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Discovery of potent thiazolidin-4-one sulfone derivatives for inhibition of proliferation of osteosarcoma in vitro and in vivo

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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 2024年 266卷 116082页

作者： chen, xuwen Luo, Zhengli Hu, Zongjing Sun, Donghui He, Yingying Lu, Jiani chen, Lili Liu, Shunying East China Normal Univ Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev Sch Chem & Mol Engn Shanghai 200062 Peoples R China Shanghai Univ Tradit Chinese Med Inst Interdisciplinary Integrat Med Res Shanghai Frontiers Sci Ctr TCM Chem Biol Shanghai 201203 Peoples R China

Chemotherapy combining with surgical treatment has been the main strategy for osteosarcoma treatment in clinical. Due to unclear pathogenesis and unidentified drug targets, significant progress has not been made in the development of targeted drugs for osteosarcoma during the past 50 years. Our previous discovery reported compound R-8i with a high potency for the treatment of osteosarcoma by phenotypic screening. However, both the metabolic stability and bioavailability of R-8i are poor (T1/2 = 5.36 min, mouse liver microsome;and bioavailability in vivo F = 52.1 %, intraperitoneal administration) which limits it use for further drug development. Here, we described an extensive structure-activity relationship study of thiazolidine-4-one sulfone inhibitors from R-8i, which led to the discovery of compound 68. Compound 68 had a potent cellular activity with an IC50 value of 0.217 mu M, much higher half-life (T1/2 = 73.8 min, mouse liver microsome) and an excellent pharmacokinetic profile (in vivo bioavailability F = 115 %, intraperitoneal administration). Compound 68 also showed good antitumor effects and low toxicity in a xenograft model (44.6 % inhibition osteosarcoma growth in BALB/c mice). These results suggest that compound 68 is a potential drug candidate for the treatment of osteosarcoma.

关键词： Osteosarcoma Thiazolidin-4-one sulfone Inhibitors Structure -activity relationship

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Exploring bifunctional molecules for anti-SARS-CoV-2 and anti-inflammatory activity through structure-based virtual screening, SAR investigation, and biological evaluation

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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES 2025年 287卷 138529页

作者： Lu, Jiani He, Yingying Li, Yaqi chen, Xixiang Li, Hongtao chen, xuwen Xu, Jianrong chen, Hongzhuan Wang, Ying He, Xiao Liu, Shunying chen, Lili Shanghai Univ Tradit Chinese Med Longhua Hosp Inst Interdisciplinary Integrat Med Res Shanghai Frontiers Sci Ctr TCM Chem Biol Shanghai 201203 Peoples R China East China Normal Univ Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev Sch Chem & Mol Engn Shanghai 200062 Peoples R China Hunan Normal Univ Coll Life Sci Natl & Local Joint Engn Lab Anim Peptide Drug Dev Changsha 410081 Peoples R China Hunan Normal Univ Inst Interdisciplinary Studies Changsha 410081 Peoples R China Hunan Normal Univ Furong Lab Peptide& Small Mol Drug R&D Plateform Changsha 410081 Hunan Peoples R China DP Technol Beijing 100080 Peoples R China Shanghai Univ Tradit Chinese Med Inst Interdisciplinary Integrat Med Res Acad Integrat Med Shanghai Frontiers Sci Ctr TCM Chem Biol Shanghai 201203 Peoples R China Shanghai Univ Tradit Chinese Med Shanghai Inst Infect Dis & Biosecur Inst Interdisciplinary Integrat Med Res Res Ctr Tradit Chinese MedShanghai Frontiers Sci Shanghai 201203 Peoples R China East China Normal Univ Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev Shanghai Frontiers Sci Ctr Mol Intelligent Synth Sch Chem & Mol Engn Shanghai 200062 Peoples R China NYU Shanghai NYU East China Normal Univ Ctr Computat Chem Shanghai 200062 Peoples R China

As new variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, they raise increasing concerns about the efficacy of neutralizing antibodies and vaccines. This situation underscores the urgent need for specific drugs against the coronavirus disease 2019 (COVID-19). Given that COVID-19 is particularly associated with substantial inflammation, the development of novel, effective antiviral and antiinflammatory agents represents a promising research direction. In this study, we virtually screened a library consisting of 2900 anti-inflammatory small molecules for their inhibitory effects on the 3-chymotrypsin-like protease (3CLpro) of SARS-CoV-2 and selected 23 promising candidates for further testing using a fluorescence resonance energy transfer (FRET) assay. The results indicated that Gnetol had the most potent inhibitory effect against SARS-CoV-2 3CLpro. Further structural modifications led to the identification of compounds 38 and 39, which displayed superior inhibitory activity. Compound 39 showed good selectivity for host proteases. Subsequently, Gnetol and its structural analogs, which demonstrated SARS-CoV-2 3CLpro inhibitory activity, were tested for their anti-inflammatory effects. Among these, Piceatannol and compound 39 exhibited enhanced antiinflammatory effects, with compound 39 alone showing the most potent antiviral and anti-inflammatory activity. Thus, our study has explored a new research strategy for discovering antiviral and anti-inflammatory bifunctional molecules. The discovery of Gnetol and its structural analogs has provided new lead candidates for the development of COVID-19 therapeutics.

关键词： COVID-19 Virtual screening Anti-inflammation Bifunctional molecule

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Discovery of Chalcone Derivatives as Bifunctional Molecules with Anti-SARS-CoV-2 and Anti-inflammatory Activities

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JOURNAL OF NATURAL PRODUCTS 2024年第12期87卷 2680-2694页

作者： chen, xuwen Li, Hongtao Wang, Meiting Sun, Donghui Lu, Jiani Zhu, Tong chen, Hongzhuan chen, Lili Liu, Shunying East China Normal Univ Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev Sch Chem & Mol Engn Shanghai 200062 Peoples R China Shanghai Univ Tradit Chinese Med Inst Interdisciplinary Integrat Med Res Shanghai Frontiers Sci Ctr TCM Chem Biol Longhua Hosp Shanghai 201203 Peoples R China Shanghai Univ Tradit Chinese Med Shanghai Inst Infect Dis & Biosecur Inst Interdisciplinary Integrat Med Res Shanghai Frontiers Sci Ctr TCM Chem Biol Shanghai 201203 Peoples R China

Danshensu extracted with traditional Chinese medicine Salvia miltiorrhiza has a wide range of bioactivities. Danshensu containing a catechol moiety has a moderate inhibitory effect on SARS-CoV-2 3CLpro (IC50 = 2.2 mu M) by a reversible covalent interaction and exhibits good anti-inflammatory activity. To enhance the inhibitory activity, we introduced Michael receptors into the side chain of danshensu as a possible covalent warhead and blocked the covalent binding sites of catechol moiety to yield chalcone derivatives. The resulting chalcone derivatives, A4 and A7, were found to inhibit SARS-CoV-2 3CLpro in vitro with IC50 values of 83.2 and 261.3 nM, respectively. Furthermore, A4 and A7 inhibit viral replication in the SARS-CoV-2 replicon system with EC50 values of 19.9 and 11.7 mu M, respectively. Time-dependent inhibition experiment and mass spectrometry show that A4 acted as a noncovalent mixed inhibitor, while A7 likely binds covalently at Cys145. The interaction mechanism between SARS-CoV-2 3CLpro and A4 or A7 was characterized by molecular docking studies. Additionally, both A4 and A7 demonstrated potent anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells. These promising results suggest that chalcone derivatives A4 and A7 can serve as bifunctional molecules with both antivirus and anti-inflammatory properties.

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CoFe2O4@Ti3C2 MXene nanocomposite-based broad-spectrum degradation of biotoxins

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APPLIED CATALYSIS B-ENVIRONMENT AND ENERGY 2024年 350卷

作者： chen, xuwen Sallach, J. Brett Ling, Wanting Zhao, Xuqiang Borch, Thomas Gao, Yanzheng Nanjing Agr Univ Inst Organ Contaminant Control & Soil Remediat Coll Resources & Environm Sci Nanjing 210095 Peoples R China Univ York Dept Environm & Geog York YO10 5NG England Colorado State Univ Dept Soil & Crop Sci Ft Collins CO 80523 USA Colorado State Univ Dept Chem Ft Collins CO 80523 USA Weigang Rd 1 Nanjing 210095 Peoples R China

A significant research priority is developing a treatment method to effectively remove biotoxins commonly found in food production and the environment. A novel CoFe2O4@Ti3C2 MXene nanocomposite was fabricated by growing ferrite on MXene, and used nanocomposite to develop an oxidation-based treatment system with persulfate (PS). The ability of this system to broad-spectrum degrade mycotoxins and plant toxins was evaluated, and the catalytic and oxidation mechanisms were characterized. Co and Fe sites provide activation efficiency towards PS with adsorption energies of -21.15 and -19.63 eV, Ti site promote activation by inducing the reduction of Co and Fe. The production of reactive oxygen species via electron transfer contributed to the degradation of fourteen biotoxins with removal rates above 88%, and the frontier molecular orbital energy explained the difference in degradation extent. Electron-rich sites were predicted to help explain the degradation mechanism. The products were harmless to the ecology and human. The observations clearly indicate that Ferrite-MXene nanocomposites are viable options for broad-spectrum degradation of a wide variety of biotoxins.

关键词： CoFe2O4@Ti(3)C(2)MXene nanocomposite Biotoxins Hydrothermal synthesis Broad-spectrum degradation Persulfate

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Iodine-catalyzed intermolecular 1,2-thio (seleno)amination of alkenes with 1,2,3-triazoles and disulfides (diselenides) in air

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ORGANIC CHEMISTRY FRONTIERS 2024年第11期11卷 3066-3071页

作者： Ji, Jian chen, xuwen Hu, Zongjing Guan, Cong Liu, Jinhua Deng, Yaqi Liu, Shunying East China Normal Univ Shanghai Engn Res Ctr Mol Therapeut & New Drug De Sch Chem & Mol Engn Shanghai 200062 Peoples R China

An iodine-catalyzed direct radical coupling method for 1,2-thio (seleno)amination of alkenes with 1,2,3-triazoles and disulfides (diselenides) in air was developed. Products were constructed in one pot with high chemoselectivity and regioselectivity as well as a wide range of substrate scopes (including terminal and internal alkenes). Preliminary mechanistic studies indicated that formation of the C-N bond proceeded via a desulfonation-associated tandem radical cross-coupling process. Iodine-catalyzed 1,2-thio (seleno)amination of alkenes via direct N- and C-centered radical cross-coupling was established to elicit highly regioselective beta-triazolized thioalkyl compounds.

关键词： Olefins

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Parameters Optimization Method for ADRC of Permanent Magnet Synchronous Motor Based on CMA-ES 43

Parameters Optimization Method for ADRC of Permanent Magnet ...

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43rd Chinese Control Conference (CCC)

作者： Jiang, Tianjian Yang, Yang Li, Zhiyuan Yang, Tianqi chen, xuwen Nanjing Univ Posts & Telecommun Coll Automat Nanjing 210023 Peoples R China Nanjing Univ Posts & Telecommun Coll Aritif Intelligence Nanjing 210023 Peoples R China Nanjing Univ Posts & Telecommun Coll Internet Things Nanjing 210023 Peoples R China

ISBN: (纸本)9798350366907;9789887581581

Active disturbance rejection control (ADRC) is widely used to control permanent magnet synchronous motors (PMSM). However, the settings of gain parameters in ADRC is often dependent on engineers' experience. Also, it is difficult to design the parameters accurately by hand to achieve satisfactory results. A method based on evolution strategy with covariance matrix adaptation (CMA-ES) for optimizing the gain parameters of ADRC is proposed. By setting up some optimization tasks and using the CMA-ES algorithm, reinforcement learning is performed on the parameters of ADRC. In view of the high population size and complexity of CMA-ES, we adopt a parallel computation method to speed up the optimization process. The method can effectively optimize the ADRC gain parameters to adapt to the specified application environment, and at the same time reduce the dependence of setting ADRC parameters on human experience as well as time consumption. Finally, we verify that this CMA-ES-based parameter optimization method can effectively improve the control performance of the motor by running simulations and comparing the motor speed changes before and after optimization.

关键词： Permanent-magnet Synchronous Motor Active Disturbance Rejection Control Field-oriented Control Swarm Optimization High Throughput Computing Modern Control

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Hydroxyl groups and vacancy defects modified Mo2C MXene as peroxymonosulfate activator for antibiotics degradation

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JOURNAL OF CLEANER PRODUCTION 2025年 486卷

作者： chen, xuwen Zhou, Zhou Gudda, Fredrick Owino Tang, Lei Wang, Hefei Czech, Bozena Oleszczuk, Patryk Gao, Yanzheng Nanjing Agr Univ Inst Organ Contaminant Control & Soil Remediat Coll Resources & Environm Sci Nanjing 210095 Peoples R China Marie Curie Sklodowska Univ Inst Chem Sci Fac Chem Dept Radiochem & Environm Chem Pl M Curie Sklodowskiej 3-541 PL-20031 Lublin Poland

Antibiotic pollution poses significant threats to ecological health and food safety, highlighting the need for effective pollution control strategies. A novel Mo2C MXene-OH&V-Mo (hydroxyl groups and Mo vacancy defects modified Mo2C MXene) was developed through etching and hydrothermal methods, which facilitated the construction of a degradation system utilizing peroxymonosulfate for antibiotics degradation. The Mo2C MXeneOH&V-Mo demonstrated enhanced adsorption of HSO5-, achieving an adsorption energy of-1.73 eV, which is superior to that of unmodified Mo2C MXene (-0.42 eV). The activation of HSO5- by Mo vacancies involved the transfer of 0.63 e, leading to the generation of reactive oxygen species ('OH, O-1(2) , SO4'-and O-2'- ) responsible for degrading three antibiotics with degradation percentages exceeding 97.00%. The presence of hydroxyl groups further improved the activation efficiency of HSO5- by optimizing the electron arrangement of Mo2C MXeneOH&V-Mo. The extent of antibiotic degradation was influenced by atomic charge distribution. Additionally, Mo2C MXene-OH&V-Mo exhibited remarkable repeatability, maintaining degradation percentages above 88.00% after four cycles. The condensed Fukui function was utilized to identify highly active sites of antibiotics, and combined with degradation products analyzed by HPLC-MS/MS, commonalities in detailed degradation pathways were revealed. Furthermore, the products were found to pose negligible toxicity risks to ecological receptors and humans. These findings hold significant implications for the future use of MXene-based catalyst' advanced oxidation technology in the treatment of organic pollutants and offer sustainable solutions for environmental remediation. Insights into the development of new catalysts through surface modification engineering were also presented in this study.

关键词： Hydroxyl functional groups Vacancy defects Antibiotics Peroxymonosulfate Mo2C MXene- OH & V-Mo Hydroxyl functional groups Vacancy defects Antibiotics Peroxymonosulfate

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Copper-Catalyzed Intermolecular 1,2-Carbotriazolization of Alkenes with N-Sulfonyl-1,2,3-Triazoles and Aldehydes

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ACS SUSTAINABLE CHEMISTRY & ENGINEERING 2023年第45期11卷 16240-16248页

作者： Ji, Jian Hu, Zongjing Guan, Cong Liu, Jinhua Deng, Yaqi chen, xuwen Liu, Shunying East China Normal Univ Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev Sch Chem & Mol Engn Shanghai 200062 Peoples R China

The first efficient example of the 1,2-carbotriazolization of alkenes with N-sulfonyl-1,2,3-triazoles and aldehydes was developed as an appealing strategy for producing beta-triazolized ketones via a copper-catalyzed radical relay process. The products were constructed in one pot with high regioselectivity and chemoselectivity as well as a wide range of substrate scopes, including aromatic and aliphatic aldehydes and alcohols. Preliminary mechanistic study indicates that the reaction proceeds via an SN2-like tandem radical relay desulfonation process. The resulting beta-triazolized ketone scaffold shows a good and selective inhibitory activity on osteosarcoma (OS) cell lines at 10 mu M, which is promising for use as an efficient pharmacophore for drug discovery.

关键词： 1,2-carboamination 1,2-carbotriazolization radical relay 1,2,3-triazoles desulfonation

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Graded Error Compensation Method for Heavy-Load Manipulators Based on Laser Tracking Measurement 16th

Graded Error Compensation Method for Heavy-Load Manipulators...

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16th International Conference on Intelligent Robotics and Applications, ICIRA 2023

作者： chen, Zhangwei Zu, Hongfei Zhang, Xiang chen, xuwen Wang, Zhirong State Key Laboratory of Fluid Power and Mechatronic Systems Zhejiang University Hangzhou310058 China School of Mechanical Engineering Zhejiang Sci-Tech University Hangzhou310018 China Zhejiang Premax Co. Ltd Ningbo315048 China Testing Standardization and Certification Changzhou Institute of Inspection Changzhou21 3000 China

ISBN: (纸本)9789819964888

In order to meet the high positioning accuracy requirements of industrial application scenarios for manipulators, the motion accuracy of industrial manipulators is generally improved through error compensation. However, due to the presence of non-geometric errors such as friction and joint backlash, error compensation is usually a complex nonlinear problem. Therefore, the existing methods of improving the absolute positioning accuracy of manipulators through model parameter calibration are difficult to obtain good performance, especially for heavy-load manipulators. To solve the above problems, this manuscript proposes a graded error compensation method for heavy-load manipulators based on laser tracking measurement, which realizes the compensation of kinematics error and joint stiffness, and improves the positioning accuracy of the manipulator in the entire workspace. Firstly, the geometric parameters were modeled and compensated by combining the distance model and the Denavit-Hartenberg (DH) model. Then, joint stiffness errors were studied and compensated. Finally, experiments were conducted on a heavy-load manipulator to verify the feasibility and effectiveness of this method. © The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023.

关键词： Error compensation

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Identification of DDX5 as a Potential Therapeutic Target of Osteosarcoma Using Thiazolone Probes

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ACS CHEMICAL BIOLOGY 2024年第8期19卷 1803-1812页

作者： Sun, Donghui Kang, Li chen, xuwen Xue, Jian Wu, Xin Wong, Jiemin Wei, Qinghua Liu, Shunying East China Normal Univ Shanghai Engn Res Ctr Mol Therapeut & New Drug Dev Sch Chem & Mol Engn Shanghai 200062 Peoples R China East China Normal Univ Fengxian Dist Cent Hosp Inst Biomed SciECNU Joint Ctr Translat Med Shanghai Key Lab Regulatory Biol Shanghai Peoples R China East China Normal Univ Sch Life Sci Shanghai 200241 Peoples R China

Osteosarcoma (OS) is a rare malignant tumor that has predominantly affected children and adolescents in the past 50 years. The genomes of OS tumors exhibit a high degree of complexity, which leads to the great challenge of target identification for anti-OS. To date, no efficient therapeutic target for the treatment of OS has been validated in clinical practice. In our previous drug hunting for the treatment of OS by phenotypic screening, we found that thiazolone derivate (R)-8i was an effective and selective inhibitor against OS in MNNG/HOS cells and in vivo. However, the mechanism of action and specific molecular targets of (R)-8i remain unclear. In this study, we design and synthesize the photo-cross-linking probes based on the lead compound (R)-8i and identify DDX5 as a potential target protein using an activity-based protein profiling strategy. Further experiments including Western blot, shRNA knockdown experiments, cell colony formation, wound healing assays, and cellular thermal shift assays support that (R)-8i binds to DDX5 and induces its degradation, which affect cell proliferation and migration through the PI3K-AKT-mTOR signaling pathway. The research shows that DDX5 is a potential therapeutic target for the treatment of OS.

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