Tetrazine-Isonitrile Bioorthogonal Fluorogenic Reactions Enable Multiplex Labeling and Wash-Free Bioimaging of Live Cells.

Developing fluorogenic probes for simultaneous live cell labeling of multiple targets is crucial for understanding complex cellular events. The emerging [4+1] cycloaddition between tetrazine and isonitriles holds promise as a bioorthogonal tool, yet existing tetrazine probes lack reactivity and fluorogenicity. Here, we present the development of a series of tetrazine-functionalized bioorthogonal probes. By incorporating pyrazole adducts into the fluorophore scaffolds, the post-reacted probes displayed remarkable fluorescence turn-on ratios, up to 3184-fold. Moreover, these modifications are generalizable to various fluorophores, enabling a broad emission range from 473 to 659 nm. Quantum chemical calculations further elucidate the turn-on mechanisms. These probes enable the simultaneous labeling of multiple targets in live cells, without the need for a washing step. Consequently, our findings pave the way for advanced multiplex imaging and detection techniques for cellular studies.

Concise Synthesis of Functionalized Cyclobutene Analogues for Bioorthogonal Tetrazine Ligation.

Novel bioorthogonal tools enable the development of new biomedical applications. Here we report the concise synthesis of a series of aryl-functionalized cyclobutene analogues using commercially available starting materials. Our study demonstrates that cyclobutene acts as a small, strained dienophile to generate stable substrates suitable for bioorthogonal tetrazine ligation.

Ni-Catalyzed Suzuki-Miyaura Cross-Coupling of α-Oxo-vinylsulfones To Prepare C-Aryl Glycals and Acyclic Vinyl Ethers.

We demonstrate that readily available and bench-stable α-oxo-vinylsulfones are competent electrophiles in Ni-catalyzed Suzuki-Miyaura cross-coupling reactions. The C-sulfone bond in the α-oxo-vinylsulfone motif is cleaved chemoselectively in these reactions, furnishing C-aryl glycals or acyclic vinyl ethers in high yields. These reactions proceed under mild conditions and tolerate a remarkable scope of heterocycles and functional groups. Preliminary mechanistic studies revealed the importance of an α-heteroatom in facilitating these transformations.

Metal- and Base-Free Room-Temperature Amination of Organoboronic Acids with N-Alkyl Hydroxylamines.

We have found that readily available N-alkyl hydroxylamines are effective reagents for the amination of organoboronic acids in the presence of trichloroacetonitrile. This amination reaction proceeds rapidly at room temperature and in the absence of added metal or base, it tolerates a remarkable range of functional groups, and it can be used in the late-stage assembly of two complex units.

Streamlined Total Synthesis of Trioxacarcins and Its Application to the Design, Synthesis, and Biological Evaluation of Analogues Thereof. Discovery of Simpler Designed and Potent Trioxacarcin Analogues.

A streamlined total synthesis of the naturally occurring antitumor agents trioxacarcins is described, along with its application to the construction of a series of designed analogues of these complex natural products. Biological evaluation of the synthesized compounds revealed a number of highly potent, and yet structurally simpler, compounds that are effective against certain cancer cell lines, including a drug-resistant line. A novel one-step synthesis of anthraquinones and chloro anthraquinones from simple ketone precursors and phenylselenyl chloride is also described. The reported work, featuring novel chemistry and cascade reactions, has potential applications in cancer therapy, including targeted approaches as in antibody-drug conjugates.

[Study of neuronal spike-frequency adaptation with transcranial magneto-acoustical stimulation].

Transcranial magneto-acoustical stimulation (TMAS), utilizing focused ultrasound and a magnetostatic field to generate an electric current in tissue fluid to regulate the activities of neurons, has high spatial resolution and penetration depth. The neuronal spike-frequency adaptation plays an important role in the treatment of neural information. In this paper, we study the effects of ultrasonic intensity, magnetostatic field intensity and ultrasonic frequency on the neuronal spike-frequency adaptation based on the Ermentrout neuron model. The simulation results show that, the peak time interval becomes smaller, the interspike interval becomes shorter and the time of the firing of the neuron is shortened with the increasing of the magnetostatic field intensity. With the increase of the adaptive variables, the initial spike-frequency is shifted to the right with the magnetostatic field intensity, and the spike-frequency is linearly related to the increase of the magnetostatic field intensity in steady state. The simulation effect with change of the ultrasonic intensity is consistent with the change of magnetostatic field intensity. The change of the ultrasonic frequency has no effect on the neuronal spike-frequency adaptation. Under the different adaptive variables, with the increase of the adaptive variables, the initial spike-frequency amplitude decreased with the increasing of the ultrasonic frequency, and the spike-frequency is linearly related to the increase of the ultrasonic frequency in steady state. These results of the study can help us to reveal the mechanism of transcranial magneto-acoustical stimulation on the neuronal spike-frequency adaptation, and provide a theoretical basis for its application in the treatment of neurological disorders.

Total Synthesis of Trioxacarcins DC-45-A1, A, D, C, and C7″-epi-C and Full Structural Assignment of Trioxacarcin C.

Trioxacarcins DC-45-A2, DC-45-A1, A, D, C7″-epi-C, and C have been synthesized through stereoselective strategies involving BF3·Et2O-catalyzed ketone-epoxide opening and gold-catalyzed glycosylation reactions, and the full structural assignment of trioxacacin C was deciphered via the syntheses of both of its C7″ epimers. The gathered knowledge sets the foundation for the design, synthesis, and biological evalution of analogues of these natural products as potential payloads for antibody-drug conjugates and other delivery systems for targeted and personalized cancer chemotherapy.

Catalytic Asymmetric Umpolung Allylation of Imines.

Here we report an iridium-catalyzed asymmetric umpolung allylation of imines as a general approach to prepare 1,4-disubstituted homoallylic amines, a fundamental class of compounds that are hitherto not straightforward to obtain. This transformation proceeds by a cascade involving an intermolecular regioselective allylation of 2-azaallyl anions and a following 2-aza-Cope rearrangement, utilizes easily available reagents and catalysts, tolerates a substantial scope of substrates, and readily leads to various enantioenriched, 1,4-disubstituted homoallylic primary amines.

Pyrrolidine-mediated direct preparation of (e)-monoarylidene derivatives of homo- and heterocyclic ketones with various aldehydes.

An efficient method for the facile synthesis of (E)-monoarylidene derivatives of homo- and heterocyclic ketones with various aldehydes in the presence of a pyrrolidine organocatalyst has been achieved. A range of α,ß-unsaturated ketones were obtained in moderate to high yields (up to 99%). Unlike the Claisen-Schmidt condensation process, the formation of undesired bisarylidene byproducts is not observed. The possible reaction mechanism suggests that the reaction proceeds via a Mannich-elimination sequence.

Pretargeted radiotherapy and synergistic treatment of metastatic, castration-resistant prostate cancer using cross-linked, PSMA-targeted lipoic acid nanoparticles.

Metastatic castration-resistant prostate cancer (CRPC) is a currently incurable disease associated with high mortality. Novel therapeutic approaches for CRPC are urgently needed to improve prognosis. In this study, we developed cross-linked, PSMA-targeted lipoic acid nanoparticles (cPLANPs), which can interact with transmembrane glycoprotein to accumulate inside prostate cancer cells, where they upregulate caspase-3, downregulate anti-apoptotic B-cell lymphoma-2 (BCL-2), and thereby induce apoptosis. The trans-cyclooctene (TCO) decoration on cPLANPs acts as a bioorthogonal handle allowing pretargeted single-photon emission computed tomography and radiotherapy, which revealed significantly enhanced tumor accumulation and minimal off-target toxicity in our experiments. The developed strategy showed a strong synergistic anti-cancer effect in vivo, with a tumor inhibition rate of up to 95.6% after 14 days of treatment. Our results suggest the potential of combining bioorthogonal pretargeted radiotherapy with suitable PSMA-targeted nanoparticles for the treatment of metastatic CRPC.

Facile creation of 3-substituted-3-hydroxy-2-oxindoles by arginine-catalyzed aldol reactions of α,ß-unsaturated ketones with isatins.

An efficient approach for the synthesis of 3-substituted-3-hydroxy-2-oxindoles has been achieved via an aldol reaction of α,ß-unsaturated ketones and isatins using arginine as an organocatalyst. A range of 3-substituted-3-hydroxy-2-oxindoles were obtained in moderate to high (up to 99%) yields. These 3-substituted-3-hydroxy-2-oxindoles with an additional enone moiety provide an opportunity for further elaboration of the products and for potentially interesting biological activities. In addition, the formation of 3-substituted-3-hydroxy-2-oxindole 3a was confirmed by X-ray crystallography. The possible reaction mechanism reveals that the reaction proceeds via a double action process.

Foreign Body Granuloma Masquerading as Remnant Lymphoma on 18F-FDG PET/CT.

ABSTRACT: A 54-year-old man complained of a growing nodule in the left upper arm, which was diagnosed as diffuse large B-cell lymphoma by postsurgical pathology. For baseline assessment, FDG PET/CT revealed intense uptake in the left upper arm, in addition to FDG-avid pleura lesions and regional, axillary, cervical, and mediastinal lymph nodes. After chemotherapy, the restaging scan showed complete remission of most involved lesions except for increased activity in the prior surgical site. The patient eventually underwent surgical resection again, and the diagnosis was confirmed as foreign body granuloma.

Tuning the Physicochemical Properties of BODIPY for Bioimaging via meso-Amino Acylation.

A series of BODIPY probes with a wide emission range were prepared via aminoacylation at the meso-position. Functional moieties were also introduced to induce bathochromic shifts in emission, improve water solubility, increase Stokes shifts, and construct bioorthogonal turn-on probes. The developed analogues were successfully used in live-cell imaging, suggesting that the described strategy can be used to prepare probes with improved bioimaging potential.

Bioorthogonal Cleavage of Tetrazine-Caged Ethers and Esters Triggered by trans-Cyclooctene.

In this study, we report the bioorthogonal cleavage of physiologically stable methylene tetrazines bearing an ether or ester linkage in the presence of trans-cyclooctene. Based on this approach, molecules with phenol or carboxylic acid moieties were efficiently released in a controlled manner, which can be effectively applied in living cells. We expect this bioorthogonal cleavage approach can be applied to several biomedical applications, including the development of antibody-drug conjugates, pretargeted prodrug release, and protein activation.

Repurposed antipsychotic chlorpromazine inhibits colorectal cancer and pulmonary metastasis by inducing G2/M cell cycle arrest, apoptosis, and autophagy.

PURPOSE: Despite efforts in developing effective therapeutic strategies, colorectal cancer (CRC) remains one of the most prevalent and lethal neoplasms. Repurposing approved drugs is an alluring strategy for developing anticancer agents. Some antipsychotic drugs, including chlorpromazine (CPZ), possess anticancer activities. However, the pharmacological effects of CPZ on CRC have not been clearly established. METHODS: MTT assay, flow cytometry, western blotting analysis, subcutaneous mice tumor, and tail-vein-injection established lung metastasis model were used to investigate the anticancer effects of CPZ on CRC and the underlying mechanism. RESULTS: We found that CPZ effectively suppressed CRC by inducing G2/M cell cycle arrest and apoptosis. Cell cycle arrest was associated with decreased activities of the cdc2/cyclin B1 complex, including suppressed expression of cyclin B1, cdc2 and cdc25c, and elevated expression levels of phosphorylated cdc2 (Tyr15). Moreover, CPZ suppressed mitochondrial membrane potential and elevated reactive oxygen species levels in cancer cells, implying that it induces mitochondria-dependent intrinsic apoptosis. CPZ blocked the autophagic flux and induced cytotoxic autophagy in CRC cells. In addition, CPZ suppressed tumor growth in two subcutaneous mouse models without causing obvious side effects. Analysis of the abundance of immune cells in the tumor microenvironment revealed that CPZ did not have an effect on their proportions. Furthermore, it significantly suppressed the lung metastasis of CT26 cells and prolonged mice survival. CONCLUSION: These findings indicated that repurposing CPZ is a novel treatment strategy for CRC patients.

Liver Fibrosis: Therapeutic Targets and Advances in Drug Therapy.

Liver fibrosis is an abnormal wound repair response caused by a variety of chronic liver injuries, which is characterized by over-deposition of diffuse extracellular matrix (ECM) and anomalous hyperplasia of connective tissue, and it may further develop into liver cirrhosis, liver failure or liver cancer. To date, chronic liver diseases accompanied with liver fibrosis have caused significant morbidity and mortality in the world with increasing tendency. Although early liver fibrosis has been reported to be reversible, the detailed mechanism of reversing liver fibrosis is still unclear and there is lack of an effective treatment for liver fibrosis. Thus, it is still a top priority for the research and development of anti-fibrosis drugs. In recent years, many strategies have emerged as crucial means to inhibit the occurrence and development of liver fibrosis including anti-inflammation and liver protection, inhibition of hepatic stellate cells (HSCs) activation and proliferation, reduction of ECM overproduction and acceleration of ECM degradation. Moreover, gene therapy has been proved to be a promising anti-fibrosis method. Here, we provide an overview of the relevant targets and drugs under development. We aim to classify and summarize their potential roles in treatment of liver fibrosis, and discuss the challenges and development of anti-fibrosis drugs.