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Novel Pt(IV) complex OAP2 induces STING activation and pyroptosis via mitochondrial membrane remodeling for synergistic chemo-immunotherapy

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1742-1758页

作者： Renming Fan Ruizhuo Lin Shuo Zhang Aohua Deng Yongrui Hai Junyan Zhuang Yang Liu maosheng cheng Gaofei Wei Institute of Medical Research Northwestern Polytechnical UniversityXi'an 710072China Research&Development Institute of Northwestern Polytechnical University in Shenzhen Shenzhen 518057China Key Laboratory of Structure-Based Drug Design and Discovery Ministry of EducationSchool of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang 110016China

Mitochondrial membrane remodeling can trigger the release of mitochondrial DNA (mtDNA), leading to the activation of cellular oxidative stress and immune responses. While the role of mitochondrial membrane remodeling in promoting inflammation in hepatocytes is well-established, its effects on tumors have remained unclear. In this study, we designed a novel Pt(IV) complex, OAP2, which is composed of oxaliplatin (Oxa) and acetaminophen (APAP), to enhance its anti-tumor effects and amplify the immune response. Our findings demonstrate that OAP2 induces nuclear DNA damage, resulting in the production of nuclear DNA. Additionally, OAP2 downregulates the expression of mitochondrial Sam50, to promote mitochondrial membrane remodeling and trigger mtDNA secretion, leading to double-stranded DNA accumulation and ultimately synergistically activating the intracellular cGAS-STING pathway. The mitochondrial membrane remodeling induced by OAP2 overcomes the limitations of Oxa in activating the STING pathway and simultaneously promotes gasdermin-D-mediated cell pyroptosis. OAP2 also promotes dendritic cell maturation and enhances the quantity and efficacy of cytotoxic T cells, thereby inhibiting cancer cell proliferation and metastasis. Briefly, our study introduces the first novel small-molecule inhibitor that regulates mitochondrial membrane remodeling for active immunotherapy in anti-tumor research, which may provide a creative idea for targeting organelle in anti-tumor therapy.

关键词： Anti-tumor drug Prodrug Platinum Chemo-immunotherapy Mitochondrial membrane modeling STING Pyroptosis mtDNA

Asymmetric Synthesis of Dihydrospirotryprostatin B via a Silica Gel-Mediated Cyclization of Tryptamine-Ynamide

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Chinese Journal of Chemistry 2024年第12期42卷 1355-1359页

作者： Changhong Han Lu Yang Kaizong Yao Sen Zhang Jiayue Fu Hanyang Sun Hongsheng Xu Bin Lin maosheng cheng Yongxiang Liu Key Laboratory of Structure:Based Drug Design and Discovery of Ministry of Education Shenyang Pharmaceutical UniversityShenyangLiaoning 110016China Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyangLiaoning 110016China Institute of Drug Research in Medicine Capital of China BenxiLiaoning 117000China Zhejiang Shapuaisi Pharmaceutical Co. LtdPinghuZhejiang 314299China

Comprehensive Summary An asymmetric synthesis of dihydrospirotryprostatin B was achieved in 15 steps(8 purifications)from *** main feature of our synthetic strategy is the efficient construction of spirocyclic oxindole intermediate containing a chiral quaternary carbon center,involving the silica gel-mediated cyclization of tryptamine-ynamide and oxidation under neat conditions.

关键词： Asymmetric synthesis Alkaloids Dihydrospirotryprostatin B Tryptamine-ynamide Cross-coupling Silica gel-mediated cyclization Oxidation

A review of structural modification and biological activities of oleanolic acid

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Chinese Journal of Natural Medicines 2024年第01期 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. Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education School of Pharmaceutical EngineeringShenyang Pharmaceutical University

Oleanolic acid(OA), a pentacyclic triterpenoid, exhibits a broad spectrum of biological activities, including antitumor,antiviral, antibacterial, anti-inflammatory, hepatoprotective, hypoglycemic, and hypolipidemic effects. Since 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 OA. Based 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.

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立式离心泵典型故障复现试验研究

排灌机械工程学报 2024年第6期42卷 563-569页

作者：胡思源董亮朱建成陈玉党程茂胜江苏大学国家水泵及系统工程技术研究中心江苏镇江212013 辽宁恒星泵业有限公司辽宁丹东118017 安徽莱恩电泵有限公司安徽宁国242300

为了给立式离心泵的故障诊断提供试验和理论依据,搭建立式离心泵仿真试验台,进行立式离心泵典型故障的仿真复现试验,分析了转子不平衡、转子不对中和支座连接松动等故障的振动特性及其频谱特征.结果表明:机脚处的振动位移信号对支座连... 详细信息

为了给立式离心泵的故障诊断提供试验和理论依据,搭建立式离心泵仿真试验台,进行立式离心泵典型故障的仿真复现试验,分析了转子不平衡、转子不对中和支座连接松动等故障的振动特性及其频谱特征.结果表明:机脚处的振动位移信号对支座连接松动故障的振动特性敏感性更高,轴系的振动信号对转子故障的振动特性敏感性更高;转子不平衡故障和转子不对中故障表现出不同的频谱特征,转子不平衡故障的频谱特征表现为1倍振动主要频率(amplitude power frequency,APF)幅值增大,且随着故障程度的增加,幅值呈现了逐渐减小的趋势,转子不对中故障的频谱特征表现为产生新的振动特征频率2APF,且随着故障程度的增大,信号幅值逐渐增大;支座连接松动故障表现为频谱图中的主频变为3APF,并出现新的2APF和1/2分数谐波频率.

关键词：立式离心泵故障复现转子不平衡转子不对中支座连接松动

N-取代-β-D-葡萄糖胺衍生物的合成及抗肿瘤活性研究

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中国药物化学杂志 2024年第3期34卷 167-179页

作者：唐丽李凤然程卯生刘洋沈阳药科大学基于靶点的药物设计与研究教育部重点实验室辽宁沈阳110016

目的设计并合成具有1,2,3-三氮唑及苯磺酰胺结构的新型N-取代-β-D-葡萄糖胺化合物,评估其在体外对人碳酸酐酶Ⅸ(CAⅨ)的抑制活性以及对HCT116肿瘤细胞的增殖抑制活性。方法运用基于片段的药物设计策略并结合计算机辅助药物设计,将取代... 详细信息

目的设计并合成具有1,2,3-三氮唑及苯磺酰胺结构的新型N-取代-β-D-葡萄糖胺化合物,评估其在体外对人碳酸酐酶Ⅸ(CAⅨ)的抑制活性以及对HCT116肿瘤细胞的增殖抑制活性。方法运用基于片段的药物设计策略并结合计算机辅助药物设计,将取代的磺酰基引入氨基葡糖胺的2位氨基,构建三氮唑基团作为连接臂与磺酰胺基团相连,以期增加化合物的选择性并减少不良反应。此外,通过计算得到的LogP(cLogP)值预测化合物的亲水性。基于拓扑极性表面积(TPSA)表征膜通透性,预测化合物对膜相关CAⅨ的选择性。结果与结论共合成了17个目标化合物,其结构均经MS、^(1)H-NMR、^(13)C-NMR谱确证。体外活性测试结果表明,化合物14b(IC_(50)=18.69μmol·L^(-1))和14c(IC_(50)=21.25μmol·L^(-1))对HCT116细胞的抑制活性最好。

关键词： 1,2,3-三氮唑碳酸酐酶Ⅸ 抗肿瘤氨基葡萄糖

Analysis and Optimization of Unsteady Flow in a Double-Suction Centrifugal Pump for a Cooling-Water Supply System in a Nuclear Reactor

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Journal of Thermal Science 2020年第6期29卷 1606-1616页

作者： YAN Hao SU Xiaozhen SHI Haixia cheng maosheng LI Yunqing School of mechanical engineering Hefei University of TechnologyHefei 230009China Anhui Line Pump Co. LtdNingguo 242300China

The management of a cooling-water supply system in a nuclear reactor is performed by valve and reactor coolant pump(RCP)control,which regulates both the pressure and the discharge between certain ***,the RCP has a significant unsteady flow when operating at different *** unsteady pressure pulsation and radial force vector are difficult to calculate because these are affected by the transient properties of the unsteady *** study explores the use of a commercial Computational Fluid Dynamics(CFD)code to comprehensively estimate the unsteady flow of the *** full 3D-URANS equations were solved for different flow rates,and some optimised cases for the unsteady flow were *** results showed that the numerical predictions were validated with the experimental data of a model *** code was used to estimate the velocity streamlines,pressure pulsation and radial force vector in the steady and transient *** flow rates were not equal for the inner and outer passage in the double volute ***,the pulsation of the pressure and radial force was effectively reduced by optimising the staggered angleα.An optimal case was observed whenα=30°.

关键词： unsteady flow reactor coolant pump(RCP) radial force pressure pulsation

Hederacolchiside A1衍生物的合成及抗肿瘤活性研究

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中国药物化学杂志 2024年第1期34卷 20-30页

作者：孙子含仲烨程卯生刘洋沈阳药科大学基于靶点的药物设计与研究教育部重点实验室辽宁沈阳110016

目的设计并合成哌嗪酰化和哌嗪磺酰化hederacolchiside A1衍生物,测试其对肿瘤细胞的抗增殖活性。方法采用半合成策略,在hederacolchiside A1的C-28位上引入磺酰化或甲酰化的哌嗪基团,同时在磺酰基和甲酰基上引入空间位阻大的芳香基团... 详细信息

目的设计并合成哌嗪酰化和哌嗪磺酰化hederacolchiside A1衍生物,测试其对肿瘤细胞的抗增殖活性。方法采用半合成策略,在hederacolchiside A1的C-28位上引入磺酰化或甲酰化的哌嗪基团,同时在磺酰基和甲酰基上引入空间位阻大的芳香基团进行进一步结构修饰,得到两个系列的目标化合物(4a~4k和5a~5k)。以苯甲酰化和乙酰化的hederacolchiside A1为起始原料,经亲电取代、亲核取代反应得到含哌嗪基团的关键中间体,该中间体与含不同取代基的苯磺酰氯进行缩合反应得到目标化合物4a~4k;与含不同取代基的苯甲酰氯进行缩合反应得到目标化合物5a~5k。采用MTT法评价目标化合物的体外抗肿瘤活性。结果与结论设计并合成了22个未见文献报道的新化合物,其结构均经ESI-MS、^(1)H-NMR、^(13)C-NMR谱确证。体外抗肿瘤活性测试结果表明,化合物5e对MCF-7肿瘤细胞表现出较强的抗增殖活性,其IC50值为(4.89±0.09)μmol·L^(-1),优于阳性对照药hederacolchiside A1[IC_(50)=(19.36±0.48)μmol·L^(-1)]和5-氟尿嘧啶[IC_(50)=(26.14±1.76)μmol·L^(-1)],具有进一步研究的价值。

关键词：三萜皂苷 hederacolchiside A1 抗肿瘤结构改造

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伏罗尼布的合成工艺研究

中国药物化学杂志 2024年第1期34卷 42-48页

作者：修晓萌成钰龙刘洋杨华丽程卯生沈阳药科大学基于靶点的药物设计与研究教育部重点实验室辽宁沈阳110016

目的优化多靶点激酶抑制剂伏罗尼布的合成工艺。方法以{[(3S)-四氢-1H-吡咯-3-基]氨基}甲烷酸-2-甲基丙-2-基酯为起始原料,通过酰化、脱Boc保护基、酸胺缩合、Claisen-Schmidt共四步反应得到伏罗尼布。结果与结论目标化合物的结构经ESI... 详细信息

目的优化多靶点激酶抑制剂伏罗尼布的合成工艺。方法以{[(3S)-四氢-1H-吡咯-3-基]氨基}甲烷酸-2-甲基丙-2-基酯为起始原料,通过酰化、脱Boc保护基、酸胺缩合、Claisen-Schmidt共四步反应得到伏罗尼布。结果与结论目标化合物的结构经ESI-MS、^(1)H-NMR、^(13)C-NMR谱确证,总收率为55.3%,纯度为99.01%(HPLC)。改进后的合成方法原料易得、操作简单、产物纯度高,适合大规模工业化生产。

关键词：伏罗尼布多靶点激酶抑制剂合成工艺

Design,Synthesis and Biological Evaluation of Pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione Derivatives as Novel Neuroprotective Agents

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Chemical Research in Chinese Universities 2021年第3期37卷 647-654页

作者： QUAN Jishun ZHANG Dongping ZHANG Zhuo WANG Jian MA Chao cheng maosheng Key Laboratory of Structure-based Drug Design&Discovery of Ministry of Education School of Pharmaceutical EngineeringShenyang Pharmaceutical UniversityShenyang110016P.R.China

A series of pyrrolo[2,1-c][1,4]benzodiazepine-3,11-dione derivatives was designed and synthesized,and their neuroprotective activity against SH-SY5Y cell injury induced by N-methyl-D-aspartic acid(NMDA)was *** the compounds showed significant neuroprotective effects,especially B16,which showed excellent performance and better activity than the positive control ifenprodil(B16:56.2%±0.6%;ifenprodil:41.0%±2.7%).Further investigation indicated that B16 could attenuate the Ca^(2+)influx induced by NMDA in SH-SY5Y cells and Western blotting also showed that B16 could attenuate the NR2B upregulation in SH-SY5Y cells induced by *** molecular docking results showed that compound B16 fitted in the binding pocket of NR2B-NMDAR well and could interact with binding sites of compounds 1 and 2 *** ADME/Tox prediction results suggested that compound B16 had good blood-brain barrier(BBB)permeability and the zero alert of Pan Assay Interference Structures(PAINS)indicated that B16 could not elicit false-positive *** results strongly suggest that B16 is a promising and effective candidate neuroprotective compound,and that NR2B-NMDAR is a potential target of B16.

关键词： Neuroprotective activity Ca^(2+)influx Western blotting NR2B-NMDA receptor Molecular docking