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中国化学快报:英文版 2023年第10期34卷 191-196页

作者： Fukui Shen Wen Yang Kaixue Zhang Yanting Jiao Jing Cui Yuanyuan Hou Gang Bai state key laboratory of Medicinal chemical biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300353China

Mitochondria are essential for eukaryotic life as powerhouses for energy metabolism. Excessive mitochondrial hyperthermia and reactive oxygen species(ROS) production have been associated with aging, cancer,neurodegenerative diseases, and other disorders. Uncoupling protein 2(UCP2) is the effector responsible for regulating cellular thermogenesis and ROS production via dissipating protons in an electrochemical gradient. A UCP2 inhibitor named genipin(GNP) is being researched for its effect on mitochondrial temperature, but little is known about its mechanisms. This study developed several molecular probes to explore the interactions between GNP and UCP2. The result indicated that the hemiacetal structure in GNP could selectively react with the ?-amine of lysine on the UCP2 proton leakage channel through ringopening condensation at the mitochondrial, cellular, and animal levels. A notable feature of the reaction is its temperature sensitivity and ability to conjugate with UCP2 at high fever as lysine-specific covalent inhibitors that prevent mitochondrial thermogenesis. The result not only clarifies the existence of an antipyretic properties of GNP via its irreversible coupling to UCP2, but also reveals a bioorthogonal reaction of hemiacetal iridoid aglycone for selectively binding with the ?-amine of lysine on proteins.

关键词： Bioorthogonal reaction Mitochondria Genipin UCP2 Irreversible binding

chemical proteomics combined with metabonomics reveals berberine targets NDUFV1 of complex Ⅰ in the respiratory chain to regulate energy metabolism

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Chinese chemical Letters 2023年第3期34卷 419-423页

作者： Xiaoyao Ma Yiman Han Kaixin Liu Yongping Bai He Gao Yuanyuan Hou Gang Bai state key laboratory of Medicinal chemical biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300381China

Berberine(BBR) is the primary alkaloid compound of the heat-clearing traditional Chinese medicine Huanglian(Coptis chinensis) and exerts regulatory effects on energy metabolism. However, the specific targets and molecular mechanisms are not clear. In this paper, the BBR-affected energy metabolism pathway was screened by nontargeted metabolomics, and a BBR-derived photoaffinity labeled(PAL) probe was designed to identify potential targets via a chemical proteomics approach. NDUFV1, a subunit of complex Ⅰ on mitochondria, was identified as a potential target of BBR. In the respiratory chain, BBR suppressed the activity of complex Ⅰ, reduced the electrochemical potential in the mitochondrial intermembrane and inhibited the generation of ATP and heat via competitive binding with NDUFV1. The results illustrated the underlying mechanism of BBR in the downregulation of energy metabolism.

关键词： Berberine Photoaffinity labeled chemical proteomics NDUFV1 ComplexⅠ Energy metabolism

Glycyrrhetinic acid binds to the conserved P-loop region and interferes with the interaction of RAS-effector proteins

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Acta Pharmaceutica Sinica B 2019年第2期9卷 294-303页

作者： Yuan Zhang Zhihua Wang Xiaoyao Ma Shengnan Yang Xueyan Hu Jin Tao Yuanyuan Houn Gang Bai state key laboratory of Medicinal chemical biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai University

Members of the RAS proto-oncogene superfamily are indispensable molecular switches that play critical roles in cell proliferation, differentiation, and cell survival. Recent studies have attempted to prevent the interaction of RAS/GTP with RAS guanine nucleotide exchange factors(GEFs), impair RASeffector interactions, and suppress RAS localization to prevent oncogenic signalling. The present study aimed to investigate the effect of the natural triterpenoic acid inhibitor glycyrrhetinic acid, which is isolated from the roots of Glycyrrhiza plant species, on RAS stability. We found that glycyrrhetinic acid may bind to the P-loop of RAS and alter its stability. Based on our biochemical tests and structural analysis results, glycyrrhetinic acid induced a conformational change in RAS. Meanwhile, glycyrrhetinic acid abolishes the function of RAS by interfering with the effector protein RAF kinase activation and RAS/MAPK signalling.

关键词： Glycyrrhetinic acid RAS Allosteric inhibitor RAS/MAPK signalling

Palladium-Catalyzed Desulfinative Cross-Coupling of Polyhalogenated Aryl Triflates with Aryl Sulfinate Salts:Inversion of Traditional Chemoselectivity

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Chinese Journal of Chemistry 2023年第8期41卷 909-914页

作者： Miao Wang On Ying Yuen Chau Ming So state key laboratory of chemical biology and drug discovery and Department of Applied biology and chemical Technology The Hong Kong Polytechnic UniversityKowloonHong KongChina Henan key laboratory of Function-Oriented Porous Materials College of Chemistry and Chemical EngineeringLuoyang Normal UniversityLuoyangHenan471934 China The Hong Kong Polytechnic University Shenzhen Research Institute ShenzhenGuangdong518057 China

Comprehensive Summary This paper presents the first general examples of palladium-catalyzed desulfinative cross-coupling reaction of polyhalogenated aryl triflates with aryl sulfinate salts showing an inversion of the conventional reactivity order of C-Br>C-Cl>C-OTf.The catalyst system,comprising of Pd(OAc)_(2)and tBuPhSelectPhos,exhibited excellent catalytic reactivity and chemoselectivity toward this reaction.This reaction had a wide range of substrate scopes and provided a simple and efficient method for the construction of functionalized biaryl motifs.Notably,the C-H···Pd interaction from the methine hydrogen of the C2-cyclohexyl group of the indolyl phosphine ligand with the Pd center may contribute a key factor in reactivity and chemoselectivity.Assisting with density functional theory(DFT)calculations,the results revealed that the oxidative addition step in this reaction was a controlling-chemoselectivity step.

关键词： Palladium Phosphane ligands IChemoselectivity Desulfurization Polyhalogenated aryl triflates

Novel seven-membered ring-fused naphthalimide derivatives with potentials for cancer theranostics

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Chinese chemical Letters 2023年第4期34卷 236-239页

作者： Yonghui Yang Xiayu Shi Zhuo Chen Yufang Xu Xuhong Qian Weiping Zhu state key laboratory of Bioreactor Engineering Shanghai Key Laboratory of Chemical BiologyShanghai key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science and TechnologyShanghai 200237China

Naphthalimide derivatives have good planarity and large conjugated structure and therefore possess photophysical properties and biological activities. Previously, our group discovered seven-membered heterocyclic derivatives via modifying 4-and 5-positions of naphthalimide skeleton and found the derivatives had good water solubility and showed large stokes shift and strong fluorescence in water. In this article, we designed and synthesized more seven-membered ring-fused naphthalimide derivatives(Y1-Y16)by introducing different substitutions on the imide group. Among them, Y1, Y5, Y9 were found to show similar cytotoxic activities with Amonafide against A549 and HL60 cells, with IC50values at 10^(-6)mol/L.What is more, the asymmetry derivatives(Y1 and Y5) showed high fluorescent quantum yields in the aqueous phase(Ф = 0.47). Considering the great fluorescence quantum yields in water and the potent anti-tumor activities of the representative seven-membered ring-fused naphthalimides, they have potentials to be used as agents for cancer theranostics.

关键词： Seven-membered ring Antitumor activity High fluorescent quantum yield Theranostics

Atractylenolide-I covalently binds to CYP11B2,selectively inhibits aldosterone synthesis, and improves hyperaldosteronism

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Acta Pharmaceutica Sinica B 2022年第1期12卷 135-148页

作者： Wenjuan Liu Zhenqiang Li Simeng Chu Xiaoyao Ma Xiaoying Wang Min Jiang Gang Bai state key laboratory of Medicinal chemical biology College of Pharmacy and Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300353China Tianjin University of Traditional Chinese Medicine Tianjin 300193China

Hyperaldosteronism is a common disease that is closely related to endocrine hypertension and other cardiovascular diseases. Cytochrome P450 11 B2(CYP11 B2), an important enzyme in aldosterone(ALD) synthesis, is a promising target for the treatment of hyperaldosteronism. However, selective inhibitors targeting CYP11 B2 are still lacking due to the high similarity with CYP11 B1. In this study,atractylenolide-I(AT-I) was found to significantly reduce the production of ALD but had no effect on cortisol synthesis, which is catalyzed by CYP11 B1. chemical biology studies revealed that due to the presence of Ala320, AT-I is selectively bound to the catalytic pocket of CYP11 B2, and the C8/C9 double bond of AT-I can be epoxidized, which then undergoes nucleophilic addition with the sulfhydryl group of Cys450 in CYP11 B2. The covalent binding of AT-I disrupts the interaction between heme and CYP11 B2 and inactivates CYP11 B2, leading to the suppression of ALD synthesis;AT-I shows a significant therapeutic effect for improving hyperaldosteronism.

关键词： Aldosterone CYP11B2 Hyperaldosteronism Atractylenolide-I Selective inhibitor

Dyngo-4a通过影响dynamin 2寡聚体的形成来保护老鼠少受轮状病毒感染导致的伤害

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Science Bulletin 2020年第21期65卷 1796-1799,M0003页

作者：张全志张秋寒许智超唐崎刘欣瑾牛丹萍高晓明蓝柯吴叔文 Institute of biology and Medical Sciences Soochow University state key laboratory of Virology College of Life Sciences Wuhan University state key laboratory of Virology Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education School of Pharmaceutical SciencesWuhan University

轮状病毒是全球范围内导致5岁以下儿童严重腹泻的病原物之一.虽然已通过审批的数个轮状病毒疫苗可以保护50%以上的人群免受轮状病毒侵害,现有的轮状病毒腹泻对症治疗手段主要是补锌和补充水分,还急需针对轮状病毒腹泻的特异性靶向治疗... 详细信息

轮状病毒是全球范围内导致5岁以下儿童严重腹泻的病原物之一.虽然已通过审批的数个轮状病毒疫苗可以保护50%以上的人群免受轮状病毒侵害,现有的轮状病毒腹泻对症治疗手段主要是补锌和补充水分,还急需针对轮状病毒腹泻的特异性靶向治疗手段以快速缓解病人的痛苦.以大规模药物筛选为手段,我们发现dyngo-4a,一个发动蛋白2(dynamin 2)的抑制剂,可以显著抑制轮状病毒感染导致的细胞病变.而且dyngo-4a还可以抑制轮状病毒在仔鼠肠道内的复制及其复制导致的腹泻.采用小干扰RNA(siRNA)敲除发动蛋白2,而非发动蛋白1,可以显著抑制轮状病毒感染,说明dyngo-4a主要通过影响发动蛋白2的功能来抑制轮状病毒.机制层面,dyngo-4a通过作用于发动蛋白2并引起发动蛋白2寡聚体异常积累来发挥其抗轮状病毒感染的功能.由此,dyngo-4a是潜在的特异性靶向治疗轮状病毒腹泻的候选药物.

关键词：轮状病毒腹泻轮状病毒疫苗轮状病毒感染细胞病变寡聚体药物筛选治疗手段

Effect of high hydrostatic pressure on prebiotic peptide synthesis

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Chinese chemical Letters 2019年第2期30卷 367-370页

作者： Jianxi Ying Peng Chen Yile Wu Xu Yang Kaili Yan Pengxiang Xu Yufen Zhao Department of Chemistry and key laboratory for chemical biology of Fujian Province College of Chemistry and Chemical EngineeringXiamen University Institute of drug discovery Technology Ningbo University key laboratory of Bioorganic Phosphorus Chemistry and chemical biology (Ministry of Education) Department of ChemistryTsinghua University

Prebiotic peptide synthesis is a central issue concerning life's origins. Many studies considered that life might come from Hadean deep-sea environment, that is, under high hydrostatic pressure conditions.However, the properties of prebiotic peptide formation under high hydrostatic pressure conditions have seldom been mentioned. Here we report that the yields of dipeptides increase with raised pressures.Significantly, effect of pressure on the formation of dipeptide was obvious at relatively low temperature.Considering that the deep sea is of high hydrostatic pressure, the pressure may serve as one of the key factors in prebiotic peptide synthesis in the Hadean deep-sea environment. The high hydrostatic pressure should be considered as one of the significant factors in studying the origin of life.

关键词： High hydrostatic pressure Sodium trimetaphosphate Prebiotic peptide synthesis Prebiotic chemistry Origin of life

New tirucallane-type triterpenoids from the resin of Boswellia carterii and their NO inhibitory activities

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Chinese Journal of Natural Medicines 2021年第9期19卷 686-692页

作者： LIU Fang-Shen ZHANG Ting-Ting XU Jun JING Qin-Xue GONG Chi DONG Bang-Jian LI Da-Hong LIU Xiao-Qiu LI Zhan-Lin YUAN Zhong HUA Hui-Ming key laboratory of Structure-Based drug Design&discovery Ministry of EducationShenyang Pharmaceutical UniversityShenyang 110016China School of Traditional Chinese Materia Medica Shenyang Pharmaceutical UniversityShenyang 110016China state key laboratory of Medicinal chemical biology College of Pharmacyand Tianjin Key Laboratory of Molecular Drug ResearchNankai UniversityTianjin 300071China

Six new tirucallane-type triterpenoids(1-6),along with ten known triterpenoids,were isolated from methylene chloride extract of the resin of Boswellia carterii Birdw.By the application of the comprehensive spectroscopic data,the structures of the compounds were clarified.The experimental electronic circular dichroism spectra were compared with those calculated,which allowed to assign the absolute configurations.Compounds 5 and 6 possesed a 2,3-seco tirucallane-type triterpenoid skeleton,which were first reported.Their inhibitory activity against NO formation in LPS-activated BV-2 cells were evaluated.Compound 9 showed appreciable inhibitory effect,with an IC_(50)value of 7.58±0.87μmol·L^(-1).

关键词： Boswellia carterii Birdw seco-Tirucallane triterpenoids NO inhibition

Chiral Br?nsted acid-catalyzed asymmetric intermolecular[4+2]annulation of ynamides with para-quinone methides

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Science China Chemistry 2023年第5期66卷 1467-1473页

作者： Hang-Hao Li Ya-Nan Meng Can-Ming Chen Yu-Qi Wang Zhi-Xin Zhang Zhou Xu Bo Zhou Long-Wu Ye key laboratory for chemical biology of Fujian Province and state key laboratory of Physical Chemistry of Solid Surfaces College of Chemistry and Chemical EngineeringXiamen UniversityXiamen 361005China Jiangsu key laboratory of New drug Research and Clinical Pharmacy School of PharmacyXuzhou Medical UniversityXuzhou 221004China state key laboratory of Elemento-Organic Chemistry Nankai UniversityTianjin 300071China state key laboratory of Organometallic Chemistry Chinese Academy of SciencesShanghai 200032China

Catalytic asymmetric transformations of ynamides have attracted considerable attention in recent years.However,most of them were limited to intramolecular reactions or required metal catalysts.Herein,a chiral Br?nsted acid-catalyzed asymmetric intermolecular[4+2]annulation of ynamides with para-quinone methides(p-QMs)is disclosed,which not only represents the first metal-free protocol for catalytic asymmetric nucleophilic addition of ynamides to electrophiles,but also constitutes the first enantioselective annulation between p-QMs and alkynes.This methodology leads to the practical synthesis of biologically important chiral 4-aryl-3,4-dihydrocoumarins and 4-aryl-coumarins.Preliminary control experiments indicate that the orthohydroxyphenyl substituted p-QMs could isomerize into ortho-quinone methides(o-QMs)in the presence of chiral catalyst,which further react with ynamides via enantioselective[4+2]annulation,to generate the chiral product.

关键词： stereoselective metal-free cyclization ynamides p-QMs