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Science China Chemistry 2024年第1期67卷 368-373页

作者： Xing-Yu Wang Pei Xu Wen-Wen Liu Hao-Qiang Jiang Song-Lei Zhu Dong Guo Xu Zhu jiangsu key laboratory of new drug research and clinical pharmacy School of PharmacyXuzhou Medical UniversityXuzhou 22100China

Unprecedented divergent synthesis of gem-difluorovinylacetic acid and glutaric acid derivatives fromα-CF_(3)alkenes with formate as the carbonyl source was *** reaction can undergo selective mono-or triple C-F bond cleavage by simply switching the photocatalyst and hydrogen atom transfer(HAT)catalyst under visible-light-induced conditions at room *** acts as both the C1 source and the reductant through the generation of CO_(2)^(·-)species,which underwent Giese radical addition to electron-deficient alkenes to trigger the consecutive C-F bond cleavage and carboxylation process.

关键词： C-F bond activation defluorocarboxylation carbon dioxide radical anion visible light

Allosterically activating SHP2 by oleanolic acid inhibits STAT3-Th17 axis for ameliorating colitis

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2598-2612页

作者： Jinbo Hu Wen Liu Yi Zou Chenyang Jiao Jiazhen Zhu Qiang Xu Jianjun Zou Yang Sun Wenjie Guo State key laboratory of Pharmaceutical Biotechnology Nanjing Drum Tower HospitalSchool of Life SciencesNanjing UniversityNanjing 210093China Department of clinical Pharmacology Nanjing First HospitalNanjing Medical UniversityNanjing 210006China jiangsu key laboratory of new drug research and clinical pharmacy Xuzhou Medical UniversityXuzhou 221004China

Src homology 2 domain-containing tyrosine phosphatase 2(SHP2)is an essential tyrosine phosphatase that is pivotal in regulating various cellular signaling pathways such as cell growth,differentiation,and *** activation of SHP2 has been shown to have a therapeutic effect in colitis and Parkinson's ***,the identification of SHP2 activators and a complete understanding of their mechanism is *** used a two-step screening assay to determine a novel allosteric activator of SHP2 that stabilizes it in an open *** acid was identified as a suitable *** binding to R362,K364,and K366 in the active center of the PTP domain,oleanolic acid maintained the active open state of SHP2,which facilitated the binding between SHP2 and its *** oleanolic acid-activated SHP2 hindered Th17 differentiation by disturbing the interaction between STAT3 and IL-6Rαand inhibiting the activation of ***,via the activation of SHP2 and subsequent attenuation of the STAT3-Th17 axis,oleanolic acid effectively mitigated colitis in *** protective effect was abrogated by SHP2 knockout or administration of the SHP2 inhibitor *** findings underscore the potential of oleanolic acid as a promising therapeutic agent for treating inflammatory bowel diseases.

关键词： Oleanolic acid SHP2 STAT3 Th17 Colitis Allosteric activator

Metformin:A promising clinical therapeutical approach for BPH treatment via inhibiting dysregulated steroid hormones-induced prostatic epithelial cells proliferation

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Journal of Pharmaceutical Analysis 2024年第1期14卷 52-68页

作者： Tingting Yang Jiayu Yuan Yuting Peng Jiale Pang Zhen Qiu Shangxiu Chen Yuhan Huang Zhenzhou Jiang Yilin Fan Junjie Liu Tao Wang Xueyan Zhou Sitong Qian Jinfang Song Yi Xu Qian Lu Xiaoxing Yin jiangsu key laboratory of new drug research and clinical pharmacy Xuzhou Medical UniversityXuzhouJiangsu221004China Department of pharmacy Affiliated Lianyungang Hospital of Xuzhou Medical UniversityLianyungangJiangsu222061China Department of pharmacy The Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsu221006China new drug Screening Center Jiangsu Center for Pharmacodynamics Research and EvaluationChina Pharmaceutical UniversityNanjing210009China School of Life Sciences University of EssexEssex CO43SQUnited Kingdom Department of Urology The Affiliated Hospital of Xuzhou Medical UniversityXuzhouJiangsu221006China Department of pharmacy Affiliated Hospital of Jiangnan UniversityWuxiJiangsu214000China

The occurrence of benign prostate hyperplasia(BPH)was related to disrupted sex steroid hormones,and metformin(Met)had a clinical response to sex steroid hormone-related gynaecological ***,whether Met exerts an antiproliferative effect on BPH via sex steroid hormones remains ***,our clinical study showed that along with prostatic epithelial cell(PEC)proliferation,sex steroid hormones were dysregulated in the serum and prostate of BPH *** the major contributor to dysregulated sex steroid hormones,elevated dihydrotestosterone(DHT)had a significant positive relationship with the clinical characteristics of BPH *** of adenosine 5'-monophosphate(AMP)-activated protein kinase(AMPK)by Met restored dysregulated sex steroid hormone homeostasis and exerted antiproliferative effects against DHT-induced proliferation by inhibiting the formation of androgen receptor(AR)-mediated Yes-associated protein(YAP1)-TEA domain transcription factor(TEAD4)***’s anti-proliferative effects were blocked by AMPK inhibitor or YAP1 overexpression in DHT-cultured BPH-1 *** findings indicated that Met would be a promising clinical therapeutic approach for BPH by inhibiting dysregulated steroid hormone-induced PEC proliferation.

关键词： Metformin Benign prostatic hyperplasia Sex steroid hormones homeostasis Proliferation DHT YAP1-TEAD4 heterodimer

Engineered extracellular vesicles efficiently deliver CRISPR-Cas9 ribonucleoprotein(RNP)to inhibit herpes simplex virus1 infection in vitro and in vivo

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1362-1379页

作者： Yuanda Wan Liren Li Ruilin Chen Jiajia Han Qiyun Lei Zhipeng Chen Xiaodong Tang Wenyu Wu Shuwen Liu Xingang Yao NMPA key laboratory for research and Evaluation of drug Metabolism Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Center of clinical pharmacy Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China State key laboratory of Ophthalmology Zhongshan Ophthalmic CenterSun Yat-sen UniversityGuangzhou 510060China key laboratory of Infectious Diseases research in South China(Southern Medical University) Ministry of EducationGuangzhou 510515China

Extracellular vesicles(EVs)have recently emerged as a promising delivery platform for CRISPR/Cas9 ribonucleoproteins(RNPs),owing to their ability to minimize off-target effects and immune ***,enhancements are required to boost the efficiency and safety of Cas9 RNP enrichment within *** response,we employed the Fc/Spa interaction system,in which the human Fc domain was fused to the intracellular domain of PTGFRN-Δ687 and anchored to the EV ***,the B domain of the Spa protein was fused to the C domain of cargos such as Cre or *** to the robust interaction between Fc and Spa,this method enriched nearly twice the amount of cargo within the *** loaded with spCas9 RNP targeting the HSV1 genome exhibited significant inhibition of viral replication in vitro and in ***,following neuron-targeting peptide RVG modification,the in vivo dosage in neural tissues substantially increased,contributing to the clearance of the HSV1 virus in neural tissues and exhibiting a lower off-target *** findings establish a robust platform for efficient EV-based SpCas9 delivery,offering potential therapeutic advantages for HSV1 infections and other neurological disorders.

关键词： Extracellular vesicles CRISPR/Cas9 Ribonucleoproteins PTGFRN Fc/Spa HSV1 Neuron-targeting Delivery

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

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Acta Pharmaceutica Sinica B 2024年第7期14卷 3232-3250页

作者： Ping Yu Tanwei Gu Yueyang Rao Weimin Liang Xi Zhang Huanguo Jiang Jindi Lu Jianglian She Jianmin Guo Wei Yang Yonghong Liu Yingfeng Tu Lan Tang Xuefeng Zhou Guangdong Provincial key laboratory of new drug Screening Guangdong-Hong Kong-Macao Joint Laboratory for New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China CAS key laboratory of Tropical Marine Bio-Resources and Ecology Guangdong Key Laboratory of Marine Materia MedicaSouth China Sea Institute of OceanologyChinese Academy of SciencesGuangzhou 510301China NMPA key laboratory for research and Evaluation of drug Metabolism School of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou 510515China Guangdong Lewwin Pharmaceutical research Institute Co. Ltd.Guangdong Provincial Key Laboratory of Drug Non-Clinical Evaluation and ResearchGuangdong Engineering Research Center for Innovative Drug Evaluation and ResearchGuangzhou 510990China

Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its *** study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)***,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS *** to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed *** developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 *** encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,*** main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated *** summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

关键词： Acute kidney injury Piericidin glycoside Peroxiredoxin 1 Nanodrug Kim-1 targeted ADME Marine drug druggability

Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

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Acta Pharmaceutica Sinica B 2024年第2期14卷 517-532页

作者： Shuang Xiang Xiaoyun Lu International Cooperative laboratory of Traditional Chinese Medicine Modernization and Innovative drug Discovery of Chinese Ministry of Education(MOE) Guangdong Provincial Key Laboratory of New Drug Design and EvaluationGuangzhou City Key Laboratory of Precision Chemical Drug DevelopmentSchool of PharmacyJinan UniversityGuangzhou 510632China

Neurotrophic receptor kinase(NTRK) fusions are actionable oncogenic drivers of multiple pediatric and adult solid tumors,and tropomyosin receptor kinase(TRK) has been considered as an attractive therapeutic target for "pan-cancer" harboring these ***,two generations TRK inhibitors have been *** representative second-generation inhibitors selitrectinib and repotrectinib were designed to overcome clinic acquired resistance of the first-generation inhibitors larotrectinib or entrectinib resulted from solvent-front and gatekeeper on-target ***,xDFG(TRKAG667C/A/S,homologous TRKCG696C/A/S) and some double mutations still confer resistance to selitrectinib and repotrectinib,and overcoming these resistances represents a major unmet clinical *** this review,we summarize the acquired resistance mechanism of the first-and second-generation TRK inhibitors,and firstly put forward the emerging selective type Ⅱ TRK inhibitors to overcome xDFG mutations mediated ***,we concluded our perspectives on new challenges and future directions in this field.

关键词： NTRK fusions TRK kinase clinical resistance xDFG mutations Selective type II inhibitors

High-throughput fluorescent screening of thioredoxin reductase inhibitors to inhibit Mycobacterium tuberculosis

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Chinese Chemical Letters 2024年第3期35卷 358-362页

作者： Fei Yan Xin Zhao Ruibo Li Xiuyan Han Qiulong Yan Lei Feng Xiulan Xin Jingnan Cui Xiaochi Ma Second Affiliated Hospital Dalian Medical UniversityDalian 116044China State key laboratory of Fine Chemicals Dalian University of TechnologyDalian 116024China jiangsu key laboratory of new drug research and clinical pharmacy Xuzhou Medical UniversityXuzhou 221004China School of Chemistry and Chemical Engineering Henan Normal UniversityXinxiang 453007China College of Bioengineering Beijing PolytechnicBeijing 100029China

Tuberculosis(TB)is a chronic infectious disease,which is caused by the pathogen Mycobacterium tuberculosis(Mtb)and reemerged as a global health risk with a significant proportion of multi-drug resistant and extensively drug resistant TB *** is very urgent to find some novel high-confidence drug targets in Mtb for discovering the effective anti-TB *** reductase(TrxR)has been identified to be a highly viable target for anti-TB drugs for its important role in protecting the pathogen from thiol-specific oxidizing stress,regulating intracellular dithiol/disulfide homeostasis and DNA replication and *** the present work,a near-infrared(NIR)fluorescent probe DDAT was developed for the detection of TrxR activity and used to high-throughput screen the TrxR inhibitors from natural *** screened TrxR inhibitors from Sappan Lignum and microbial metabolites that were further used to inhibit Mycobacterium *** the results indicate that DDAT is a practical fluorescent molecular tool for the discovery of potential anti-TB drugs.

关键词： Thioredoxin reductase NIR fluorescent probe Fluorescence imaging High-throughput screening inhibitors Inhibit Mycobacterium tuberculosis

Cooperative NHC/Photoredox Catalysis:Three-Component Reaction of Aroyl Fluorides,Styrenes and Oxalates

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Chinese Journal of Chemistry 2024年第5期42卷 511-515页

作者： Zheng Lin Guanghui Lv Jianghong Liu Jiangyan Tang Binsong Mu Jian Chen Tianle Huang Zhongzhen Yang Yong Wu key laboratory of drug-Targeting and drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengduSichuan610041 China Department of pharmacy Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem CellsTaihe HospitalHubei University of MedicineShiyanHubei442000 China

Cooperative NHC/photoredox catalysis has emerged as an important research field in recent ***,this article describes the use of cesium salt derivatives of tert-alcohols as alkyl radical precursors in a three-component reaction with styrene and aromatic acyl fluorides to synthesizeα-arylalkyl aryl *** aroyl fluoride reacts with the NHC catalyst,leading to the formation of an acyl azolium *** acyl azolium ion can then be reduced by the photoredox catalyst,generating the corresponding ketyl radical *** C-radical generated from oxalate oxidation undergoes an addition reaction with the styrene derivative,followed by cross-coupling of the addition radical with the ketone radical,which is fragmented by NHC to give the target ketone.

关键词： Three-component Photoredox NHC Aryl ketones Iridium Radical C—C coupling Amides

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

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