Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

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Stimulator of interferon genes (STING) is a crucial adaptor protein in the innate immune response. STING activation triggers cytokine secretion, including type Ⅰ interferon and initiates T cell-mediated adaptive immunity. The activated immune system converts "cold tumors" into "hot tumors" that are highly responsive to T cells by recruiting them to the tumor microenvironment, ultimately leading to potent and long-lasting anti-tumor effects. Unlike most immune checkpoint inhibitors, STING agonists represent a groundbreaking class of innate immune agonists that hold great potential for effectively targeting various cancer populations and are poised to become a blockbuster in tumor immunotherapy. This review will focus on the correlation between the STING signaling pathway and tumor immunity, as well as explore the impact of STING activation on other biological processes. Ultimately, we will summarize the development and optimization of STING agonists from a medicinal chemistry perspective, evaluate their potential in cancer therapy, and identify possible challenges for future advancement.

Facile and Efficient Production of Biomass‐Derived Isosorbide Dioxides via Epoxidation Using In situ‐generated DMDO under Ultrasonication

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Herein, we present a facile synthetic process for producing biomass-derived isosorbide (ISB) dioxides using dimethyl dioxirane (DMDO) as an efficient oxidizing agent, which was generated in situ from acetone and KHSO5. To achieve high conversion and product yield, the KHSO5 concentration, KHSO5 flow rate, and reaction temperature were optimized. Under the optimal conditions, rapid and efficient epoxidation using the in situ-generated DMDO was observed under ultrasonication, yielding the desired product within 35 min at 0 °C. This study offers a convenient and efficient method for generating biomass-derived ISB building blocks, which have significant potential for the fabrication of bioplastics.

Auranofin sensitizes breast cancer cells to paclitaxel chemotherapy by disturbing the cellular redox system

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Abstract

The intrinsic redox status of cancer cells limits the efficacy of chemotherapeutic drugs. Auranofin, a Food and Drug Administration-approved gold-containing compound, documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel-sensitizing effect of auranofin by targeting redox balance in the MDA-MB-231 and MCF-7 breast cancer cell lines. Auranofin treatment depletes the activities of superoxide dismutase, catalase, and glutathione peroxidase and alters the redox ratio in the breast cancer cell lines. Furthermore, it has been noticed that auranofin augmented paclitaxel-mediated cytotoxicity in a concentration-dependent manner in both MDA-MB-231 and MCF-7 cell lines. Moreover, auranofin increased the levels of intracellular reactive oxygen species (observed using 2, 7-diacetyl dichlorofluorescein diacetate staining) and subsequently altered the mitochondrial membrane potential (rhodamine-123 staining) in a concentration-dependent manner. Further, the expression of apoptotic marker p21 was found to be higher in auranofin plus paclitaxel-treated breast cancer cells compared to paclitaxel-alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA-MB-231 and MCF-7 breast cancer cell lines via oxidative metabolism. Therefore, auranofin could be considered a chemosensitizing agent during cancer chemotherapy.

Eight‐Membered Palladacycle Intermediate Enabled Synthesis of Cyclic Biarylphosphonates

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Transition-metal-catalyzed coupling reactions that involve the direct functionalization of insert C-H bond represent one of the most efficient strategies for forming carbon-carbon bonds. Herein, a palladium-catalyzed intramolecular C-H bond arylation of triaryl phosphates is reported to access seven-membered cyclic biarylphosphonate targets. The reaction is achieved via a unique eight-membered palladacyclic intermediate and shows good functional group compatibility. Meanwhile, the product can be readily converted into other valuable phosphate compounds.

Functionalization of Dodecaborates by Mild and Efficient Pd‐Catalyzed Formation of B‐C Bonds with Boronic Acids

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Hybrid organic-inorganic molecules have recently received great interest due to their unique properties, which give access to their implementation in biological and material sciences. Herein, a new synthetic approach for the direct-linkage of the purely inorganic dodecaborate cluster to organic building blocks through B-C bond is established, using boronic acids as functional groups on the organic moiety, reacting under Suzuki-Miyaura coupling conditions with iodo-undecahydridododecaborate. The choices of ligand (DavePhos) and solvent (N-methylpyrrolidone for electron-poor, CD3CN for electron-rich groups) are essential for the successful coupling. Ultimately, the newly described methodology is found to be functional-group tolerant covering a wide spectrum of substrates including electron-poor arenes.

An Efficient Chemoenzymatic Route towards Biologically Active Pyridinic Amines

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Starting from the easily prepared 1-(pyridin-2-yl)- or 1-(4-chloropyridin-2-yl)ethan-1-ones bearer of different substituents (cyclohexyl, phenyl, pyridin-2-yl) in the position 2, the corresponding primary pyridinic ethanamines have been synthesized in very high enantiomeric excesses (ee ≥ 97%). The strategy involves a highly enantioselective ketoreductase (KRED) catalyzed reduction, mesylation of the resulting optically active alcohol followed by nucleophilic substitution with azide anion and, finally, reduction of the azide function. Some of these pyridinic amines obtained in such manner are precursors of biologically active compounds such as Ontazolast.