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Late-stage modification of bioactive compounds:Improving druggability through efficient molecular editing

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1030-1076页

作者： Tongyu Huo Xinyi Zhao Zengrui Cheng Jialiang Wei Minghui Zhu Xiaodong Dou ning jiao State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Changping Laboratory Beijing 102206China Shanghai Key Laboratory of Green Chemistry and Chemical Processes East China Normal UniversityShanghai 200062China

Synthetic chemistry plays an indispensable role in drug discovery,contributing to hit compounds identification,lead compounds optimization,candidate drugs preparation,and so on.As Nobel Prize laureate James Black emphasized,“the most fruitful basis for the discovery of a new drug is to start with an old drug”1.Late-stage modification or functionalization of drugs,natural products and bioactive compounds have garnered significant interest due to its ability to introduce diverse elements into bioactive compounds promptly.Such modifications alter the chemical space and physiochemical properties of these compounds,ultimately influencing their potency and druggability.To enrich a toolbox of chemical modification methods for drug discovery,this review focuses on the incorporation of halogen,oxygen,and nitrogen—the ubiquitous elements in pharmacophore components of the marketed drugs—through late-stage modification in recent two decades,and discusses the state and challenges faced in these fields.We also emphasize that increasing cooperation between chemists and pharmacists may be conducive to the rapid discovery of new activities of the functionalized molecules.Ultimately,we hope this review would serve as a valuable resource,facilitating the application of late-stage modification in the construction of novel molecules and inspiring innovative concepts for designing and building new drugs.

关键词： Late-stage modification Drug space Halogenation Oxygenation Nitrogenation Synthetic chemistry

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C—F Bond Insertion into Indoles with CHBr_(2)F:An Efficient Method to Synthesize Fluorinated Quinolines and Quinolones

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Chinese Journal of Chemistry 2024年第10期42卷 1128-1132页

作者： Chao Li Lei Chen Hongye Wang Zixi Yan Bin Lyu Weiping Lyu Changwei Jiang Dehua Lu Jiaxing Li ning jiao Song Song State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityXue Yuan Rd.38Beijing 100191China

A mild and practical method for synthesizing fluorinated quinoline derivatives,which have a wide range of applications in pharmaceuticals,materials,and organic synthesis,was described through C—F bond insertion into indoles using CHBr_(2)F.The simple conditions,readily availability of CHBr_(2)F,as well as the versatility of the transformations make this strategy very powerful in synthesizing 3-fluoroquinoline and 3-fluoroquinolone.The mechanistic studies reveal that bromofluorocarbene generated in-situ under basic condition was the key intermediate.

关键词： Skeleton edit Fluorocarbene Ring expansion Quinoline Quinolone

Catalytic conversion of mixed polyolefins under mild atmospheric pressure

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The Innovation 2024年第2期5卷 98-106页

作者： Binzhi Zhao Hui Tan Jie Yang Xiaohui Zhang Zidi Yu Hanli Sun Jialiang Wei Xinyi Zhao Yufeng Zhang Lili Chen Dali Yang Jin Deng Yao Fu Zheng Huang ning jiao State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Beijing National Laboratory for Molecular Sciences College of Chemistry and Molecular EngineeringPeking UniversityBeijing 100871China The Institute for Advanced Studies Wuhan UniversityWuhan 430072China Hefei National Laboratory for Physical Sciences at the Microscale CAS Key Laboratory of Urban Pollutant ConversionAnhui Province Key Laboratory of Biomass Clean EnergyiChEMUniversity of Science and Technology of ChinaHefei 230026China State Key Laboratory of Organometallic Chemistry Chinese Academy of SciencesShanghai 200032China

The chemical recycling of polyolefin presents a considerable challenge,especially as upcycling methods struggle with the reality that plastic wastes typically consist of mixtures of polyethylene(PE),polystyrene(PS),and polypropylene(PP).We report a catalytic aerobic oxidative approach for polyolefins upcycling with the corresponding carboxylic acids as the product.This method encompasses three key innovations.First,it operates under atmospheric pressure and mild conditions,using O_(2) or air as the oxidant.Second,it is compatible with high-density polyethylene,low-density polyethylene,PS,PP,and their blends.Third,it uses an economical and recoverable metal catalyst.It has been demonstrated that this approach can efficiently degrade mixed wastes of plastic bags,bottles,masks,and foam boxes.

关键词： mixed Catalytic oxidative

An aircraft brake control algorithm with torque compensation based on RBF neural network

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Chinese Journal of Aeronautics 2024年第1期37卷 438-450页

作者： ning BAI Xiaochao LIU Juefei LI Zhuangzhuang WANG Pengyuan QI Yaoxing SHANG Zongxia jiao School of Automation Science and Electrical Engineering Beihang UniversityBeijing 100191China Science and Technology on Aircraft Control Laboratory Beihang UniversityBeijing 100191China Key Laboratory of Advanced Aircraft Systems(Beihang University) Ministry of Industry and Information TechnologyBeijing 100091China Research Institute for Frontier Science Beihang UniversityBeijing 100191China ningbo Institute of Technology of Beihang University Ningbo 315800China Tianmushan Laboratory Xixi Octagon CityYuhang DistrictHangzhou 310023China

The wheel brake system of an aircraft is the key to ensure its safe landing and rejected takeoff.A wheel’s slip state is determined by the brake torque and ground adhesion torque,both of which have a large degree of uncertainty.It is this nature that brings upon the challenge of obtaining high deceleration rate for aircraft brake control.To overcome the disturbances caused by the above uncertainties,a braking control law is designed,which consists of two parts:runway surface recognition and wheel’s slip state tracking.In runway surface recognition,the identification rules balancing safety and braking efficiency are defined,and the actual identification process is realized through recursive least square method with forgetting factors.In slip state tracking,the LuGre model with parameter adaptation and a brake torque compensation method based on RBF neural network are proposed,and their convergence are proven.The effectiveness of our control law is verified through simulation and ground experiment.Especially in the experiments on the ground inertial test bench,compared to the improved pressure-biased-modulation(PBM)anti-skid algorithm,fewer wheel slips occur,and the average deceleration rate is increased by 5.78%,which makes it a control strategy with potential for engineering applications.

关键词： Aircraft landing Brakes Disturbance observer Neural networks Runway identification

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Should we perform sigmoidoscopy for colorectal cancer screening in people under 45 years?

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World Journal of Gastrointestinal Oncology 2024年第4期16卷 1248-1255页

作者： Waiian Leong Jia-Qi Guo Chun ning Fei-Fei Luo Rui jiao Dong-Ye Yang Division of Gastroenterology&Hepatology The University of Hong Kong-Shenzhen HospitalShenzhen 518053Guangdong ProvinceChina Department of Accident&Emergency The University of Hong Kong-Shenzhen HospitalShenzhen 518053Guangdong ProvinceChina Department of Anatomical Pathology The University of Hong Kong-Shenzhen HospitalShenzhen 518053Guangdong ProvinceChina Endoscopy Center The University of Hong Kong-Shenzhen HospitalShenzhen 518053Guangdong ProvinceChin

BACKGROUND The strategy for preventing colorectal cancer is screening by colonoscopy,which offers a direct way for detection and removal of adenomatous polyps(APs).American College of Gastroenterology guidelines recommend that people aged≥45 years should undergo colonoscopy;however,how to deal with people aged≤45 years is still unknown.AIM To compare the prevalence of APs and high-grade neoplasia between the left and right colon in patients≤45 years.METHODS A retrospective observational study was conducted at a single tertiary III hospital in China.This study included patients aged 18-45 years with undergoing initial colonoscopy dissection and pathological diagnosis AP or high-grade neoplasia between February 2014 and January 2021.The number of APs in the entire colon while screening and post-polypectomy surveillance in following 1-3 years were evaluated.RESULTS A total of 3053 cases were included.The prevalence of APs in the left and right colon was 55.0%and 41.6%,respectively(OR 1.7,95%CI 1.6-2.4;P3 polyps(14.1%;OR 0.3,95%CI 0.1-0.6;Pning in people aged≤45 years and would be a more cost-effective and safe strategy.

关键词： Adenomatous polyps High-grade neoplasia Colonoscopy Flexible sigmoidoscopy

Rhodium-Catalyzed Transannulation of 1,2,3-Thiazoles with Alkynes for the Direct Synthesis of Thiochromenones

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Chinese Journal of Chemistry 2023年第5期41卷 509-513页

作者： Jun Pan Ziyao Zhang Lili Chen ning jiao State Key Laboratory of Natural and Biomimetic Drugs Chemical Biology CenterSchoolof Pharmaceutical SciencesPeking University XueYuanRd.38Beijing 100191China Shanghai Key Laboratory of Green Chemistry and Chemical Processes East China Normal UniversityShanghai 200062China

A rhodium-catalyzed denitrogenative carbonylation of 1,2,3-thiadiazole with alkynes to construct(benzo)thiochromenones is developed.Both terminal and internal alkynes were compatible in this[3+2+1]cycloaddition,affording a broad range of poly-substituted thiochromenones.Unsymmetrical alkyne substrates exhibited good regioselectivity.

关键词： Rh-catalysis Transannulation Thiadiazoles Alkynes Thiochromenones

Chromosome-level assembly of triploid genome of Sichuan pepper(Zanthoxylum armatum)

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Horticultural Plant Journal 2024年第2期10卷 437-449页

作者： Lizhi Song Yue Huang Hao Zuo ning Tang Zhengguo Li Wenbiao jiao Feng Xu Qiang Xu Zexiong Chen National Key Laboratory for Germplasm Innovation and Utilization for Fruit and Vegetable Horticultural Crops Huazhong Agricultural UniversityWuhanHubei 430070China Chongqing Key Laboratory of Economic Plant Biotechnology Chongqing University of Arts and SciencesChongqing 402160China School of Life Sciences Chongqing UniversityChongqing 400030China College of Horticulture and Gardening Yangtze UniversityJingzhouHubei 434025China College of Informatics Huazhong Agricultural UniversityWuhanHubei 430070China

As an important spice species in Rutaceae, the Sichuan pepper (Zanthoxylum armatum) can provide pungent and numbing taste, as well as aroma in its mature fruit. Here we assembled a chromosome-level genome of green prickly ash which was widely cultivated in a major production area including Chongqing and Sichuan province, China. We generated 712 Gb (~112×) PacBio long reads and 511 Gb (~82×) Hi-C data, and yielded an assembly of 99 pseudochromosomes with total size of 5.32 Gb and contig N50 of 796 kb. The genomic analyses and cytogenetic experiments both indicated that the cultivarZhuye Huajiao’ was a triploid. We identified a Zanthoxylum-specific whole genome duplication event emerging about 24.8 million years ago (Mya). We also detected a transposition burst event (0.3-0.4 Mya) responsible for the large genome size of Z. armatum. Metabolomic analysis of the Zanthoxylum fruits during development stages revealed profiles of39 volatile aroma compounds and 528 secondary metabolites, from which six types of sanshools were identified. Based on metabolomic and transcriptomic network analysis, we screened candidate genes encoding long chain acyl-CoA synthetase, fatty acid desaturase,branched-chain amino acid aminotransferase involved in sanshool biosynthesis and three genes encoding terpene synthase during fruit development. The multi-omics data provide insights into the evolution of Zanthoxylum and molecular basis of numbing and aroma flavor of Sichuan pepper.

关键词： Zanthoxylum armatum Genome Sanshool Terpenoid

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Tongxinluo Activates PI3K/AKT Signaling Pathway to Inhibit Endothelial Mesenchymal Transition and Attenuate Myocardial Fibrosis after Ischemia-Reperfusion in Mice

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Chinese Journal of Integrative Medicine 2024年第7期30卷 608-615页

作者： WEI Ya-ru HOU Yun-long YIN Yu-jie LI Zhen LIU Yi HAN ning-xin WANG Zi-xuan LIU Lu WANG Xiao-qi HAO Yuan-jie MA Kun GU jiao-jiao JIA Zhen-hua Graduate School Hebei University of Chinese Medicine Shijiazhuang Yiling Pharmaceutical New Drug Evaluation Center Hebei Institute of Integrated Traditional and Western Medicine National Key Laboratory for Innovation and Transformation of Luobing Theory Department of Cardiology Hebei Yiling Hospital Graduate School Hebei Medical University

Objective: To investigate the potential role of Tongxinluo(TXL) in attenuating myocardial fibrosis after myocardial ischemia-reperfusion injury(MIRI) in mice. Methods: A MIRI mouse model was established by left anterior descending coronary artery ligation for 45 min. According to a random number table, 66 mice were randomly divided into 6 groups(n=11 per group): the sham group, the model group, the LY-294002 group, the TXL group, the TXL+LY-294002 group and the benazepril(BNPL) group. The day after modeling, TXL and BNPL were administered by gavage. Intraperitoneal injection of LY-294002 was performed twice a week for 4 consecutive weeks. Echocardiography was used to measure cardiac function in mice. Masson staining was used to evaluate the degree of myocardial fibrosis in mice. Qualitative and quantitative analysis of endothelial mesenchymal transition(EndMT) after MIRI was performed by immunohistochemistry, immunofluorescence staining and flow cytometry, respectively. The protein expressions of platelet endothelial cell adhesion molecule-1(CD31), α-smoth muscle actin(α-SMA), phosphatidylinositol-3-kinase(PI3K) and phospho protein kinase B(p-AKT) were assessed using Western blot. Results: TXL improved cardiac function in MIRI mice, reduced the degree of myocardial fibrosis, increased the expression of CD31 and inhibited the expression of α-SMA, thus inhibited the occurrence of EndMT(P0.05). In addition, the use of the PI3K/AKT pathway-specific inhibitor LY-294002 to block this pathway and combination with TXL intervention, eliminated the protective effect of TXL, further supporting the protective effect of TXL. Conclusion: TXL activated the PI3K/AKT signaling pathway to inhibit EndMT and attenuated myocardial fibrosis after MIRI in mice.

关键词： myocardial fibrosis endothelial mesenchymal transition myocardial ischemia-reperfusion injury phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway

Bilateral iridocorneal endothelial syndrome-Chandler’s syndrome:a case report and literature review

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International Journal of Ophthalmology(English edition) 2024年第4期17卷 773-776页

作者： Xiao-Hua Pan Yu-Fei Tao Ming-Min Yang Xiao-Li Shen jiao Si Ming Li ning Fan Shenzhen Eye Hospital Jinan UniversityShenzhen 518040Guangdong ProvinceChina

Dear Editor,I ridocorneal endothelial syndrome(ICE)is a rare ocular disease first proposed by Eagle et al[1]in 1979.It is mainly characterized by corneal endothelial abnormalities,accompanied by iris atrophy,iris pigmented nodules and peripheral anterior synechiae.ICE syndrome is typically unilateral,and classified into three clinical variants based on the changes of the cornea and iris,including progressive iris atrophy,Chandler’s syndrome,and Cogan-Reese syndrome.

关键词： corneal atrophy clinical