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Hydrophobic tag tethering degrader as a promising paradigm of protein degradation:Past,present and future perspectives

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Chinese Chemical Letters 2024年第8期35卷 187-200页

作者： Si Ha Jiacheng Zhu Hua Xiang Guoshun Luo State Key laboratory of Natural Medicines and Department of medicinal chemistry China Pharmaceutical UniversityNanjing 211198China

Small molecule inhibitors have dominated the pharmaceutical landscape for a long time as the primary therapeutic paradigm targeting pathogenic ***,their efficacy heavily relies on the amino acid composition and spatial constitution of proteins,rendering them susceptible to drug resistance and failing to target undruggable *** recent years,the advent of targeted protein degradation(TPD)technology has captured substantial attention from both industry and *** an event-driven mode,TPD offers a novel approach to eliminate pathogenic proteins by promoting their degrada-tion,thus circumventing the limitations associated with traditional small molecule ***-bic tag tethering degrader(HyTTD)technology represents one such TPD approach that is currently in the burgeoning *** employ endogenous protein degradation systems to induce the degrada-tion of target proteins through the proteasome pathway,which displays significant potential for medical *** this review,we provide a comprehensive overview of the development history and the reported mechanism of action of ***,we delve into the physiological roles,structure-activity re-lationships,and medical implications of HyTTDs targeting various disease-associated ***,we propose insights into the challenges that necessitate resolution for the successful development of HyTTDs,with the ultimate goal of initiating a new age of clinical treatment leveraging the immense po-tential of HyTTDs.

关键词： Targeted protein degradation(TPD) Hydrophobic tag Degrader Hydrophobic tag tethering degrader(HyTTD) Targeted therapy

Electricity-driven enantioselective cross-dehydrogenative coupling of two C(sp^(3))-H bonds enabled by organocatalysis

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Chinese Chemical Letters 2024年第9期35卷 130-134页

作者： Yuemin Chen Yunqi Wu Guoao Wang Feihu Cui Haitao Tang Yingming Pan State Key laboratory for chemistry and Molecular Engineering of medicinal Resources School of Chemistry and Pharmaceutical Sciences of Guangxi Normal UniversityGuilin 541004China

An efficient and scalable electrochemical asymmetric protocol with metal-free catalysts and even without additional oxidants for the cross-dehydrogenative coupling reaction(CDC)of two C(sp^(3))-H bonds is reported.A series of aldehydes including natural products and various substrates containing C(sp^(3))-H bonds including xanthenes,acridines,cycloheptatrienes and even diarylmethane have been shown to undergo asymmetric CDC to afford a series of carbon-carbon bond coupling products with up to 94%yield and 98%*** studies such as radical clock experiment suggest that the reaction proceeds via nucleophilic attack by enamine under electrochemical conditions.

关键词： Aminocatalysis Electrochemistry Asymmetric catalysis CDC of C(sp^(3))-H bonds

Simultaneous Bulk-and Surface-initiated Living Polymerization Studied with a Heterogeneous Stochastic Reaction Model

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Chinese Journal of Polymer Science 2024年第3期42卷 364-372,I0008页

作者： Jia-Shu Ma Zhi-Ning Huang Jia-Hao Li Bang-Ping Jiang Yan-Da Liao Shi-Chen Ji Xing-Can Shen State Key laboratory for chemistry and Molecular Engineering of medicinal Resources Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources(Ministry of Education of China)School of Chemistry and Pharmaceutical SciencesGuangxi Normal UniversityGuilin 541004China School of Computer Science and Engineering&School of Software Guangxi Normal UniversityGuilin 541004China

To better characterize the properties of surface-initiated polymers, simultaneous bulk-and surface-initiated polymerizations are usually carried out by assuming that the properties of the surface-initiated polymers resemble those of the bulk-initiated polymers. Through a Monte Carlo simulation using a heterogeneous stochastic reaction model, it was discovered that the bulk-initiated polymers exhibit a higher molecular weight and a lower dispersity than the corresponding surface-initiated polymers, which indicates that the equivalent assumption is invalid. Furthermore, the molecular weight distributions of the two types of polymers are also different, suggesting different polymerization mechanisms. The results can be simply explained by the heterogeneous distributions of reactants in the system. This study is helpful to better understand surface-initiated polymerization.

关键词： Surface-initiated polymerization Polymer brush Stochastic reaction model Heterogeneous polymerization Simultaneous polymerization

Colorimetric Sensor for Detection of Tabun Mimic Diethyl Cyanophosphonate

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Journal of Analysis and Testing 2024年第3期8卷 374-384页

作者： Madhu Bala Dheeraj Pandey Nikita Patel Sheetal Yadav Abha Sharma Department of medicinal chemistry National Institute of Pharmaceutical Education and Research RaebareliTransit Campus

Herein,a colorimetric chemosensor （probe 7） was designed and synthesized for sensing diethyl cyanophosphonate （DCNP）,a Tabun nerve agent *** sensitive,selective,fast response and photostable probe 7 in dimethylsulfoxide （DMSO）responded to DCNP at low concentrations with visual naked eye color change from pink to pale yellow and displayed unresponsive behaviour against various interferences except for copper ions,which can be di?erentiated by adding ethylene diamine where the yellow color persisted in the case of DCNP but turned to pink in the case of copper ***,the yellow aqueous solution of probe 7 at pH 10 and 12 turned colorless against the response of *** limit of detection（LOD） of probe 7 was found to be 50 nmol/L in an aqueous basic solution at pH 10 for the detection of *** formation of the cyclized product was elucidated by1H and31P NMR nuclear magnetic resonance (1H NMR,31P NMR),Fourier transform infrared spectroscopy （FTIR）,and high-resolution mass spectrometry （HRMS） ***?lter paper and silica plate loaded with probe 7 were fabricated for real-time and on-site detection of DCNP.

关键词： Chemosensor Colorimetric Fluorescence Tabun mimic

Discovery of GluN2A subtype-selective N-methyl-d-aspartate(NMDA)receptor ligands

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1987-2005页

作者： Liyang Jiang Na Liu Fabao Zhao Boshi Huang Dongwei Kang Peng Zhan Xinyong Liu Department of medicinal chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

The N-methyl-d-aspartate(NMDA)receptors,which belong to the ionotropic Glutamate receptors,constitute a family of ligand-gated ion *** the various subtypes of NMDA receptors,the GluN1/2A subtype plays a significant role in central nervous system(CNS)*** present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors,encompassing negative allosteric modulators(NAMs),positive allosteric modulators(PAMs)and competitive ***,the ligands’structure–activity relationships(SARs)and the binding models of representative ligands are also discussed,providing valuable insights for the clinical rational design of effective drugs targeting CNS diseases.

关键词： NMDA receptors GluN2A subtype Subtype-selective ligands SARs Protein ligand interactions

MKK4 inhibitor:the hope for liver failure prevention and potential small liver graft transplantation

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Chinese Journal of Natural Medicines 2024年第6期22卷 483-485页

作者： ZHANG Yanqiu ZHANG Hao Jiangsu Key laboratory of Bioactive Natural Product Research Department of Natural Medicinal ChemistryChina Pharmaceutical UniversityNanjing 210009China

Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical *** Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subjected to a severe *** was bound to a rock where,each day,an eagle would feast on his liver,which would then miracu-lously regenerate *** myth underscores the liver’s unique regenerative abilities,a feature that is not just le-gendary but also scientifically recognized.

关键词： Liver regeneration Partial hepatectomy MKK4 Drug discovery and development First-in-human phase I trial

Tumor-targeted metabolic inhibitor prodrug labelled with cyanine dyes enhances immunoprevention of lung cancer

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Acta Pharmaceutica Sinica B 2024年第2期14卷 751-764页

作者： Wen Li Jiali Huang Chen Shen Weiye Jiang Xi Yang Jingxuan Huang Yueqing Gu Zhiyu Li Yi Ma Jinlei Bian State Key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China Department of Biomedical Engineering School of EngineeringChina Pharmaceutical UniversityNanjing 210009China Jiangsu Key laboratory of Drug Design and Optimization Department of Medicinal ChemistrySchool of PharmacyChina Pharmaceutical UniversityNanjing 210009China

Recent progress in targeted metabolic therapy of cancer has been limited by the considerable toxicity associated with such *** address this challenge,we developed a smart theranostic prodrug system that combines a fluorophore and an anticancer drug,specifically 6-diazo-5-oxo-L-norleucine(DON),using a thioketal linkage(TK).This system enables imaging,chemotherapy,photodynamic therapy,and on-demand drug release upon radiation *** optimized prodrug,DON-TK-BM3,incorporating cyanine dyes as the fluorophore,displayed potent reactive oxygen species release and efficient tumor cell *** the parent drug DON,DON-TK-BM3 exhibited no toxicity toward normal ***,DON-TK-BM3 demonstrated high tumor accumulation and reduced side effects,including gastrointestinal toxicity,in *** study provides a practical strategy for designing prodrugs of metabolic inhibitors with significant toxicity stemming from their lack of tissue selectivity.

关键词： Smart prodrug system Glutamineantagonists Immunotherapy Photodynamictherapy Reactive oxygen species Metabolicinhibitor Cyaninedye Non-small-cell lung cancer(NSCLC)

Peroxisome Proliferator-Activated Receptor-γCoactivator-1αin the Spotlight with Multiple Sclerosis

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Neuroscience Bulletin 2024年第2期40卷 268-272页

作者： Ya-Na Yang Mao-Qing Zhang Feng-Lin Yu Bing Han Ming-Yue Bao Yan He Xing Li Yuan Zhang Key laboratory of medicinal Resources and Natural pharmaceutical chemistry(Shaanxi Normal University) The Ministry of EducationXi’an 710119China College of Life Sciences Shaanxi Normal UniversityXi’an 710119China

Multiple sclerosis(MS)is a chronic and incurable autoimmune disease of the central nervous system(CNS)that results in neuro-inflammation and *** therapies for MS alleviate symptoms to some extent but fail to realize myelin ***,it is crucial to identify effective targets to promote *** a widely expressed transcriptional regulator,peroxisome proliferatoractivated receptor-coactivator-1α(PGC-1α)expresses in different cells with high energy consumption,including skeletal muscle cells,brown fat cells,neurons,astrocytes,and oligodendrocyte precursor cell(OPC)[1].Targeting PGC-1αmay be beneficial for CNS development and various neurodegenerative diseases.

关键词： inflammation myelin autoimmune

“Three-in-one” strategy of trifluoromethyl regulated blood-brain barrier permeable fluorescent probe for peroxynitrite and antiepileptic evaluation of edaravone

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Chinese Chemical Letters 2024年第10期35卷 386-389页

作者： Lei Shen Hongmei Liu Ming Jin Jinchao Zhang Caixia Yin Shuxiang Wang Yutao Yang Key laboratory of medicinal chemistry and Molecular Diagnosis of the Ministry of Education Chemical Biology Key Laboratory of Hebei Province State Key Laboratory of New Pharmaceutical Preparations and Excipients College of Chemistry and Materials Science Hebei University Key laboratory of Chemical Biology and Molecular Engineering of Ministry of Education Institute of Molecular Science Shanxi University

Epilepsy, as a chronic neurological disease of the brain, is closely related to oxidative stress, and the peroxynitrite(ONOO-) significantly rise up in this event. Therefore, ONOO-is considered as a potential biomarker for early prediction of epilepsy. However, some potential diagnostic reagents for epilepsy are hindered by the blood-brain barrier(BBB). Meanwhile, “drug repurposing” is attracting a growing interest. Edaravone(EDA), as a first-line drug in the clinical treatment of cerebral ischemia, plays antioxidant roles in scavenging free radicals, promising potential antiepileptic activity. Thus, it is imperative to develop fluorescent probes for monitoring ONOO-fluctuations in the epileptic brain. Hence, we proposed a novel fluorescent probe with the thiocarbonate as the promising recognition unit for ONOO-and dicyanoisophorone derivative as the fluorophore. Moreover, by the “three-in-one” strategy, the introduction of trifluoromethyl into DCI-ONOO-3 can extend the emission wavelength of the fluorophore, shorten the response and increase lipophilicity. Consequently, DCI-ONOO-3 was used for monitoring ONOO-fluxes in brain of epileptic mice and evaluating the antiepileptic efficacy of EDA. It opens up a new way for the design of BBB permeable fluorescent probes, and provides a convincing new method for the diagnosis and treatment of epilepsy.

关键词： Blood-brain barrier Drug repurposing Epilepsy Fluorescent probe Peroxynitrite