Search

Abstract Conventional bivalent antibodies against cell surface receptors often initiate unwanted signal transduction by crosslinking two antigen molecules. Biparatopic antibodies (BpAbs) bind to two different epitopes on the same antigen, thus altering crosslinking ability. In this study, we develop BpAbs against tumor necrosis factor receptor 2 (TNFR2), which is an attractive immune checkpoint target. Using different pairs of antibody variable regions specific to topographically distinct TNFR2 epitopes, we successfully regulate the size of BpAb–TNFR2 immunocomplexes to result in controlled agonistic activities. Our series of results indicate that the relative positions of the two epitopes recognized by the BpAb are critical for controlling its signaling activity. One particular antagonist, Bp109-92, binds TNFR2 in a 1:1 manner without unwanted signal transduction, and its structural basis is determined using cryo-electron microscopy. This antagonist suppresses the proliferation of regulatory T cells expressing TNFR2. Therefore, the BpAb format would be useful in designing specific and distinct antibody functions.

ABSTRACTFermented foods demonstrate remarkable health benefits owing to probiotic bacteria or microproducts produced via bacterial fermentation. Fermented foods are produced by the fermentative action of several lactic acid bacteria, including Leuconostoc mesenteroides; however, the exact mechanism of action of these foods remains unclear. Here, we observed that prebiotics associated with L. mesenteroides-produced exopolysaccharides (EPS) demonstrate substantial host metabolic benefits. L. mesenteroides-produced EPS is an indigestible α-glucan, and intake of the purified form of EPS improved glucose metabolism and energy homeostasis through EPS-derived gut microbial short-chain fatty acids, and changed gut microbial composition. Our findings reveal an important mechanism that accounts for the effects of diet, prebiotics, and probiotics on energy homeostasis and suggests an approach for preventing lifestyle-related diseases by targeting bacterial EPS.

Abstract A major class of bispecific antibodies (BsAbs) utilizes heterodimeric Fc to produce the native immunoglobulin G (IgG) structure. Because appropriate pairing of heavy and light chains is required, the design of BsAbs produced through recombination or reassembly of two separately-expressed antigen-binding fragments is advantageous. One such method uses intein-mediated protein trans-splicing (IMPTS) to produce an IgG1-based structure. An extra Cys residue is incorporated as a consensus sequence for IMPTS in successful examples, but this may lead to potential destabilization or disturbance of the assay system. In this study, we designed a BsAb linked by IMPTS, without the extra Cys residue. A BsAb binding to both TNFR2 and CD30 was successfully produced. Cleaved side product formation was inevitable, but it was minimized under the optimized conditions. The fine-tuned design is suitable for the production of IgG-like BsAb with high symmetry between the two antigen-binding fragments that is advantageous for screening BsAbs.

Abstract Small extracellular vesicles (sEVs) are nano‐sized vesicles secreted from various cells that contain bioactive metabolites and function as key regulators for intercellular communication. sEVs modulate diverse biological and pathological processes in the body, and the amount of circulating sEVs has been reported to correlate with certain disease progression. Therefore, the identification of small molecular compounds that can control sEV production may become a novel therapeutic strategy. In this study, a rapid, highly sensitive sEV quantification method utilizing fusion proteins consisting of Gaussia luciferase (gLuc) reporter protein and sEV markers (CD63 and CD82) was developed. A total of 480 compounds were screened to identify potent inducers and inhibitors of gLuc activity. Two novel compounds, KPYC08425 and KPYC12163, showed significant and dose‐dependent changes in gLuc activity with minimal cytotoxicity based on the LDH assay. The efficacy of these two compounds was further evaluated by protein quantification of the isolated sEVs. Further evaluation of KPYC12163 suggested that the autolysosomal pathway may be involved in its inhibitory effect on sEV production.

Thermal [2+2] cycloaddition of allenes with an additional multiple bonds are described. The results of this study are in good accordance with the stepwise mechanism through a biradical intermediate with a coplanar allyl radical.

Cascade reactions (also represented as domino reactions) realize the step-economical direct construction of natural product core structures. The use of atom-economical elementary reactions in cascade processes can minimize waste production and avoid prefunctionalization of the substrates. Palladium catalysis, which promotes a variety of atom-economical elementary reactions, has long been used as a powerful approach to the direct formation of complex heterocycles. In this short review, palladium-catalyzed cascade reactions for the construction of core structures of natural products reported in the last decade are highlighted. 1 Introduction 2 Reactions Terminated with Heteronucleophiles 2.1 Termination with Nitrogen Nucleophiles 2.2 Termination with Oxygen Nucleophiles 3 Reactions Terminated with Carbon Functional Groups 3.1 Termination with Carbon Nucleophiles 3.2 Termination with Heck-Type Reactions 4 Conclusion [ABSTRACT FROM AUTHOR]

The article presents a study that determines the applications and synthesis of vinylaziridines and ethynylaziridines. It offers brief overview of the method of the study which observes the direct synthesis of vinylaziridines in different ways. It outlines the result of the study which indicates the useful transformation of vinylaziridines and ethynylaziridines with general comments on their applications.

Transition-metal-catalyzed reactions have the potential to provide significant improvements to the syntheses of complex target molecules. These reactions can be used to achieve a variety of different atom-economical transformations and cascade reactions and, therefore, provide access to synthetic strategies that would otherwise be unavailable using classical organic chemistry. To exemplify the utility of the latest transition-metal-catalyzed reactions for the construction of important target structures, we have been involved in the total synthesis of natural products bearing widely known chemical scaffolds. In this account, we report our recent studies on the use of a palladium-catalyzed cascade cyclization reaction and a gold(I)-catalyzed hydroamination reaction for the construction of the core structures of alkaloids, as well as their application to the total syntheses of lysergic acid, lysergol, isolysergol, and quinocarcin. 1 Introduction 2 Ergot Alkaloid Synthesis 2.1 Construction of the Core Structure by Palladium-Catalyzed Cascade Cyclization 2.2 Asymmetric Total Syntheses of (+)-Lysergic Acid and Related Alkaloids 3 Quinocarcin Synthesis 3.1 Construction of the Core Structure by Gold-Catalyzed Hydroamination 3.2 Asymmetric Total Synthesis of (-)-Quinocarcin 4 Concluding Remarks [ABSTRACT FROM AUTHOR]

The title electron-donors with two units of a disk-shaped heterocyclicdiamine undergo two-stage stepwise one-electron oxidation to the corresponding cation radicals and dication diradicals. They adopt a stacked geometry as inpimers and π-dimers, respectively. In contrast, the third and fourth oxidation processes occur nearly at the same potential, indicating that tricationic/tetracationic species prefer the extended geometry. The similar redox-induced conformational changes were not observed in 1,5-pentylene or o-xylylene derivatives, which prefer the extended geometry irrespective of the oxidation states. [ABSTRACT FROM AUTHOR]

The palladium-catalyzed domino cyclization of propargyl bromides having two nucleophilic functional groups is described. Treatment of 1,7-diamino-5-bromohept-3-yne derivatives with catalytic Pd(PPh3)4in the presence of NaH in MeOH gives the 2,7-diazabicyclo4.3.0non-5-enes in good yields. Interestingly, the regioselectivity of the reaction is completely controlled by the relative reactivity of the amine functional groups, irrespective of the position of the nucleophiles. The malonate derivative also undergoes domino cyclization to produce a hexahydroindole derivative. [ABSTRACT FROM AUTHOR]

Through gold(I)-catalyzed cascade cyclization as a key step, the title electron donor was prepared, which adopts a planar geometry, as confirmed by an X-ray analysis. Due to 1,4-phenylenediamine moiety incorporated in the framework, it undergoes reversible one-electron oxidation. Upon electrolysis, it exhibited an electrochromic response in the UV-vis-NIR region, which was accompanied by a drastic change in the fluorescence spectrum since only the neutral donor is highly fluorescent. [ABSTRACT FROM AUTHOR]

Tetrahydropyrimidine works efficiently as a directing group in Cu(ii)-mediated oxidative aromatic C–H functionalisation for the selective introduction of oxygen or nitrogen to the ortho-position. [ABSTRACT FROM AUTHOR]

Treatment of allenic bromoalkenes bearing a nucleophilic moiety with a catalytic amount of palladium(0) in the presence of TBAF or Cs2CO3 in MeCN affords bicyclic heterocycles in good to high yields, through zipper-mode cascade cyclisation. [ABSTRACT FROM AUTHOR]

Copper(i)-catalysed domino four-component coupling–cyclisation using 2-ethynylbenzaldehydes, paraformaldehyde, secondary amine, and t-BuNH2 in DMF leads to direct and efficient formation of 3-(aminomethyl)isoquinolines in good to high yields. [ABSTRACT FROM AUTHOR]

Direct construction of fused aromatic ring systems by “zipper-mode” double C−H bond activation is described. Treatment of (Z)-3-bromo-N-(2-bromo-3-phenylprop-2-enyl)aniline derivatives with a catalytic amount of Pd(OAc)2and PCy3·HBF4in the presence of Cs2CO3in dioxane affords 4,5-naphtho3,2,1-cdindole derivatives in good yields. Introduction of heterocycles such as benzofuran, benzothiophene, or indole moieties into the substrates leads to the efficient construction of highly fused heterocyclic aromatic ring systems via C−H bond activation of the heteroaromatic rings. [ABSTRACT FROM AUTHOR]

One-pot N-arylation and oxidative coupling can be promoted by a common palladium catalyst in the presence of appropriate additives: palladium-catalyzed N-arylation of anilines with aryl triflates under the standard conditions followed by addition of acetic acid under oxygen or air atmosphere afforded various types of functionalized carbazoles in good to excellent yields. [ABSTRACT FROM AUTHOR]