocarcinoma and a preliminary functional study
Authors: Shen Xiuqing , Zeng Yanfen , Yang Caihong , Jiang Lili , Chen Shaoting , Chen Falin , Cao Pengju
Published: October 2022

Among malignant tumors, lung adenocarcinoma (LUAD) is the leading cause of death worldwide. This study explored the diagnostic, prognostic value, and preliminary functional verification of sialic acid binding Ig like lectin 17, pseudogene (SIGLEC17P) in LUAD. Prognostic lncRNAs for LUAD were identified by The Cancer Genome Atlas and quantitative real‐time PCR (qRT‐PCR) was used to detect the expression of SIGLEC17P in LUAD and paracarcinoma tissues. Subsequently, lentiviral vectors were used to overexpress SIGLEC17P in A549 and H1299 cells. The effects of SIGLEC17P overexpression on the proliferation, migration, and invasiveness of LUAD cells (A549 and H1299) were evaluated by Cell Counting Kit‐8, wound healing, and transwell migration assays, respectively. Bioinformatics analyses were performed to reveal the potential pathways in which SIGLEC17P is involved in LUAD. qRT‐PCR results revealed low SIGLEC17P expression in LUAD tissues and a significant association with the N stage, T stage, and tumor node metastasis stage. Furthermore, the receiver operating characteristic curve demonstrated a reliable diagnostic value. The proliferation, migration, and invasion of LUAD cells were inhibited by overexpression of SIGLEC17P. Bioinformatics analyses suggested that SIGLEC17P might exert antioncogenic effects in LUAD through the mir‐20‐3p/ADH1B or mir‐4476‐5p/DPYSL axis. In summary, our results revealed that SIGLEC17P acts as a prognostic biomarker, independent prognostic factor, and potential therapeutic target for patients with LUAD.
HELQ suppresses migration and proliferation of non‐small cell lung cancer cells by repairing DNA damage and inducing necrosis
Authors: Zhong Nan Shan , Tong Wei Lai , Zhang Yu , Xiao Shi Ning , Liu Jia Ming , Li An An , Yao Ge Liang , Lin Qing , Liu Zhi Li
Published: October 2022

HELQ plays a key role in DNA damage response and cell‐cycle checkpoint regulation. It has been implicated in ovarian and pituitary tumors and may play a role in germ cell maintenance. This study investigated the role of HELQ in lung cancer. The expression of HELQ in patients with non‐small‐cell lung cancer (NSCLC) was downregulated compared with normal human lungs. Clinical prognostic analysis of Kaplan–Meier plots revealed that patients with NSCLC with low HELQ levels had a reduced overall survival. Further, we found that HELQ depletion enhanced lung cancer cell malignancy. Furthermore, overexpression of HELQ in lung cancer cells reduced cell migration in vitro, while DNA damage repair was inhibited. Both in vitro and in vivo studies have shown that HELQ induces cell death. Mechanistically, we found that cells overexpressing HELQ showed a tendency to induce necrosis. After analyzing the database of HELQ interactors. we found that RIPK3 may interact with it and proved this conclusion by immunoprecipitation. Our findings identified the tumor suppressive role of HELQ in malignant human lung cancer and unraveled a potential therapeutic strategy for cancer treatment through HELQ activation. Moreover, HELQ may also be a predictive biomarker for the clinical predisposition, progression, and prognosis of lung cancer.