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791.
Kevin Bauer Prof. Dr. Uli Kazmaier 《Angewandte Chemie (International ed. in English)》2023,62(32):e202305445
We present the first total synthesis of the thiamyxins A–C and the now fully characterized thiamyxin E, an interesting class of thiazole- and thiazoline-rich depsipeptides with diverse antiviral activity. The synthesis features a parallel closing of two methyl thiazoline units, with low epimerization of the very labile adjacent stereocenter. It also includes the three-step synthesis of an uncommon hydroxy acid and the oxidation-free elimination of a phenylselenide to form a dehydroalanine moiety. The exploitation of the acid-labile stereocenter at the isoleucine moiety and the reopening of the macrolactones gave access to the four thiamyxins with good yields and diastereomeric purities from a single precursor. The modular total synthesis allows further testing of the biological activity and gives opportunities to explore the pharmacophore and antiviral target through derivatization. 相似文献
792.
Dr. Wei Zheng Dr. Kosuke Oki Dr. Ranajit Saha Dr. Yuh Hijikata Prof. Eiji Yashima Dr. Tomoyuki Ikai 《Angewandte Chemie (International ed. in English)》2023,62(11):e202218297
Defect-free one-handed contracted helical tubular ladder polymers with a π-electron-rich cylindrical helical cavity were synthesized by alkyne benzannulations of the random-coil precursor polymers containing 6,6′-linked-1,1′-spirobiindane-7,7′-diol-based chiral monomer units. The resulting tightly-twisted helical tubular ladder polymers showed remarkably high enantioseparation abilities toward a variety of chiral hydrophobic aromatics with point, axial, and planar chiralities. The random-coil precursor polymer and analogous rigid-rod extended helical ribbon-like ladder polymer with no internal helical cavity exhibited no resolution abilities. The molecular dynamics simulations suggested that the π-electron-rich cylindrical helical cavity formed in the tightly-twisted tubular helical ladder structures is of key importance for producing the highly-enantioseparation ability, by which chiral aromatics can be enantioselectively encapsulated by specific π-π and/or hydrophobic interactions. 相似文献
793.
794.
Yan Zhao Haolin Jiang Jiazhen Yu Luyao Wang Prof. Juanjuan Du 《Angewandte Chemie (International ed. in English)》2023,62(38):e202304692
Currently, the clinical application of protein/peptide therapeutics is mainly limited to the modulation of diseases in extracellular spaces. Intracellular targets are hardly accessed, owing largely to the endosomal entrapment of internalized proteins/peptides. Here, we report a strategy to design and construct peptides that enable endosome-to-cytosol delivery based on an extension of the “histidine switch” principle. By substituting the Arg/Lys residues in cationic cell-penetrating peptides (CPPs) with histidine, we obtained peptides with pH-dependent membrane-perturbation activity. These peptides do not randomly penetrate cells like CPPs, but imitate the endosomal escape of CPPs following cellular uptake. Working with one such 16-residue peptide (hsLMWP) with high endosomal escape capacity, we engineered modular fusion proteins and achieved antibody-targeted delivery of diverse protein cargoes—including the pro-apoptotic protein BID (BH3-interacting domain death agonist) and Cre recombinase—into the cytosol of multiple cancer cell types. After extensive in vitro testing, an in vivo analysis with xenograft mice ultimately demonstrated that a trastuzumab-hsLMWP-BID fusion conferred strong anti-tumor efficacy without apparent side effects. Notably, our fusion protein features a modular design, allowing flexible applications for any antibody/cargo combination of choice. Therefore, the potential applications extend throughout life science and biomedicine, including gene editing, cancer treatment, and immunotherapy. 相似文献
795.
Laiben Gao Dr. Xiaoqiu Dou Chao Xing Fengli Gao Zichao Jiang Kaikai Yang Prof. Dr. Changli Zhao Prof. Dr. Chuanliang Feng 《Angewandte Chemie (International ed. in English)》2023,62(24):e202303812
The induction of diverse chirality regulation in nature by multiple binding sites of biomolecules is ubiquitous and plays an essential role in determining the biofunction of biosystems. However, mimicking this biological phenomenon and understanding at a molecular level its mechanism with the multiple binding sites by establishing an artificial system still remains a challenge. Herein, abundant chirality inversion is achieved by precisely and multiply manipulating the co-assembled binding sites of phenylalanine derivatives (D/LPPF) with different naphthalene derivatives (NA, NC, NP, NF). The amide and hydroxy group of naphthalene derivatives prefer to bind with the carboxy group of LPPF, while carboxylic groups and fluoride atoms tend to bind with the amide moiety of LPPF. All these diverse interaction modes can precisely trigger helicity inversion of LPPF nanofibers. In addition, synergistically manipulating the carboxy and amide binding sites from a single LPPF molecule to simultaneously interact with different naphthalene derivatives leads to chirality regulation. Typically, varying the solvent may switch the interaction modes and the switched new interaction modes can be employed to further regulate the chirality of the LPPF nanofibers. This study may provide a novel approach to explore chirality diversity in artificial systems by regulating the intermolecular binding sites. 相似文献
796.
Zhiming Cheng Dr. Emily J Thompson Dr. Lorena Mendive-Tapia Dr. Jamie I Scott Dr. Sam Benson Dr. Takanori Kitamura Ana Senan-Salinas Dr. Youhani Samarakoon Dr. Edward W Roberts Dr. Maykel A Arias Prof. Dr. Julian Pardo Dr. Eva M Galvez Prof. Dr. Marc Vendrell 《Angewandte Chemie (International ed. in English)》2023,62(8):e202216142
Cytotoxic immune cells, including T lymphocytes (CTLs) and natural killer (NK) cells, are essential components of the host response against tumors. CTLs and NK cells secrete granzyme A (GzmA) upon recognition of cancer cells; however, there are very few tools that can detect physiological levels of active GzmA with high spatiotemporal resolution. Herein, we report the rational design of the near-infrared fluorogenic substrates for human GzmA and mouse GzmA. These activity-based probes display very high catalytic efficiency and selectivity over other granzymes, as shown in tissue lysates from wild-type and GzmA knock-out mice. Furthermore, we demonstrate that the probes can image how adaptive immune cells respond to antigen-driven recognition of cancer cells in real time. 相似文献
797.
Dr. Alessandro Colombano Dr. Luca Dalponte Dr. Sergio Dall'Angelo Claudia Clemente Dr. Mohannad Idress Ahmad Ghazal Dr. Wael E. Houssen 《Angewandte Chemie (International ed. in English)》2023,62(16):e202215979
Aromatic prenyltransferases from cyanobactin biosynthetic pathways catalyse the chemoselective and regioselective intramolecular transfer of prenyl/geranyl groups from isoprene donors to an electron-rich position in these macrocyclic and linear peptides. These enzymes often demonstrate relaxed substrate specificity and are considered useful biocatalysts for structural diversification of peptides. Herein, we assess the isoprene donor specificity of the N1-tryptophan prenyltransferase AcyF from the anacyclamide A8P pathway using a library of 22 synthetic alkyl pyrophosphate analogues, of which many display reactive groups that are amenable to additional functionalization. We further used AcyF to introduce a reactive moiety into a tryptophan-containing cyclic peptide and subsequently used click chemistry to fluorescently label the enzymatically modified peptide. This chemoenzymatic strategy allows late-stage modification of peptides and is useful for many applications. 相似文献
798.
Dr. Marat Meleshin Lukas Koch Dr. Christoph Wiedemann Prof. Dr. Mike Schutkowski 《Angewandte Chemie (International ed. in English)》2023,62(25):e202301543
Herein we report a mild, efficient, and epimerization-free method for the synthesis of peptide-derived 2-thiazolines and 5,6-dihydro-4H-1,3-thiazines based on a cyclodesulfhydration of N-thioacyl-2-mercaptoethylamine or N-thioacyl-3-mercaptopropylamine derivatives. The described reaction can be easily carried out in aqueous solutions at room temperature and it is triggered by change of the pH, leading to complex thiazoline or dihydrothiazine derivatives without epimerization in excellent to quantitative yields. The new method was applied in the total synthesis of the marine metabolite mollamide F, resulting in the revision of its stereochemistry. 相似文献
799.
Cheuk Yin Li Zhenghua Liang Lejian Liu Prof. Yi Kuang 《Angewandte Chemie (International ed. in English)》2023,62(37):e202306533
Synthetic messenger RNA (mRNA) switches are powerful tools for in situ cell purification, especially for cells derived from stem cells. However, the retention effectiveness of the target cells is limited by the leaky expression of toxic protein. The elimination efficiency of non-target cells is also constrained due to the lack of signal amplification. In this study, we designed a novel approach that uses synthetic mRNA switch to convey intracellular marker molecule information into spatially controlled extracellular toxic assembly formation. The approach bypasses the use of toxic protein to ensure high target cell recovery effectiveness. Meanwhile, the marker molecule information is amplified at multiple levels to ensure high non-target cell elimination effectiveness. Our approach can be tailored to meet various in situ cell purification needs, promising high-quality in situ cell purification for a wide range of biomedical applications. 相似文献