Visible-Light-Driven Deoxygenative Heteroarylation of Alcohols with Heteroaryl Sulfones.

The visible-light-promoted deoxygenative radical heteroarylation of alcohols was achieved in the absence of any external photosensitizers. The processes occur through the generation of xanthate salts from alcohols, followed by SET and fragmentation, delivering alkyl radicals to react with heteroaryl sulfones. This method is amenable for a wide range of alcohols with good functional group tolerance, providing a practical strategy for the alkylation of benzo-heteroaromatics. Mechanism studies indicate that direct visible-light excitation of xanthate anions and subsequent SET initiate the reactions.

miR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism.

MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is also poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 effectively treated HCC. Compared with FDA-approved lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and T cells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing T cells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC effect of miR-22. Additionally, miR-22 expanded cytotoxic T cells and reduced regulatory T cells (Treg). Moreover, depleting cytotoxic T cells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high HCC had upregulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment.

A Practical Method for Synthesizing Iptacopan.

Iptacopan, the first orally available small-molecule complement factor B inhibitor, was developed by Novartis AG of Switzerland. Iptacopan for the treatment of PNH was just approved by the FDA in December 2023. Other indications for treatment are still in phase III clinical trials. Iptacopan is a small-molecule inhibitor targeting complement factor B, showing positive therapeutic effects in the treatment of PNH, C3 glomerulonephritis, and other diseases. Although Iptacopan is already on the market, there has been no detailed synthesis process or specific parameter report on the intermediates during the synthesis of its compounds except for the original research patent. In this study, a practical synthesis route for Iptacopan was obtained through incremental improvement while a biosynthesis method for ketoreductase was used for the synthesis of the pivotal intermediate 12. Moreover, by screening the existing enzyme library of our research group on the basis of random as well as site-directed mutagenesis methods, an enzyme (M8) proven to be of high optical purity with a high yield for biocatalectic reduction was obtained. This enzyme was used to prepare the compound benzyl (2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)-phenyl)-piperidine-1-carboxylate) white powder (36.8 g HPLC purity: 98%, ee value: 99%). In the synthesis of intermediate 15, the reaction was improved from two-step to one-step, which indicated that the risk of chiral allosterism was reduced while the scale was expanded. Finally, Iptacopan was synthesized in a seven-step reaction with a total yield of 29%. Since three chiral intermediate impurities were synthesized directionally, this paper lays a solid foundation for the future of pharmaceutical manufacturing.

Visible-Light-Driven Multicomponent Reactions for the Versatile Synthesis of Thioamides by Radical Thiocarbamoylation.

Thioamides are widely used structures in pharmaceuticals and agrochemicals, as well as important synthons for the construction of sulfur-containing heterocycles. This report presents a series of visible-light-driven multicomponent reactions of amines, carbon disulfide, and olefins for the mild and versatile synthesis of linear thioamides and cyclic thiolactams. The use of inexpensive and readily available carbon disulfide as the thiocarbonyl source in a radical pathway enables the facile assembly of structurally diverse amine moieties with non-nucleophilic carbon-based reaction partners. Radical thiocarbamoylative cyclization provides a practical protocol that complements traditional approaches to thiolactams relying on deoxythionation. Mechanistic studies reveal that direct photoexcitation of in situ formed dithiocarbamate anions as well as versatile photoinduced electron transfer with diverse electron acceptors are key to the reactions.

Visible-Light-Driven Photocatalyst-Free Deoxygenative Radical Transformation of Alcohols to Oxime Ethers.

A visible-light-driven deoxygenative cross-coupling of alcohols with sulfonyl oxime ethers has been developed by using xanthate salts as alcohol-activating groups. Upon convenient generation and direct photoexcitation of xanthate anions, a broad range of alcohols including primary ones can efficiently undergo this transformation to afford diverse oxime ethers and derivatives. This one-pot protocol features mild conditions, broad substrate scope, and late-stage applicability, without the need for any external photocatalysts or electron donor-acceptor complex formation.

Deoxygenative coupling of alcohols with aromatic nitriles enabled by direct visible light excitation.

A general and practical protocol is presented for visible-light-driven deoxygenative coupling of alcohols with aromatic nitriles in the absence of external photocatalysts. Utilizing a hydroxyl activation strategy with carbon disulfide, this C(sp3)-C(sp2) constructing platform accommodates a broad scope of alcohols and aryl nitriles to deliver various alkyl-substituted arenes. Mechanism studies show that a single electron transfer event between a photoexcited aryl nitrile and a xanthate anion is key to the transformation.

GmYSL7 controls iron uptake, allocation, and cellular response of nodules in soybean.

Iron (Fe) is essential for DNA synthesis, photosynthesis and respiration of plants. The demand for Fe substantially increases during legumes-rhizobia symbiotic nitrogen fixation because of the synthesis of leghemoglobin in the host and Fe-containing proteins in bacteroids. However, the mechanism by which plant controls iron transport to nodules remains largely unknown. Here we demonstrate that GmYSL7 serves as a key regulator controlling Fe uptake from root to nodule and distribution in soybean nodules. GmYSL7 is Fe responsive and GmYSL7 transports iron across the membrane and into the infected cells of nodules. Alterations of GmYSL7 substantially affect iron distribution between root and nodule, resulting in defective growth of nodules and reduced nitrogenase activity. GmYSL7 knockout increases the expression of GmbHLH300, a transcription factor required for Fe response of nodules. Overexpression of GmbHLH300 decreases nodule number, nitrogenase activity and Fe content in nodules. Remarkably, GmbHLH300 directly binds to the promoters of ENOD93 and GmLbs, which regulate nodule number and nitrogenase activity, and represses their transcription. Our data reveal a new role of GmYSL7 in controlling Fe transport from host root to nodule and Fe distribution in nodule cells, and uncover a molecular mechanism by which Fe affects nodule number and nitrogenase activity.

Nuclear receptor RORγ inverse agonists/antagonists display tissue- and gene-context selectivity through distinct activities in altering chromatin accessibility and master regulator SREBP2 occupancy.

The nuclear receptor RORγ is a major driver of autoimmune diseases and certain types of cancer due to its aberrant function in T helper 17 (Th17) cell differentiation and tumor cholesterol metabolism, respectively. Compound screening using the classic receptor-coactivator interaction perturbation scheme led to identification of many small-molecule modulators of RORγ(t). We report here that inverse agonists/antagonists of RORγ such as VTP-43742 derivative VTP-23 and TAK828F, which can potently inhibit the inflammatory gene program in Th17 cells, unexpectedly lack high potency in inhibiting the growth of TNBC tumor cells. In contrast, antagonists such as XY018 and GSK805 that strongly suppress tumor cell growth and survival display only modest activities in reducing Th17-related cytokine expression. Unexpectedly, we found that VTP-23 significantly induces the cholesterol biosynthesis program in TNBC cells. Our further mechanistic analyses revealed that VTP-23 enhances the local chromatin accessibility, H3K27ac mark and the cholesterol master regulator SREBP2 recruitment at the RORγ binding sites, whereas XY018 exerts the opposite activities. Yet, they display similar inhibitory effects on circadian rhythm program. Similar distinctions and contrasting activities between TAK828F and SR2211 in their effects on local chromatin structure at Il17 genes were also observed. Together, our study shows for the first-time that structurally distinct RORγ antagonists possess different or even contrasting activities in tissue/cell-specific manner. Our findings also highlight that the activities at natural chromatin are key determinants of RORγ modulators' tissue selectivity.

Bionic orientation method based on polarization imaging in HDR scenes.

An increasing number of bio-inspired navigation approaches have been designed based on polarization cameras. However, digital cameras can sense a much narrower field of vision than the vision of insects or human beings. In this study, we propose an adaptive skylight polarized orientation method for high dynamic range (HDR) scenes. Initially, we built a model of the image acquisition pipeline that can recover HDR irradiance maps from polarization images. Subsequently, the orientation method was designed based on a combination of the irradiance maps and the least squares methods. Some preprocessing steps were utilized to eliminate occlusion interference. In addition, an autoexposure adjustment method was proposed using information entropy and heuristic segmentation. Finally, the experimental results show that the proposed method can improve the accuracy of bionic orientation and adaption to skylight with occlusions and interference in natural conditions.

A facile turn-on chemiluminescence probe for sensitive imaging on aminopeptidase N activity.

Aminopeptidase N, as a target for drug discovery, shows marked relationships with many diseases, especially liver injury and cancer. Here, we explored a chemiluminescence (CL) probe for sensing APN by tethering the APN-specific substrate group to the ortho-acrylated phenoxy-dioxetane scaffold. In this way, two CL probes (APN-CL and BAPN-CL) were designed with noncapped leucine and butoxy-carbonyl capped leucine as the protecting group to preserve the chemiexcitation energy. The uncovered leucine was demonstrated to be essential for detection of APN activity by comparing the CL intensity of two CL probes. Probe APN-CL was turned on upon APN cleavage, resulting in a high chemiluminescent emission, whereas the chemiexcitation energy of probe BAPN-CL was still restrained even with the high-level APN. The result was further elucidated by molecular docking simulations. Probe APN-CL exhibited a fast response and high sensitivity with a detection limit of 0.068 U/L, and an excellent specificity for the discrimination of APN from biological ions, small molecules, and other proteases commonly found in living system. By virtue of good stability and cell viability, probe APN-CL imaged abnormal levels of APN in tumour cells and tumour-bearing mice. Moreover, this probe APN-CL could be easily used to evaluate APN inhibitors and APN levels in plasma samples from 20 patients. Overall, as a facile and cost-effective probe, APN-CL will be a promising alternative in the early diagnosis of pathologies and for cost-effective screening of inhibitors.