“… Most transition‐metal catalysts and organocatalysts do not meet the requirements for modern industrial manufacturing processes. Their main limitation is low efficiency. The need to develop highly ...efficient catalysts and related catalytic reactions is a never‐ending challenge in synthetic chemistry …” Read more in the Editorial by Qi‐Lin Zhou.
Lung cancer is the second most prevalent and the deadliest among all cancer types. Chemotherapy is recommended for lung cancers to control tumor growth and to prolong patient survival. Systemic ...chemotherapy typically has very limited efficacy as well as severe systemic adverse effects, which are often attributed to the distribution of anticancer drugs to non-targeted sites. In contrast, inhalation routes permit the delivery of drugs directly to the lungs providing high local concentrations that may enhance the anti- tumor effect while alleviating systemic adverse effects. Preliminary studies in animals and humans have suggested that most inhaled chemotherapies are tolerable with manageable pulmonary adverse effects, including cough and bronchospasm, Promoting the deposition of anticancer drugs in tumorous cells and minimizing access to healthy lung cells can further augment the efficacy and reduce the risk of local toxicities caused by inhaled chemotherapy. Sustained release and tumor localization characteristics make nanoparticle formulations a promising candidate for the inhaled delivery of chemotherapeutic agents against lung cancers. However, the physiology of respiratory tracts and lung clearance mechanisms present key barriers for the effective deposition and retention of inhaled nanoparticle formulations in the lungs. Recent research has focused on the development of novel formulations to maximize lung deposition and to minimize pulmonary clearance of inhaled nanoparticles. This article systematically reviews the challenges and opportunities for the pulmonary delivery of nanoparticle formulations for the treatment of lung cancers.
Carbon–heteroatom bonds (C–X) are ubiquitous and are among the most reactive components of organic compounds. Therefore investigations of the construction of C–X bonds are fundamental and vibrant ...fields in organic chemistry. Transition-metal-catalyzed heteroatom–hydrogen bond (X–H) insertions via a metal carbene or carbenoid intermediate represent one of the most efficient approaches to form C–X bonds. Because of the availability of substrates, neutral and mild reaction conditions, and high reactivity of these transformations, researchers have widely applied transition-metal-catalyzed X–H insertions in organic synthesis. Researchers have developed a variety of rhodium-catalyzed asymmetric C–H insertion reactions with high to excellent enantioselectivities for a wide range of substrates. However, at the time that we launched our research, very few highly enantioselective X–H insertions had been documented primarily because of a lack of efficient chiral catalysts and indistinct insertion mechanisms. In this Account, we describe our recent studies of copper- and iron-catalyzed asymmetric X–H insertion reactions by using chiral spiro-bisoxazoline and diimine ligands. The copper complexes of chiral spiro-bisoxazoline ligands proved to be highly enantioselective catalysts for N–H insertions of α-diazoesters into anilines, O–H insertions of α-diazoesters into phenols and water, O–H insertions of α-diazophosphonates into alcohols, and S–H insertions of α-diazoesters into mercaptans. The iron complexes of chiral spiro-bisoxazoline ligands afforded the O–H insertion of α-diazoesters into alcohols and water with unprecedented enantioselectivities. The copper complexes of chiral spiro-diimine ligands exhibited excellent reactivity and enantioselectivity in the Si–H insertion of α-diazoacetates into a wide range of silanes. These transition-metal-catalyzed X–H insertions have many potential applications in organic synthesis because the insertion products, including chiral α-aminoesters, α-hydroxyesters, α-hydroxyphosphonates, α-mercaptoesters, and α-silyl esters, are important building blocks for the synthesis of biologically active compounds. The electronic properties of α-diazoesters and anilines markedly affected the enantioselectivity of N–H insertion reaction, which supports a stepwise ylide insertion mechanism. A novel binuclear spiro copper complex was isolated and fully characterized using X-ray diffraction analysis and ESI-MS analysis. The positive nonlinear effect indicated that binuclear copper complexes were the catalytically active species. The 14-electron copper centers, trans coordination model, perfect C 2-symmetric chiral pocket, and Cu–Cu interaction facilitate the performance of the chiral spiro catalysts in X–H insertion reactions.
Chiral carboxylic acid moieties are widely found in pharmaceuticals, agrochemicals, flavors, fragrances, and health supplements. Although they can be synthesized straightforwardly by ...transition-metal-catalyzed enantioselective hydrogenation of unsaturated carboxylic acids, because the existing chiral catalysts have various disadvantages, the development of new chiral catalysts with high activity and enantioselectivity is an important, long-standing challenge. Ruthenium complexes with chiral diphosphine ligands and rhodium complexes with chiral monodentate or bidentate phosphorus ligands have been the predominant catalysts for asymmetric hydrogenation of unsaturated acids. However, the efficiency of these catalysts is highly substrate-dependent, and most of the reported catalysts require a high loading, high hydrogen pressure, or long reaction time for satisfactory results. Our recent studies have revealed that chiral iridium complexes with chiral spiro-phosphine-oxazoline ligands and chiral spiro-phosphine-benzylamine ligands exhibit excellent activity and enantioselectivity in the hydrogenation of α,β-unsaturated carboxylic acids, including α,β-disubstituted acrylic acids, trisubstituted acrylic acids, α-substituted acrylic acids, and heterocyclic α,β-unsaturated acids. On the basis of an understanding of the role of the carboxy group in iridium-catalyzed asymmetric hydrogenation reactions, we developed a carboxy-group-directed strategy for asymmetric hydrogenation of olefins. Using this strategy, we hydrogenated several challenging olefin substrates, such as β,γ-unsaturated carboxylic acids, 1,1-diarylethenes, 1,1-dialkylethenes, and 1-alkyl styrenes in high yield and with excellent enantioselectivity. All these iridium-catalyzed asymmetric hydrogenation reactions feature high turnover numbers (up to 10000) and turnover frequencies (up to 6000 h–1), excellent enantioselectivities (greater than 95% ee with few exceptions), low hydrogen pressure (<12 atm), and operational simplicity. These features make chiral iridium catalysts superior or comparable to well-established chiral ruthenium and rhodium catalysts for asymmetric hydrogenation of unsaturated carboxylic acids. A number of chiral natural products and pharmaceuticals have been prepared by concise routes involving an iridium-catalyzed asymmetric hydrogenation of an unsaturated carboxylic acid as a key step. As part of a mechanistic study of iridium-catalyzed asymmetric hydrogenation of unsaturated acids, we isolated, for the first time, the migratory insertion intermediate in the iridium-catalyzed asymmetric hydrogenation of olefins, and this result strongly supports the involvement of an Ir(III)/Ir(V) catalytic cycle. The rigid, bulky scaffold of the chiral spiro-P,N-ligands of the catalysts not only prevents them from undergoing deactivating aggregation under the hydrogenation conditions but also is responsible for the efficient chiral induction. The carboxy group of the substrate acts as an anchor to ensure coordination of the substrate to the iridium center of the catalyst during the reaction and makes the hydrogenation proceed smoothly.
Antibiotic resistance is a major global health challenge and, worryingly, several key Gram negative pathogens can become resistant to most currently available antibiotics. Polymyxins have been ...revived as a last-line therapeutic option for the treatment of infections caused by multidrug-resistant Gram negative bacteria, in particular
,
, and Enterobacterales. Polymyxins were first discovered in the late 1940s but were abandoned soon after their approval in the late 1950s as a result of toxicities (e.g., nephrotoxicity) and the availability of "safer" antibiotics approved at that time. Therefore, knowledge on polymyxins had been scarce until recently, when enormous efforts have been made by several research teams around the world to elucidate the chemical, microbiological, pharmacokinetic/pharmacodynamic, and toxicological properties of polymyxins. One of the major achievements is the development of the first scientifically based dosage regimens for colistin that are crucial to ensure its safe and effective use in patients. Although the guideline has not been developed for polymyxin B, a large clinical trial is currently being conducted to optimize its clinical use. Importantly, several novel, safer polymyxin-like lipopeptides are developed to overcome the nephrotoxicity, poor efficacy against pulmonary infections, and narrow therapeutic windows of the currently used polymyxin B and colistin. This review discusses the latest achievements on polymyxins and highlights the major challenges ahead in optimizing their clinical use and discovering new-generation polymyxins. To save lives from the deadly infections caused by Gram negative "superbugs," every effort must be made to improve the clinical utility of the last-line polymyxins. SIGNIFICANCE STATEMENT: Antimicrobial resistance poses a significant threat to global health. The increasing prevalence of multidrug-resistant (MDR) bacterial infections has been highlighted by leading global health organizations and authorities. Polymyxins are a last-line defense against difficult-to-treat MDR Gram negative pathogens. Unfortunately, the pharmacological information on polymyxins was very limited until recently. This review provides a comprehensive overview on the major achievements and challenges in polymyxin pharmacology and clinical use and how the recent findings have been employed to improve clinical practice worldwide.
Rearrangement reactions have attracted considerable interest over the past decades due to their high bond-forming efficiency and atom economy in the construction of complex organic architectures. In ...contrast to the well-established 3,3-rearrangement, 1,3 O-to-C rearrangement has been far less vigorously investigated, and stereospecific 1,3-rearrangement is extremely rare. Here, we report a metal-free intramolecular hydroalkoxylation/1,3-rearrangement, leading to the practical and atom-economical assembly of various valuable medium-sized lactams with wide substrate scope and excellent diastereoselectivity. Moreover, such an asymmetric cascade cyclization has also been realized by chiral Brønsted acid-catalyzed kinetic resolution. In addition, biological tests reveal that some of these medium-sized lactams displayed their bioactivity as antitumor agents against melanoma cells, esophageal cancer cells and breast cancer cells. A mechanistic rationale for the reaction is further supported by control experiments and theoretical calculations.
Transition metal-catalyzed carbene insertion into X-H bonds (X = N, O, S, and C) represents a typical carbene transfer reaction and has been widely used in organic synthesis. The ...enantioselectivity-determining step in some of these insertion reactions is the proton transfer of active intermediates such as ylides, metal enolates, or free enols. Since most of the traditional chiral transition metal catalysts tend to dissociate from these active intermediates and cannot be involved in the proton-transfer step, enantiocontrol of these insertion reactions has long been a challenging task. Since 2011, we have developed chiral spiro phosphoric acids as chiral proton-transfer shuttle (CPTS) catalysts, which have been proven to be efficient catalysts for the proton transfer of active intermediates in carbene insertion reactions. Upon combining with achiral dirhodium catalysts, the CPTS catalysts accomplish highly enantioselective insertions of N-H, S-H, and C-H bonds. Herein, a number of important chiral building blocks, including α-amino acid derivatives, α-amino ketones, α-thioesters, and α,α-diaryl acetates, were prepared with high yields and high enantioselectivities through these insertion reactions.
The development of chiral proton-transfer shuttles provides a totally new enantiocontrol strategy for transition metal-catalyzed asymmetric carbene insertion reactions.
Purpose
Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water ...solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution.
Methods
The produced powder formulations were characterized regarding particle size, morphology, surface composition and
in-vitro
aerosolization performance. Effects of L-leucine on the solubility and
in-vitro
dissolution of azithromycin were also evaluated.
Results
The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced
in-vitro
dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations.
Conclusions
We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.
Internet of Things (IoT) is being widely developed in various fields, and its penetration rate in daily life is continuously increasing. The nature of the social function of objects and giving them ...an identity has made it possible to successfully integrate this technology into many traditional systems and improve their performance by automation. Libraries are one of the most obvious examples of smartening by IoT architecture. So far, various architectures have been presented for smartening libraries through IoT technology. However, a low-cost and ideal architecture that can cover all the requirements in a wide range of smart library applications has not been provided. This article attempts to fill some of the existing research gaps in this field by presenting a new architecture for smartening libraries. In the proposed method, Software Defined Networking (SDN) is used to reduce implementation costs and improve the management process of network components. In this architecture, the communication platform of network active objects is formed based on a cluster-based topology. Also, passive Radio Frequency IDentification (RFID) tags are utilized to manage books and library property. Two stages of evaluation have been conducted for the suggested method's performance: actual deployment and computer simulations. Based on the findings, it can be concluded that this study has succeeded in creating an effective and affordable design for smart libraries, which is a major advancement over conventional libraries.
A Ni‐catalyzed hydroarylation of styrenes and 1,3‐dienes with organoboron compounds has been developed. The reaction offers a highly selective approach to diarylalkanes and allylarenes under ...redox‐neutral conditions. In this hydroarylation reaction, a new strategy that uses the proton of methanol to generate the active catalyst species Ni−H was developed. The Ni‐catalyzed hydroarylation, combined with a Ir‐catalyzed C−H borylation, affords a very efficient and straightforward access to a retinoic acid receptor agonist.
OH yeah: A nickel(0)‐catalyzed hydroarylation of alkenes with organoboron reagents using an alcohol OH group as the H‐atom source is reported. The reaction offers a highly selective approach to diarylalkanes and allylarenes under redox‐neutral conditions.
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