Diversity-Oriented Catalytic Asymmetric Dearomatization of Indoles with o-Quinone Diimides.

Herein, the first diversity-oriented catalytic asymmetric dearomatization of indoles with o-quinone diimides (o-QDIs) is reported. The catalytic asymmetric dearomatization (CADA) of indoles is one of the research focuses in terms of the structural and biological importance of dearomatized indole derivatives. Although great achievements have been made in target-oriented CADA reactions, diversity-oriented CADA reactions are regarded as more challenging and remain elusive due to the lack of synthons featuring multiple reaction sites and the difficulty in precise control of chemo-, regio-, and enantio-selectivity. In this work, o-QDIs are employed as a versatile building block, enabling the chemo-divergent dearomative arylation and [4 + 2] cycloaddition reactions of indoles. Under the catalysis of chiral phosphoric acid and mild conditions, various indolenines, furoindolines/pyrroloindolines, and six-membered-ring fused indolines are collectively prepared in good yields with excellent enantioselectivities. This diversity-oriented synthesis protocol enriches the o-quinone chemistry and offers new opportunities for CADA reactions.

The Yeast and Hypha Phases of Candida krusei Induce the Apoptosis of Bovine Mammary Epithelial Cells via Distinct Signaling Pathways.

Infection with Candida spp. is a significant cause of bovine mastitis globally. We previously found that C. krusei was the main pathogen causing mycotic mastitis in dairy cows in Yinchuan, Ningxia, China. However, whether the infection of this pathogen could induce apoptosis in BMECs remained unclear. In this report, we explored the apoptosis and underlying mechanism of BMECs induced by C. krusei yeast and hypha phases using a pathogen/host cell co-culture model. Our results revealed that both the yeast and hypha phases of C. krusei could induce BMEC apoptosis; however, the yeast phase induced more cell apoptosis than the hypha phase, as assessed via electronic microscopy and flow cytometry assays. This finding was further corroborated via the measurement of the mitochondrial membrane potential (MMP) and the TUNEL test. Infection by both the yeast and hypha phases of C. krusei greatly induced the expression of proteins associated with cell death pathways and important components of toll-like receptor (TLR) signaling, including TLR2 and TLR4 receptors, as determined via a Western blotting assay. BMECs mainly underwent apoptosis after infection by the C. krusei yeast phase through a mitochondrial pathway. Meanwhile, BMEC apoptosis induced by the C. krusei hypha phase was regulated by a death ligand/receptor pathway. In addition, C. krusei-induced BMEC apoptosis was regulated by both the TLR2/ERK and JNK/ERK signaling pathways. These data suggest that the yeast phase and hypha phase of C. krusei induce BMEC apoptosis through distinct cell signaling pathways. This study represents a unique perspective on the molecular processes underlying BMEC apoptosis in response to C. krusei infection.

Zn-ProPhenol catalyzed asymmetric inverse-electron-demand Diels-Alder reaction.

The first Zn-ProPhenol catalyzed asymmetric inverse-electron-demand Diels-Alder reaction has been accomplished. This protocol was carried out by a dual-activation mode under mild conditions, allowing the preparation of various biologically important dihydropyrans in good yields with excellent stereoselectivities.

Catalytic asymmetric de novo construction of 4-pyrrolin-2-ones via intermolecular formal [3+2] cycloaddition of azoalkenes with azlactones.

The chiral phosphoric acid-catalyzed asymmetric intermolecular formal [3+2] cycloaddition of azoalkenes with azlactones has been established. This convergent protocol leads to a facile and enantioselective de novo construction of a wide range of fully substituted 4-pyrrolin-2-ones bearing a fully substituted carbon atom in good yields and with excellent enantioselectivities (26 examples, 72-95% yields and 87-99% ee).

A dandelion-like nanomedicine via hierarchical self-assembly for synergistic chemotherapy and photo-dynamic cancer therapy.

The synergistic effect of chemotherapy and photo-dynamic therapy (PDT) is an effective way to improve the efficiency of tumor treatment. However, most synergistic therapeutic drugs have poor water solubility and stability, so it is difficult to achieve high therapeutic effects while avoiding the severe side effects. Herein, a unique dandelion-like nanomedicine (named as cRGDfk-CCPT-mCe6) was successfully synthesized using Ce6-loaded amphiphilic ß-cyclodextrins (ß-CD) doped lipid-based vesicles as the core (receptacle) and ß-CD modified camptothecin (CPT) pro-drug as the flyable dandelion seeds. The ß-CD modified CPT pro-drug was introduced into the core vesicles in succession via host-guest interaction between inter-molecular ß-CD and CPT, and cRGDfk peptides were further introduced as the outermost layer (stigma) to enhance the internalization into cancer cells. CPT interacted with ß-CD through glutathione (GSH)-cleavable disulfide bonds, which led to drug release in glutathione-rich cancer cells, just as spread of dandelion seeds in the wind. GSH consumption further disrupted the intracellular redox homeostasis of cancer cells through combined action of Ce6 with light irradiation and the synergistic anti-tumor effect was thus achieved, resulting in apoptosis of cancer cells. Therefore, the nanomedicine provides a facile and versatile anti-tumor strategy, as well as a persistent anti-cancer effects.

Catalytic asymmetric inverse-electron-demand aza-Diels-Alder reaction of 1,3-diazadienes with 3-vinylindoles.

A facile chiral phosphoric-acid catalyzed asymmetric inverse-electron-demand aza-Diels-Alder reaction of 1,3-diazadienes with 3-vinylindoles was established. By using this mild and practical protocol, a broad range of benzothiazolopyrimidines with three contiguous stereogenic centers were prepared in good yields and excellent diastereo- and enantio-selectivities (43 examples, up to 83% yield, >99% ee and all >20 : 1 dr). A plausible concerted reaction pathway enabled by the dual hydrogen-bonding effect was proposed to account for the observed excellent enantioselectivity and specific trans-trans diastereoselectivity.

Natural source, bioactivity and synthesis of 3-Arylcoumarin derivatives.

3-arylcoumarins with different pharmacological properties widely exist in a variety of natural plants. The extensive research on 3-arylcoumarins was attributed to its therapeutic and relatively easy isolation. Therefore, 3-arylcoumarins can be recognised as useful structures for the design of novel compounds with potential pharmacological interest, particularly in the fields of anti-inflammatory, anti-cancer, antioxidant, Monoamine oxidase (MAO) enzyme inhibition, etc. The current review highlights the biological activities, design, and chemical synthetic methods of 3-arylcoumarins derivatives as well as their important natural product sources.

Synthesis and biological evaluation of 2-arylbenzofuran derivatives as potential anti-Alzheimer's disease agents.

Alzheimer's disease (AD) is a type of progressive dementia caused by degeneration of the nervous system. A single target drug usually does not work well. Therefore, multi-target drugs are designed and developed so that one drug can specifically bind to multiple targets to ensure clinical effectiveness and reduce toxicity. We synthesised a series of 2-arylbenzofuran derivatives and evaluated their in vitro activities. 2-Arylbenzofuran compounds have good dual cholinesterase inhibitory activity and ß-secretase inhibitory activity. The IC50 value of compound 20 against acetylcholinesterase inhibition (0.086 ± 0.01 µmol·L-1) is similar to donepezil (0.085 ± 0.01 µmol·L-1) and is better than baicalein (0.404 ± 0.04 µmol·L-1). And most of the compounds have good BACE1 inhibitory activity, of which 3 compounds (8, 19 and 20) show better activity than baicalein (0.087 ± 0.03 µmol·L-1). According to experimental results, 2-arylbenzofuran compounds provide an idea for drug design to develop prevention and treatment for AD.

Synthesis and anti-rheumatoid arthritis activities of 3-(4-aminophenyl)-coumarin derivatives.

Rheumatoid arthritis is a chronic systemic disease characterised by an unknown aetiology of inflammatory synovitis. A large number of studies have shown that synoviocytes show tumour-like dysplasia in the pathological process of RA, and the changes in the expression of related cytokines are closely related to the pathogenesis of RA. In this thesis, a series of novel 3-(4-aminophenyl) coumarins containing different substituents were synthesised to find new coumarin anti-inflammatory drugs for the treatment of rheumatoid arthritis. The results of preliminary activity screening showed that compound 5e had the strongest inhibitory activity on the proliferation of fibroid synovial cells, and it also had inhibitory effect on RA-related cytokines IL-1, IL-6, and TNF-α. The preliminary mechanism study showed that compound 5e could inhibit the activation of NF-κB and MAPKs signal pathway. The anti-inflammatory activity of compound 5e in vivo was further determined in the rat joint inflammation model.

Recent advances in the biomedical applications of black phosphorus quantum dots.

Zero-dimensional (0D) black phosphorus quantum dots (BPQDs), the new derivatives of black phosphorus (BP) nanomaterials, have attracted considerable attention since they were first prepared in 2015. Compared to traditional two-dimensional (2D) BP nanosheets, BPQDs exhibit some unique properties and demonstrate great potential for a broad range of applications, especially in the field of biomedicine. Due to the rapid development and substantial research interest in this area, it is urgent to review the current advances, challenges and near-future possibilities of BPQD-related biomedical research, which will benefit the further development of this field. This review is mainly focused on the latest progress of BPQD related applications in the biomedical field, including photothermal therapy (PTT), photodynamic therapy (PDT), drug delivery, biological imaging, etc. The challenges and future prospects are also discussed.

Synthesis and biological evaluation of 3-arylbenzofuranone derivatives as potential anti-Alzheimer's disease agents.

Multi-target drugs can better address the cascade of events involved in oxidative stress and the reduction in cholinergic transmission that occur in Alzheimer's disease than cholinesterase inhibitors alone. We synthesised a series of 3-arylbenzofuranone derivatives and evaluated their antioxidant activity, cholinesterase inhibitory activity, and monoamine oxidase inhibitory activity. 3-Arylbenzofuranone compounds exhibit good antioxidant activity as well as selective acetylcholinesterase inhibitory activity. The IC50 value of anti-acetylcholinesterase inhibition of Compound 20 (0.089 ± 0.01 µM) is similar to the positive drug donepezil (0.059 ± 0.003 µM). According to the experimental results, Compounds 7, 13 show a certain effect in the in vitro evaluation performed and have the potential as drug candidates for the treatment of Alzheimer's disease.

Synthesis and biological evaluation of 4-arylcoumarins as potential anti-Alzheimer's disease agents.

Alzheimer's disease (AD) is a progressive neurological degenerative disease that has complex pathogenesis. A variety of studies in humans indicate that several enzymes inhibitors can be useful in the treatment of AD, including acetylcholinesterase (AchE), butyrylcholinesterase (BuChE) and monoamine oxidase (MAO). Various substituted 4-arylcoumarin derivatives were synthesised, and their activity in vitro were investigated, including AChE/BuChE inhibitory activity, MAO inhibitory activity, and antioxidant activity. Most of the compounds were found to exhibit high inhibitory activity, and individual compounds have extremely excellent activities. Therefore 4-arylcoumarins provides an idea for drugs design for the development of therapeutic or preventive agents for AD.

Dinuclear zinc cooperative catalytic three-component reactions for highly enantioselective synthesis of 3,3'-dihydrofuran spirooxindoles.

A new dinuclear zinc cooperative catalytic enantioselective three-component reaction via a domino Knoevenagel /Michael/cyclization sequence has been developed. A series of chiral 3,3'-dihydrofuran spirooxindoles are obtained in excellent yields (up to 99%) and enantioselectivities (up to 99% ee). In addition, the reaction is carried out smoothly on a gram scale under mild conditions.

Dinuclear Zinc-AzePhenol Catalyzed Asymmetric Aza-Henry Reaction of N-Boc Imines and Nitroalkanes under Ambient Conditions.

The asymmetric aza-Henry reaction of N-Boc imines and nitroalkanes was realized in the presence of 10 mol % dinuclear zinc-AzePhenol catalysts under ambient conditions. A variety of nitroamines were obtained in good yields (up to 97%) with excellent enantioselectivities (up to 99% ee) and high diasteroselectivity (up to 14:1 dr). Our protocol combined the operational simplicity and mild reaction conditions, thus making the process amenable for technical applications.

Natural source, bioactivity and synthesis of benzofuran derivatives.

Benzofuran compounds are a class of compounds that are ubiquitous in nature. Numerous studies have shown that most benzofuran compounds have strong biological activities such as anti-tumor, antibacterial, anti-oxidative, and anti-viral activities. Owing to these biological activities and potential applications in many aspects, benzofuran compounds have attracted more and more attention of chemical and pharmaceutical researchers worldwide, making these substances potential natural drug lead compounds. For example, the recently discovered novel macrocyclic benzofuran compound has anti-hepatitis C virus activity and is expected to be an effective therapeutic drug for hepatitis C disease; novel scaffold compounds of benzothiophene and benzofuran have been developed and utilized as anticancer agents. Novel methods for constructing benzofuran rings have been discovered in recent years. A complex benzofuran derivative is constructed by a unique free radical cyclization cascade, which is an excellent method for the synthesis of a series of difficult-to-prepare polycyclic benzofuran compounds. Another benzofuran ring constructed by proton quantum tunneling has not only fewer side reactions, but also high yield, which is conducive to the construction of complex benzofuran ring systems. This review summarizes the recent studies on the various aspects of benzofuran derivatives including their important natural product sources, biological activities and drug prospects, and chemical synthesis, as well as the relationship between the bioactivities and structures.