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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

Generic Interpretable Reaction Condition Predictions with open Reaction Condition Datasets and Unsupervised Learning of Reaction Center

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Research 2024年第2期2023卷 773-794页

作者： Xiaorui Wang Chang-Yu Hsieh Xiaodan Yin Jike Wang Yuquan Li Yafeng Deng Dejun Jiang Zhenxing Wu Hongyan Du Hongming Chen Yun Li Huanxiang Liu Yuwei Wang Pei Luo Tingjun Hou Xiaojun Yao Dr.Neher's Biophysics laboratory for lnnovative drug discovery State Key Laboratory of Quality Research in Chinese MedicineMacao Institute for Applied Research in Medicine and HealthMacao University of Science and TechnologyMacao999078China innovation institute for Artificial Intelligence in Medicine of Zhejiang University College of Pharmaceutical SciencesZhejiang UniversityHangzhou310058China Faculty of Applied Sciences Macao Polytechnic UniversityMacao999078China College of Chemistry and chemical Engineering Lanzhou UniversityLanzhou730000China Carbon Silicon AI technology Co. LtdHangzhouZhejiang 310018China Center of Chemistry and chemical biology Guangzhou Regenerative Medicine and Health Guangdong LaboratoryGuangzhou 510530China College of Pharmacy Shaanxi University of Chinese MedicineXianyangShaanxi712044China

Effective synthesis planning powered by deep learning(DL)can significantly accelerate the discovery of new drugs and ***,most DL-assisted synthesis planning methods offer either none or very limited capability to recommend suitable reaction conditions(RCs)for their reaction ***,the prediction of RCs with a DL framework is hindered by several factors,including:(a)lack of a standardized dataset for benchmarking,(b)lack of a general prediction model with powerful representation,and(c)lack of *** address these issues,we first created 2 standardized RC datasets covering a broad range of reaction classes and then proposed a powerful and interpretable Transformer-based RC predictor named *** careful design of the model architecture,pretraining method,and training strategy,Parrot improved the overall top-3 prediction accuracy on catalysis,solvents,and other reagents by as much as 13.44%,compared to the best previous model on a newly curated ***,the mean absolute error of the predicted temperatures was reduced by about 4℃.Furthermore,Parrot manifests strong generalization capacity with superior cross-chemical-space prediction *** analysis indicates that Parrot effectively captures crucial chemical information and exhibits a high level of interpretability in the prediction of *** proposed model Parrot exemplifies how modern neural network architecture when appropriately pretrained can be versatile in making reliable,generalizable,and interpretable recommendation for RCs even when the underlying training dataset may still be limited in diversity.

关键词： versatile absolute generalization

Evolution of chemistry and selection technology for DNA-encoded library

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Acta Pharmaceutica Sinica B 2024年第2期14卷 492-516页

作者： Peixiang Ma Shuning Zhang Qianping Huang Yuang Gu Zhi Zhou Wei Hou Wei Yi Hongtao Xu Shanghai Key laboratory of Orthopedic Implants Department of OrthopedicsShanghai Ninth People’s HospitalShanghai Jiao Tong UniversitySchool of MedicineShanghai 200025China Shanghai institute for Advanced Immunochemical Studies ShanghaiTech UniversityShanghai 201210China Guangzhou Municipal and Guangdong Provincial Key laboratory of molecular Target&Clinical Pharmacology The NMPA and State Key Laboratory of Respiratory DiseaseGuangzhou Medical UniversityGuangzhou 511436China College of Pharmaceutical Science and institute of drug Development&chemical biology Zhejiang University of TechnologyHangzhou 310014China

DNA-encoded chemical library(DEL)links the power of amplifiable genetics and the nonself-replicating chemical phenotypes,generating a diverse chemical *** analogy with the biological world,the DEL world can evolve by using a chemical central dogma,wherein DNA replicates using the PCR reactions to amplify the genetic codes,DNA sequencing transcripts the genetic information,and DNA-compatible synthesis translates into chemical ***,DNA-compatible synthesis is the key to expanding the DEL chemical ***,the evolution-driven selection system pushes the chemicals to evolve under the selective pressure,i.e.,desired selection *** this perspective,we summarized recent advances in expanding DEL synthetic toolbox and panning strategies,which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.

关键词： DNA-encoded library drug discovery High-throughput selection DNA-compatible synthesis In vitro evolution chemical central dogma

A selective HK2 degrader suppresses SW480 cancer cell growth by degrading HK2

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Chinese chemical Letters 2024年第8期35卷 201-204页

作者： Yang Liu Yan Liu Kaiyin Yang Zhiruo Zhang Wenbo Zhang Bingyou Yang Hua Li Lixia Chen Wuya College of Innovation Key Laboratory of Structure-Based Drug Design&DiscoveryMinistry of EducationShenyang Pharmaceutical UniversityShenyang 110016China Key laboratory of Basic and Application Research of Beiyao Ministry of EducationHeilongjiang University of Chinese MedicineHarbin 150006China institute of Structural Pharmacology&TCM chemical biology College of PharmacyFujian University of Traditional Chinese MedicineFuzhou 350122China Hubei Key laboratory of Natural Medicinal Chemistry and Resource Evaluation School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Hexokinase 2(HK2)is the rate-limiting enzyme in the first step of glycolysis,catalyzing glucose to glucose-6-phosphate,and overexpressed in most cancer ***2 also binds to voltage-dependent anion channel(VDAC)to stabilize the mitochondrial outer membrane,which inhibits cancer cell ***,HK2 has become a potential target for cancer *** targeting chimeras(PROTACs)are hetero-bifunctional molecules that recruit an E3 ubiquitin ligase to a given substrate protein resulting in its targeted *** potent and specific PROTACs targeting dissimilar targets have been *** this study,an HK2 PROTAC,4H-5P-M,was developed and induced the degradation of HK2 relying on the ubiquitin-proteasome *** was found that 4H-5P-M as an effective HK2 degrader induced HK2 degradation in a dose-and time-dependent manner and suppressed the growth of SW480 cells.4H-5P-M selectively induced HK2 degradation at a lower concentration than other hexokinase ***,it could suppress glycolysis and accelerate the apoptosis of cancer ***,it provided a new insight into the development of anti-tumor drugs.

关键词： HK2 PROTACs Degrader Anti-tumor SW480

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

Advancements in life-on-a-chip: The impact of “Beyond Limits Manufacturing” technology

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Chinese chemical Letters 2024年第5期35卷 13-16页

作者： Weiwei He Hongbo Zhang Xudong Lin Lili Zhu Tingting Zheng Hao Pei Yang Tian Min Zhang Guoyue Shi Lei Wu Jianlong Zhao Gulinuer Wumaier Shengqing Li Yufang Xu Honglin Li Xuhong Qian Shanghai Key laboratory of New drug Design School of PharmacyEast China University of Science and TechnologyShanghai 200237China School of Mechanical and Power Engineering East China University of Science and TechnologyShanghai 200237China Guangdong Provincial Key laboratory of Sensor technology and Biomedical Instrument School of Biomedical EngineeringShenzhen Campus of Sun Yat-sen UniversityShenzhen 518000China Shanghai Key laboratory of Green Chemistry and chemical Processes Department of ChemistrySchool of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai 200241China Shanghai institute of Microsystem and Information technology Chinese Academy of SciencesShanghai 200050China Department of Pulmonary and Critical Care Medicine Huashan HospitalFudan UniversityShanghai 200040China Innovation Center for AI and drug discovery East China Normal UniversityShanghai 200062China Lingang laboratory Shanghai 200031China

This review explores the concept of life-on-a-chip,which involves the creation of miniaturized biological systems,such as organs,tissues,and model organisms,on microscale platforms called microfluidic *** chips consist of intricately etched channels,wells,and chambers that enable precise control and observation of fluids,cells,and biochemical reactions,facilitating the simulation of various aspects of human or animal physiology and the study of responses to different stimuli,drugs,or disease *** review highlights the application of a novel technology,“Beyond Limit Manufacturing”(BLM),in the development of sophisticated three-dimensional cell models and model organism ***-on-a-chip and organ-on-a-chip(OoC)are among the thriving developments in the field of microfluidics,allowing for the reconstruction of living microenvironments and implementation of multiple *** review discusses the latest advancements in life-on-a-chip technology using BLM and outlines potential future research directions,emphasizing the significant role of these chips in studying complex biological processes in a controlled and scalable manner.

关键词： Beyond Limit Manufacturing Model-organism-on-a-chip Organ-on-a-chip

Design,synthesis,and biological evaluation of 1,2,4-triazole derivatives as potent antitubercular agents

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Chinese chemical Letters 2024年第3期35卷 326-331页

作者： Yu Wen Shichun Lun Yuxue Jiao Wei Zhang Tianyu Hu Ting Liu Fan Yang Jie Tang Bing Zhang William R.Bishai Li-Fang Yu Shanghai Engineering Research Center of molecular Therapeutics and New drug Development School of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai 200062China Center for Tuberculosis Research Department of MedicineDivision of Infectious DiseaseJohns Hopkins School of MedicineBaltimoreMD21231-1044United States Shanghai institute for Advanced Immunochemical Studies and School of Life Science and technology ShanghaiTech UniversityShanghai 201210China Shanghai Key laboratory of Green Chemistry and chemical Process School of Chemistry and Molecular EngineeringEast China Normal UniversityShanghai 200062China

Inhibition of mycobacterial membrane protein large 3(MmpL3)thereby affecting the mycolic acid biosynthetic pathway has been proven to be an effective strategy for developing antitubercular *** on the X-ray crystal structure of MmpL3 inhibitor complexes,a series of novel 1,2,4-triazole derivatives were designed,synthesized and evaluated antitubercular activity against Mtb strain *** structure–activity relationship exploration resulted in the identification of compounds 21 and 28,which possess potent antitubercular activity against Mtb strain H37Rv[minimum inhibitory concentration(MIC)=0.03–0.13μg/mL]and the clinical isolates of multidrug resistance(MDR)and extensive drug resistance(XDR)tuberculosis(MIC=0.06–1.0μg/mL).Moreover,compounds 21 and 28 showed neglectable cytotoxicity(IC_(50)≥32μg/mL)to the mammalian Vero cells and favorable physicochemical and pharmacokinetic properties according to the in silico absorption,distribution,metabolism and excretion(ADME)***,the potential target of representative 1,2,4-triazole 28 was identified to be MmpL3 using a microscale thermophoresis(MST)assay.

关键词： Tuberculosis MDR and XDR-TB MmpL3 inhibitor 1 2 4-Triazole Structure-based drug design

Bio-soft matter derived from traditional Chinese medicine:Characterizations of hierarchical structure,assembly mechanism,and beyond

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Journal of Pharmaceutical Analysis 2024年第6期14卷 823-839页

作者： Guiya Yang Yue Liu Yuying Hu Yue Yuan Yunan Qin Quan Li Shuangcheng Ma School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing102488China institute for Control of Chinese Traditional Medicine and Ethnic Medicine National Institutes for Food and Drug ControlBeijing100050China Tianjin Key laboratory of Therapeutic Substance of Traditional Chinese Medicine School of Chinese Materia MedicaTianjin University of Traditional Chinese MedicineTianjin301617China Collaborative Innovation Center for Advanced Organic chemical Materials Co-constructed by the Province and Ministry Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional MoleculesCollege of Chemistry and Chemical EngineeringHubei UniversityWuhan430062China

Structural and functional explorations on bio-soft matter such as micelles,vesicles,nanoparticles,aggregates or polymers derived from traditional Chinese medicine(TCM)has emerged as a new topic in the field of *** discovery of such cross-scaled bio-soft matter may provide a unique perspective for unraveling the new effective material basis of TCM as well as developing innovative medicine and *** the rapid rise of TCM-derived bio-soft matter,their hierarchical structure and assembly mechanism must be unambiguously probed for a further in-depth understanding of their pharmacological *** this review,the current emerged TCM-derived bio-soft matter assembled from either small molecules or macromolecules is introduced,and particularly the unambiguous elucidation of their hierarchical structure and assembly mechanism with combined electron microscopic and spectroscopic techniques is *** pros and cons of each technique are also *** future challenges and perspective of TCM-derived bio-soft matter are outlined,particularly the requirement for their precise in situ structural determination is highlighted.

关键词： Electron microscopy Spectroscopy Traditional Chinese medicine Bio-soft matter Structural characterization

Intelligent design and construction of novel APN-based theranostic probe driven by advanced computational methods

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Chinese chemical Letters 2024年第2期35卷 352-357页

作者： Yingli Zhu Jie Qian Kunqian Yu Jing Hou Yeshuo Ma Fei Chen Jie Dong Wenbin Zeng Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410083China National Engineering Research Center of Rice and Byproduct Deep Processing School of Food Science and EngineeringCentral South University of Forestry and TechnologyChangsha 410004China State Key laboratory of drug Research Drug Discovery and Design CenterShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Department of Geriatrics Third Xiangya HospitalCentral South UniversityChangsha 410013China

Multifunctional molecules with both optical signal and pharmacological activity play an important role in drug development,disease diagnosis,and basic theoretical *** N(APN),as a representative tumor biomarker with anti-tumor potential,still lacks a high-precision theranostic probe specifically targeting *** this study,a novel quaternity design strategy for APN theranostic probe was *** proposed strategy utilizes advanced machine learning and molecular dynamics simulations,and cleverly employs the strategy of conformation-induced fluorescence recovery to achieve multi-objective optimization and integration of functional *** this strategy,a unique“Off-On”theranostic probe,ABTP-DPTB,was ingeniously constructed to light up APN through fluorescence restoration,relying on conformation-induced effects and solvent *** from the common diagnostic probes,the intelligent design with non-substrated linkage makes ABTP-DPTB for long-term in-situ *** fabricated probe was used for detecting and inhibiting APN in various environments,with a better in vitro inhibitory than golden-standard drug bestatin.

关键词： Theranostic probe Artificial intelligence Conformational restriction Fluorescence restoration Design strategy