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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

discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer

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Acta Pharmaceutica Sinica B 2024年第8期14卷 3605-3623页

作者： Zehui Tan Ning Guo Zhi Cao Shuyu Liu Jiayu Zhang Deyi Ma Jiahao Zhang Wencai Lv Nan Jiang Linghe Zang Lihui Wang Xin Zhai key laboratory of Structure-Based drug design and discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmacology Shenyang Pharmaceutical UniversityShenyang 110016China

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung ***,a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q *** most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation,self-renewal,migration,and invasion of lung cancer cell lines at low micromolar *** cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS *** the H460R231Q OE cell-derived xenograft(CDX)model,37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks(TGI=54.38%),without obvious toxicities.A pharmacokinetic study revealed that 37 possessed tolerable properties(t_(1/2)=1.93±0.91 h,F=97.2%)after intraperitoneal administration in *** study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling ***,analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the“Induced-fit”allosteric model in favor to the discovery of potent DOT1L candidates.

关键词： DOT1L R231Q mutation Lung cancer Adenosine-containing inhibitors Epigenetics

Sigmatropic rearrangements of B(MIDA)-propargylic alcohols towards the diverse synthesis of α-functionalized organoborons

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Science China Chemistry 2024年第2期67卷 568-575页

作者： Jiasheng Qian Li-Cai Liu Zhi-Hao Chen Yuan Liu Yin Li Qingjiang Li Honggen Wang Guangdong key laboratory of Chiral Molecule and drug discovery School of Pharmaceutical SciencesSun Yat-Sen UniversityGuangzhou510006China

α-Functionalized organoborons are useful building blocks and key structural elements in functional *** previous synthesis relied on the famous Matteson reaction or the late-stage borylative modification of alkynes or ***,the synthetic transformation of borylated building blocks offers another useful strategy and is currently actively *** report herein that B(MIDA)-propargylic alcohols(BPAs) are a useful type of borylated building *** two complementary functional group handles(alkyne and hydroxyl) in close proximity,the redox-neutral [3,3] and [2,3] sigmatropic rearrangements of BPAs allow the efficient synthesis of several types of α-functionalized boronates,including α,β-unsaturated acylborons,α-S/P-substituted allenylborons,boryl-substituted thiazoles and a borylated α,β-unsaturated hydrazine,some of which are otherwise challenging targets using other synthetic methods.

关键词： organoboron diverse synthesis sigmatropic rearrangement heteroarene amide

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

discovery of antitumor diterpenoids from Casearia graveolens targeting VEGFR-2 to inhibit angiogenesis

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Chinese Journal of Natural Medicines 2024年第9期22卷 842-853页

作者： WANG Sibei LIU Yuhui LIANG Yue XI Yaru ZHAI Yupeng LEE Dongho XU Jing GUO Yuanqiang State key laboratory of Medicinal Chemical Biology College of Pharmacyand Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300350China State key laboratory of Functions and Applications of Medicinal Plants Guizhou Medical UniversityGuiyang 550014China Department of Plant Biotechnology College of Life Sciences and BiotechnologyKorea UniversitySeoul 02841South Korea

Eight novel clerodane diterpenoids(1-8)were isolated from the twigs of Casearia *** structures were elucidated through comprehensive nuclear magnetic resonance(NMR),high-resolution electrospray ionization mass spectrometry(HRESI-MS),and electronic circular dichroism(ECD)*** addition to structural determination,surface plasmon resonance(SPR)assays were conducted to investigate molecular interactions,revealing that compound 8 exhibited high affinity for vascular endothelial growth factor receptor 2(VEGFR2),a key regulator of tumor *** in vivo experiments demonstrated that compound 8 effectively inhibited angiogenesis and displayed significant antitumor activity by suppressing tumor proliferation and metastasis in zebrafish xenograft *** findings suggest that compound 8 holds promise as an anticancer lead compound targeting VEGFR-2 to obstruct tumor angiogenesis.

关键词： Clerodane diterpenoids Casearia graveolens Surface plasmon resonance Vascular endothelial growth factor receptor 2 Antitumor activity Zebrafish

A review of structural modification and biological activities of oleanolic acid

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Chinese Journal of Natural Medicines 2024年第1期22卷 15-30页

作者： YANG Huali DENG Minghui JIA Hongwei ZHANG Kaicheng LIU Yang CHENG Maosheng XIAO Wei State key laboratory of New-tech for Chinese Medicine Pharmaceutical Process Jiangsu Kanion Pharmaceutical Co.Ltd.Lianyungang 222001China key laboratory of Structure-Based drug design&discovery of Ministry of Education School of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang 110016China

Oleanolic acid(OA),a pentacyclic triterpenoid,exhibits a broad spectrum of biological activities,including antitumor,antiviral,antibacterial,anti-inflammatory,hepatoprotective,hypoglycemic,and hypolipidemic *** its initial isolation and identification,numerous studies have reported on the structural modifications and pharmacological activities of OA and its *** this,there has been a dearth of comprehensive reviews in the past two decades,leading to challenges in subsequent research on *** on the main biological activities of OA,this paper comprehensively summarized the modification strategies and structureactivity relationships(SARs)of OA and its derivatives to provide valuable reference for future investigations into OA.

关键词： Oleanolic acid Derivatives Pentacyclic triterpenoid Structural modification Biological activities

Understanding the cooperative effects in the catalysis of homodimeric fluoroacetate dehalogenase

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Science China Chemistry 2024年第7期67卷 2382-2391页

作者： Ke-Wei Chen Jia-Nan Chen Jun Zhang Chao Wang Tian-Yu Sun Yun-Dong Wu key laboratory of Computational Chemistry and drug design State Key Laboratory of Chemical OncogenomicSchool of Chemical Biology and BiotechnologyPeking University Shenzhen Graduate SchoolShenzhen 518055China Institute of Chemical Biology Shenzhen Bay LaboratoryShenzhen 518132China College of Chemistry and molecular Engineering Peking UniversityBeijing 100871China Changping laboratory Beijing 102200China

Fluoroacetate dehalogenases(FAcD),a homodimeric enzyme,catalyzes the conversion of fluoroacetic acid to glycolic acid(GoA).It has been proved that the enzyme has a half-of-the-site ***,its catalytic(C)subunit converts the first substrate to a covalent intermediate;then,the non-catalytic(NC)subunit binds a second substrate and promotes the conversion of the intermediate in the C subunit into the final *** the release of the product,the C subunit becomes the NC subunit,and the previous NC subunit becomes the C *** elucidate the detailed mechanism behind this cooperative catalysis,we have conducted microsecond-scale MD simulations along the reaction *** simulations indicate that the substrate in the NC subunit induces W185 and Y141 adopting an open conformation in the C *** opening of W185(C)facilitates the entry of catalytic water,enhancing the catalytic activity for product formation,while the opening of Y141(C)creates an unfavorable environment for product binding,promoting its *** interaction network analysis reveals that the substrate in the NC subunit can induce conformational changes through a conserved water chain at the interface.

关键词： enzyme catalysis molecular dynamics cooperative effect pre-reaction state

A lateral-immobilization zebrafish microfluidic chip-based system for in vivo real-time evaluation of antithrombotic agents

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Chinese Chemical Letters 2024年第3期35卷 312-315页

作者： Lijuan He Hongxia Du Yi Yang Zhihua Guan Jinjin Li Honglin Li Xudong Lin Lili Zhu Shanghai key laboratory of New drug design School of PharmacyEast China University of Science&TechnologyShanghai 200237China Guangdong Provincial key laboratory of Sensor Technology and Biomedical Instrument School of Biomedical EngineeringShenzhen Campus of Sun Yat-sen UniversityShenzhen 518000China Innovation Center for AI and drug discovery East China Normal UniversityShanghai 200062China

Thrombosis remains a major global health concern mainly characterized by high rates of morbidity and *** models serve as an indispensable tool to understand the underlying pathogenesis of thrombosis and assess the efficacy of novel antithrombotic ***,zebrafish has emerged as a valuable model organism for thrombosis ***,the traditional method of studying zebrafish thrombosis requires a laborious and time-consuming procedure,including anesthesia and manual immobilization of *** this study,based on hydrodynamic force,a lateral-immobilization zebrafish microfluidic chip(LIZMC)was designed to evaluate the cardiovascular system of multiple larvae within a single microscope field of ***,coupling with microscope imaging,real-time monitoring of the peripheral blood circulation in the tail of phenylhydrazine(PHZ)-induced zebrafish thrombosis was ***,the reliability of LIZMC for in vivo evaluation of antithrombotic agents in zebrafish was verified using ***,this novel LIZMC-based system can be used for in vivo zebrafish thrombosis studies and rapid screening of antithrombotic agents.

关键词： Microfluidic chip Zebrafish Thrombosis In vivo evaluation Real-time monitor

Rapid discovery of two unprecedented meroterpenoids from Daphne altaica *** molecular networking integrated with MolNetEnhancer and Network Annotation Propagation

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Chinese Chemical Letters 2024年第8期35卷 294-298页

作者： Wei-Yu Zhou Zi-Han Xi Ning-Ning Du Li Ye Ming-Hao Jiang Jin-Le Hao Bin Lin Guo-Dong Yao Xiao-Xiao Huang Shao-Jiang Song key laboratory of Computational Chemistry-Based Natural Antitumor drug Research&Development Liaoning ProvinceEngineering Research Center of Natural Medicine Active Molecule Research&DevelopmentLiaoning ProvinceKey Laboratory of Natural Bioactive Compounds Discovery&ModificationShenyangSchool of Traditional Chinese Materia Medic1Shenyang Pharmaceutical UniversityShenyang 110016China key laboratory of Structure-Based drug design and discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China

Under the guidance of the approach which integrates molecular networking,MolNetEnhancer and Net-work Annotation Propagation(NAP),daphnaltaicanoids A and B(1 and 2)with unprecedented 9-oxa-tetracyclo[6.***.1.0^(2,6).0^(8,13)]pentadecane and tetracyclo[5.***.0.1^(2,5).2^(4,11)]tridecane central frameworks were iso-lated from Daphne altaica Pall.,representing two types of unparalleled meroterpenoid *** struc-tures were elucidated by extensive spectroscopic analysis,nuclear magnetic resonance(NMR)calcula-tions,DP4+analysis and electronic circular dichroism(ECD)*** plausible biosynthetic path-ways for 1 and 2 were ***,2 exerted potent neuroprotective activities which were su-perior to trolox at 12.5 and 25μmol/***,1 and 2 exhibited more noticeable acetylcholinesterase inhibitory activities than *** docking simulations were performed to explore the inter-molecular interaction of compounds 1 and 2 with *** bioactivity evaluation results highlight the prospects of 1 and 2 as a novel category of neurological agents.

关键词： Daphne altaica Pall. molecular networking MolNetEnhancer NAP Unprecedented meroterpenoid frameworks Neuroprotective activities Acetylcholinesterase inhibitors