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Genes & Diseases 2024年第2期11卷 542-545页

作者： Jiyan Wang Tao He Qingle Gao Hongkai Chang Xintong Dai Juze Yang Shuangping Liu Shuai Zhang Changliang Shan Chunze Zhang State key laboratory of Medicinal Chemical Biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300350China Departments of Pathology Characteristic Medical Center of The Chinese People's Armed Police ForceTianjin 300162China Department of Respiratory Medicine Sir Run Run Shaw Hospital and Institute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang 310016China Department of Pathology Medical SchoolDalian UniversityDalianLiaoning 116622China School of Integrative Medicine Tianjin University of Traditional Chinese MedicineTianjin 301617China Department of Colorectal Surgery Tianjin Union Medical CenterNankai UniversityTianjin 300121China

The tumor heterogeneity results in different clinical characteristics of tumor patients,so precise therapy is a popular treatment strategy *** instability(MSI)is found in 10%-15%of colorectal cancer(CRC)patients and exhibits different clinical outcomes than microsatellite stable(MSS)***,MSI patients have a better prognosis than patients with stable *** patients exhibit clinical features that are not responsive to chemotherapy,however,Msl patients showed excellent responses to immunotherapy.'Although the subtype classification of MSI is beneficial to the clinical treatment of CRC patients,the mechanism of MSl remains unclear.

关键词： immunotherapy colorectal clinical

Synergistic Brønsted Base/Photoredox-Catalyzed Three-Component Coupling with Malonates to Synthesize δ-Hydroxy Esters and δ-Keto Esters

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Chinese Journal of Chemistry 2024年第9期42卷 957-962页

作者： Ting Li Wei Wang Ming Dong Zhije Zhang Sha Yu Zhengchu Chen Siping Wei Dong Yi Green Pharmaceutical Technology key laboratory of Luzhou City Central Nervous System Drug Key Laboratory of Sichuan ProvinceSchoolof PharmacySouthwestMedicalUniversityLuzhouSichuan 646000China Nuclear Medicine and Molecular Imaging key laboratory of Sichuan Province LuzhouSichuan 646000China

Multicomponent alkene 1,2-dicarbofunctionalizations(DCFs)have emerged as a powerful strategy to rapidly incorporate both two carbon subunits across one C-C double bond in one step for enhancing molecular complexity and *** the best of our knowledge,there is only one report on photoredox-catalyzed three-component DCFs with malonates through the radical−radical cross-coupling,while photoredox-catalyzed radical-polar crossover(RPC)-type DCFs with malonates were still ***,we describe a redox-neutral RPC-type 1,2-dialkylation of styrenes with malonates and aldehydes through the synergistic Brønsted base/photoredox catalysis *** transition-metal-free strategy provides an efficient and clean approach to a broad variety ofδ-hydroxy esters and also features exceptionally mild conditions,wide compatibility of substrate scope and functional groups,and high atomic ***,three-component 1,2-alkylacylation from the same starting materials was achieved in one-pot manner through such RPC-type coupling and subsequent two-electron oxidation process,providing a set ofδ-keto esters of interest in pharmaceutical research.

关键词： Alkene difunctionalization Photoredox catalysis Malonates Radical reactions C-C coupling Synthetic methods Aldehydes Alkylation Multicomponentreactions

Design,synthesis and biological evaluation of fluorescent derivatives of ursolic acid in living cells

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Chinese Chemical Letters 2024年第5期35卷 287-289页

作者： Wenyi Mei Lijuan Xie Xiaodong Zhang Cunjian Shi Fengzhi Wang Qiqi Fu Zhenjiang Zhao Honglin Li Yufang Xu Zhuo Chen Shanghai key laboratory of New drug Design State Key Laboratory of Bioreactor EngineeringSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China Innovation Center for AI and drug Discovery East China Normal UniversityShanghai 200062China Lingang laboratory Shanghai 200031China

Ursolic acid(UA)is a naturally occurring ursane triterpenoid,which exhibits a wide range of unique biological *** clarify its mechanism of action(MOA),a series of fluorescent derivatives of UA(5a-c)were designed and synthesized by conjugation with 7-nitrobenzo-2-oxa-1,3-diazole(NBD)*** them,5c exhibited similar anti-proliferative activity with UA against HCT116 cells(half maximal inhibitory concentration(IC_(50))=9.21±0.50μmol/L).Cell imaging experiment indicated that 5c was rapidly taken up in HCT116 cells in a dose and time-dependent ***,5c was found to localize in endoplasmic reticulum(ER),lysosomes,and mitochondria,but not in nucleus of HCT116 cells by confocal microscopy *** MOA proved that UA induced autophagy with a unique intracellular distribution mechanism involving ER and *** all,our work provides new clues for revealing the molecular mechanism of UA as an antitumor agent.

关键词： Pentacyclic triterpenoid Ursolic acid Fluorescent derivatives Autophagy Apoptosis

Palladium-catalyzed multi components oxy-aminofluorination and aminofluorination of gem-difluoroalkenes

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Chinese Chemical Letters 2024年第2期35卷 420-425页

作者： Fen Wu Xin Li Junbiao Chang Dachang Bai State key laboratory of Antiviral drugs NMPA Key Laboratory for Research and Evaluation of Innovative DrugKey Laboratory of Green Chemical Media and ReactionsMinistry of EducationSchool of Chemistry and Chemical EngineeringPingyuan LaboratoryHenan Normal UniversityXinxiang 453007China State key laboratory of Organometallic Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

Organofluorine compounds are widely used in the realm of drug discovery and material ***,we developed palladium catalyzed intermolecular aminofluorination and oxy-aminofluorination of gem‑difluoroalkenes with N-fluorobenzenesulfonimide(NFSI),in which NFSI was used as the nitrogen source and *** reaction provides an efficient and straightforward synthesis route of a series ofα-trifluoromethyl benzylic ***,three/four components oxy-aminofluorination processes were realized to giveα-trifluoromethyl benzylic ether with a terminal amino group,which proceed through C(sp^(3))-O bond cleavage of easily available ether and simultaneous introduced a fluorine,an amino and an oxy substituent in one pot with excellent *** divergent reactivity not only included the incorporation of one ether molecular,but also much more challenged two ether insertion with excellent selectivity through succession C(sp^(3))-O bonds *** protocol allows for concise synthesis of high value amines with fluoroalkyl-substituents and selectively transformation of easily available ethers by high-valent palladium catalysis.

关键词： Palladium Multi components Aminofluorination Oxy-aminofluorination C(sp^(3))-O bond cleavage

Effective protective agents against the organ toxicity of T-2 toxin and corresponding detoxification mechanisms: A narrative review

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Animal Nutrition 2024年第1期16卷 251-266页

作者： Pengju Wang Lv-hui Sun Xu Wang Qinghua Wu Aimei Liu Hubei key laboratory of Diabetes and Angiopathy Medicine Research Institute Xianning Medical College Hubei University of Science and Technology Hubei Hongshan laboratory College of Animal Science and Technology Huazhong Agricultural University National Reference laboratory of Veterinary drug Residues (HZAU) and MAO key laboratory for Detection of Veterinary drug Residues Huazhong Agricultural University College of Life Science Yangtze University

T-2 toxin is one of the most widespread and toxic fungal toxins in food and feed. It can cause gastrointestinal toxicity, hepatotoxicity, immunotoxicity, reproductive toxicity, neurotoxicity, and nephrotoxicity in humans and animals. T-2 toxin is physicochemically stable and does not readily degrade during food and feed processing. Therefore, suppressing T-2 toxin-induced organ toxicity through antidotes is an urgent issue. Protective agents against the organ toxicity of T-2 toxin have been recorded widely in the literature, but these protective agents and their molecular mechanisms of detoxification have not been comprehensively summarized. In this review, we provide an overview of the various protective agents to T-2 toxin and the molecular mechanisms underlying the detoxification effects. Targeting appropriate targets to antagonize T-2 toxin toxicity is also an important option. This review will provide essential guidance and strategies for the better application and development of T-2 toxin antidotes specific for organ toxicity in the future.

关键词： T-2 toxin Organ toxicity Protective agent Detoxification mechanism

Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies

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Acta Pharmaceutica Sinica B 2024年第2期14卷 533-578页

作者： Xiaopeng Peng Zhihao Hu Limei Zeng Meizhu Zhang Congcong Xu Benyan Lu Chengpeng Tao Weiming Chen Wen Hou Kui Cheng Huichang Bi Wanyi Pan Jianjun Chen College of Pharmacy Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases of Ministry of EducationGannan Medical UniversityGanzhou 314000China College of Basic Medicine Gannan Medical UniversityGanzhou 314000China Guangdong Provincial key laboratory of New drug Screening NMPA Key Laboratory for Research and Evaluation of Drug MetabolismSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators(e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges,including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result,the design of new epigenetic modulators(e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging(Hy T) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review,we aim to provide an in-depth illustration of new degrading strategies(2017-2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.

关键词： Epigenetic Degrader PROTAC Molecularglue Hydrophobic tagging

Total synthesis of a putative yuzurimine-type Daphniphyllum alkaloid C_(14)–epi-deoxycalyciphylline H

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Chinese Chemical Letters 2024年第4期35卷 336-339页

作者： Jingping Hu Jing Xu Shenzhen Grubbs Institute and Department of Chemistry and Guangdong Provincial key laboratory of Catalysis and Shenzhen key laboratory of Small Molecule drug Discovery and Synthesis Southern University of Science and TechnologyShenzhen 518055China

One of the largest subfamilies within the famous Daphniphyllum alkaloid family is made up of the yuzurimine-type(or macrodaphniphyllamine-type) alkaloids. Their complex aza-polycyclic caged structures, several contiguous stereogenic centers, and vicinal all-carbon quaternary centers make these alkaloids formidable challenge for synthetic chemists. Recently, synthesis of these alkaloids has received extensive attention from our community. Herein, we wish to report the total synthesis of C_(14)–epideoxycalyciphylline H, a putative member of yuzurimine-type alkaloid subfamily. key transformations employed in our approach include an intramolecular Prins reaction and a Pd-catalyzed enyne cycloisomerization. In addition, synthesis of a daphnezomine L-type alkaloid, paxdaphnidine A, was also studied.

关键词： Total synthesis Daphniphyllum alkaloids Yuzurimine-type alkaloids Prins reaction Enyne cycloisomerization

5S-Heudelotinone alleviates experimental colitis by shaping the immune system and enhancing the intestinal barrier in a gut microbiota-dependent manner

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2153-2176页

作者： Qing Meng Jianshuang Guo Ke Lv Yang Liu Jin Zhang Mingyue Li Xirui Cheng Shenghua Chen Xiaoguang Huo Quan Zhang Yue Chen Jing Li State key laboratory of Medicinal Chemical Biology College of PharmacyNankai UniversityTianjin 300353China College of Chemistry and Frontiers Science Center for New Organic Matter Haihe Laboratory of Sustainable Chemical TransformationsNankai UniversityTianjin 300071China Accendatech Company Ltd.Tianjin 300193China

Aberrant changes in the gut microbiota are implicated in many diseases,including inflammatory bowel disease(IBD).Gut microbes produce diverse metabolites that can shape the immune system and impact the intestinal barrier integrity,indicating that microbe-mediated modulation may be a promising strategy for preventing and treating *** fecal microbiota transplantation and probiotic supplementation are well-established IBD therapies,novel chemical agents that are safe and exert strong effects on the gut microbiota are urgently ***,we report the total synthesis of heudelotinone and the discovery of 5S-heudelotinone(an enantiomer)as a potent agent against experimental colitis that acts by modulating the gut microbiota.5S-Heudelotinone alters the diversity and composition of the gut microbiota and increases the concentration of short-chain fatty acids(SCFAs);thus,it regulates the intestinal immune system by reducing proinflammatory immune cell numbers,and maintains intestinal mucosal integrity by modulating tight junctions(TJs).Moreover,5S-heudelotinone(2)ameliorates colitis-associated colorectal cancer(CAC)in an azoxymethane(AOM)/dextran sulfate sodium(DSS)-induced in situ carcinoma ***,these findings reveal the potential of a novel natural product,namely,5S-heudelotinone,to control intestinal inflammation and highlight that this product is a safe and effective candidate for the treatment of IBD and CAC.

关键词： 5S-heudelotinone Total synthesis Inflammatory bowel disease Gut microbiota Short-chain fatty acids Immune system Intestinal barrier drug discovery

Deciphering the high-carbonization-temperature triggered enzymatic activity of wool-derived N,S-co-doped carbon nanosheets

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Chinese Chemical Letters 2024年第3期35卷 182-188页

作者： Jiachen Zhao Deshuai Yu Jianmin Chen Shihao Lin Yonghua Tang Chaoyu Fan Dongfang Zhou Youhui Lin Department of Physics Research Institute for Biomimetics and Soft MatterFujian Provincial Key Laboratory for Soft Functional Materials ResearchXiamen UniversityXiamen 361005China School of Pharmacy and Medical Technology Putian UniversityPutian 351100China key laboratory of Mental Health of the Ministry of Education NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China key laboratory of Pharmaceutical Analysis and laboratory Medicine(Putian University) Fujian Province UniversityPutian 351100China

It is well-established that high carbonization temperature will trigger the enzyme-like activity of carbon-based ***,the catalytic mechanism is still ambiguous,which hinders the further rational design of nanomaterials as enzyme ***,N,S-rich carbonized wool nanosheets(CWs)were synthesized at different pyrolysis *** expected,only CWs treated with high-temperature possess intrinsic oxidase-and peroxidase-like ***,density functional theory(DFT)calculations demonstrate that graphitic nitrogen and the co-existence of nitrogen and sulfur in the carbon matrix serve as the active sites for the enzyme-like *** importantly,combining theoretical calculations and experimental observations,the high-temperature triggered catalytic mechanism can be ascribed to the fact that an appropriate high-temperature maximizes the graphitization degree to a certain extent,at which most of the catalytic active sites are well retained rather than ***,coupling with excellent photothermal conversion efficiency and catalytic performance,CWs can be applied to photothermal-catalytic cancer therapy under near-infrared region(NIR)light *** believe this work will contribute to understanding the catalytic mechanism of carbon-based nanozymes and promote the development of new biomedical and pharmaceutical applications.

关键词： Carbon-based nanozyme Catalytic mechanism Density functional theory high-temperature carbonization

A Transformer-Based Ensemble Framework for the Prediction of Protein-Protein Interaction Sites

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Research 2024年第2期2023卷 703-718页

作者： Minjie Mou Ziqi Pan Zhimeng Zhou Lingyan Zheng Hanyu Zhang Shuiyang Shi Fengcheng Li Xiuna Sun Feng Zhu College of Pharmaceutical Sciences The Second Affliated HospitalZhejiang University School of MedicineNational Key Laboratory of Advanced Drug Delivery and Release SystemsZhejiang UniversityHangzhou 310058China Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University Alibaba-Zhejiang University Joint Research Center of Future Digital HealthcareHangzhou 330110China

The identification of protein-protein interaction (PPI) sites is essential in the research of protein function and the discovery of new drugs. So far, a variety of computational tools based on machine learning have been developed to accelerate the identification of PPI sites. However, existing methods suffer from the low predictive accuracy or the limited scope of application. Specifically, some methods learned only global or local sequential features, leading to low predictive accuracy, while others achieved improved performance by extracting residue interactions from structures but were limited in their application scope for the serious dependence on precise structure information. There is an urgent need to develop a method that integrates comprehensive information to realize proteome-wide accurate profiling of PPI sites. Herein, a novel ensemble framework for PPI sites prediction, EnsemPPIS, was therefore proposed based on transformer and gated convolutional networks. EnsemPPIS can effectively capture not only global and local patterns but also residue interactions. Specifically, EnsemPPIS was unique in (a) extracting residue interactions from protein sequences with transformer and (b) further integrating global and local sequential features with the ensemble learning strategy. Compared with various existing methods, EnsemPPIS exhibited either superior performance or broader applicability on multiple PPI sites prediction tasks. Moreover, pattern analysis based on the interpretability of EnsemPPIS demonstrated that EnsemPPIS was fully capable of learning residue interactions within the local structure of PPI sites using only sequence information. The web server of EnsemPPIS is freely available at http://***/ensemppis.

关键词： residue extracting ensemble