JOURNAL OF ORGANIC CHEMISTRY
·
2023
·
IF 3.6
Yunying Yan,Jianjun Hao,Fenfen Xie,Fen Han,Linhai Jing,Pan Han
Magnesium-mediated reductive carboxylation of p-QMs with CO2 via an Umpolung strategy has been developed, which can be used for the preparation of various aryl acetic acids. This protocol featured high atom economy, mild conditions, and operational simplicity. The creation of this Umpolung carboxylation of p-QMs will unprecedentedly extend the application of p-QMs to nucleophilic reagents.
研究领域:
有机化学
·
环境化学
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 22
·7962
·
IF 4.927
Shuhan Chen,Wei Wen,Xue Zhao,Zelang Zhang,Weishuang Li,Yaoyao Zhang,Bojie Li,Lei Zhu
Here, we describe the preparation of copper nanoparticles that are stabilized on a chitosan composite film (CP@Cu). This material could catalyze the 1,6-hydroboration reactions ofp-quinone methides with B2pin2as a boron source under mild conditions. This reaction exhibited very good functional group compatibility, and the organoboron compounds that were formed could easily be converted into corresponding hydroxyl products with good to excellent yields. This newly developed methodology provides an efficient and sequential pathway for the synthesis ofgem-disubstituted methanols.Keywords:copper nanoparticles;chitosan composite film;hydroboration reactions;p-quinone methides;organoboron compounds
研究领域:
化学
·
材料科学
·
有机合成
✓ 已验证
产品关联
DOI
PubMed
高影响因子
XENOBIOTICA
·
2021
·
IF 1.908
Yilin Li,Yang Wang,Na Zhang,Shenzhi Zhou,Ying Peng,Jiang Zheng
Venlafaxine (VLF), an antidepressant agent, is widely used to combat major depressive disorders, particularly for the treatment of selective serotonin reuptake inhibitor-resistant depression. VLF has been shown to cause liver injury. The present study aimed to investigate the metabolic activation of VLF and explore the mechanisms of hepatotoxicity induced by VLF.One glutathione (GSH) conjugate and one cysteine conjugate were both detected in mouse and human liver microsomal incubations containing VLF and GSH or cysteine. The two conjugates were also detected in cultured mouse primary hepatocytes and bile of rats after exposure to VLF. The in vitro and in vivo studies demonstrated that VLF was metabolized to a quinone methide intermediate reactive to GSH and cysteine residues of hepatic protein. The observed protein covalent binding revealed dose-dependency. The metabolic activation of VLF was P450-dependent, and CYP3A4 was found as the predominant enzyme involved in the bioactivation process.These findings facilitate better understanding of the metabolic activation-hepatotoxicity relationship of VLF and provide chemists with information about new potential structural alerts during drug design process.
研究领域:
药理学
·
毒理学
·
药物代谢
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ORGANIC CHEMISTRY
·
2021
·
IF 4.354
Chunfang Yang,Chunshuai Huang,Chunyan Fang,Liping Zhang,Siqiang Chen,Qingbo Zhang,Changsheng Zhang,Wenjun Zhang
Inactivation of the flavoenzyme-encoding gene flsO1 in fluostatin biosynthesis led to the isolation of four new angucyclinone derivatives (11, 12, 14, and 15), among which fluostarenes A (14) and B (15) featured the unprecedented 6/6/5/6/6 pentacyclic skeleton with fusion of a benzo[b]fluorene and a six-membered lactone ring. Both 14 and 15 were putatively generated via quinone methide-mediated nonenzymatic reactions. Fluostarene B (15) exhibited cytotoxicity against several cancer cell lines with IC50 values ranging from 7 to 10 μM. Fluostarenes A (14), B (15), and PK1 (16) showed α-glucosidase inhibition activity with IC50 of 0.89, 1.58, and 0.13 μM, respectively. Successful complementation of the ΔflsO1 mutant with alpK from kinamycin biosynthesis suggests that FlsO1 should function equivalently to AlpK as a putative C-5 hydroxylase.
研究领域:
药理学
·
生物化学
·
分子生物学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF FOOD SCIENCES AND NUTRITION
·
2019
·
IF 2.792
Jin Li,Jian Zeng,Jinming Peng,Yangyang Jia,Chun-Mei Li
A-type epigallocatechin-3-gallate (EGCG) and epicatechin-3-O-gallate (ECG) dimers have multiply biological activities. In this study, the pharmacokinetics of them were investigated in mice after a single dose intravenous administration, and the metabolites in mice plasma and urine were investigated by ultra-performance liquid chromatography-Quadrupole-time of flight mass spectrometer (UPLC-QTOF-MS). Our results showed that the half-life (t1/2) of A-type EGCG and ECG dimers were 116.37 min and 33.04 min, respectively, and the maximal concentration in plasma was 32.81 μg/mL and 55.59 μg/mL, respectively. It was found that two dimers were firstly experienced by quinone methide (QM) fission to form the EGCG and ECG analogue, and the phase II metabolites were generated subsequently. The main metabolites in plasma and urine were glucuronidation and sulphation derivatives. In addition, small molecule weight of phenolic acids were detected in urine.
研究领域:
药理学
·
分析化学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2023
·
IF 4.1
Aixuan Wang,Qiang Zhao,Minglu Liu,Yang Wang,Guode Zhao,Weiwei Li,Ying Peng,Jiang Zheng
Tolterodine (TOL) is an antimuscarinic drug used for the treatment of patients with overactive bladder presenting urinary frequency, urgency, and urge incontinence. During the clinical use of TOL, adverse events such as liver injury took place. The present study aimed at the investigation of the metabolic activation of TOL possibly associated with its hepatotoxicity. One GSH conjugate, two NAC conjugates, and two cysteine conjugates were found in both mouse and human liver microsomal incubations supplemented with TOL, GSH/NAC/cysteine, and NADPH. The detected conjugates suggest the production of a quinone methide intermediate. The same GSH conjugate was also observed in mouse primary hepatocytes and in the bile of rats receiving TOL. One of the urinary NAC conjugates was observed in rats administered TOL. One of the cysteine conjugates was found in a digestion mixture containing hepatic proteins from animals administered TOL. The observed protein modification was dose-dependent. CYP3A primarily catalyzes the metabolic activation of TOL. Ketoconazole (KTC) pretreatment reduced the generation of the GSH conjugate in mouse liver and cultured primary hepatocytes after TOL treatment. In addition, KTC reduced the susceptibility of primary hepatocytes to TOL cytotoxicity. The quinone methide metabolite may be involved in TOL-induced hepatotoxicity and cytotoxicity.
研究领域:
药理学
·
毒理学
·
药物代谢
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 21
·5166
·
IF 4.2
Peng Wang,Xu Zhang,Xi Le,Junjun Chen,Guangyan Zhang,Junjian An,Nianjie Feng,Junxian Xie
A thorough understanding of the lignin–carbohydrate complex (LCC) structure has a significant meaning in the high-value utilization of lignocellulose. In this work, the complex (DHPKGC) was obtained by an addition reaction between konjac glucomannan (KGM) and quinone methides generated in the synthesis of dehydrogenation polymers (DHPs) to simulate the formation of LCCs. The effect of pH on the prepared DHPKGC was investigated. The structure of the DHPKGC was characterized by Fourier Transform Infrared (FTIR),13C-Nuclear Magnetic Resonance (13C-NMR), and two-dimensional Heteronuclear Single Quantum Coherence Nuclear Magnetic Resonance (2D HSQC NMR) analyses. The results indicated the pH of 4.0 was conducive to the polymerization reaction between DHPs and oxidized KGM by the TEMPO/NaClO/NaBr system. In addition, the resultant DHPKGC was connected by benzyl ester linkages. Overall, this study aims to gain greater insight into the process of LCC formation in plants.
研究领域:
化学
·
材料科学
·
生物化学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2021
·
IF 13.273
Ting Su,Furong Cheng,Yuji Pu,Jun Cao,Shuibin Lin,Guizhi Zhu,Bin He
Cancer has been one of the major healthcare burdens, which demands innovative therapeutic strategies to improve the treatment outcomes. Combination therapy hold great potential to leverage multiple synergistic pathways to improve cancer treatment. Cancer cells often exhibit an increased generation of reactive oxygen species (ROS) and antioxidant species compared with normal cells, and the levels of these species can be further elevated by common therapeutic modalities such as photodynamic therapy (PDT) or chemotherapy. Taking advantage that cancer cells are vulnerable to further oxidative stress, we aim to design a drug delivery system by simultaneously increasing the cellular ROS level, reducing antioxidative capacity, and inducing anticancer chemotherapy in cancer cells. Here, we designed a star-shape polymer, PEG(- b -PCL-Ce6)- b -PBEMA, based on the Passerini three-component reaction, which can both enhance ROS generation during PDT and decrease the GSH level in cancer cells. The polycaprolactone conjugated with photosensitizer Ce6 served as hydrophobic segments to promote micelle formation, and Ce6 was used for PDT. The H 2 O 2 -labile group of arylboronic esters pendent on the third segment was designed for H 2 O 2 -induced quinone methide (QM) release for GSH depletion. We thoroughly investigated the spectral properties of blank micelle during its assembling process, ROS generation, and H 2 O 2 -induced QM release in vitro . Moreover, this polymeric micelle could successfully load hydrophobic anti-cancer drug Doxorubicin (DOX) and efficiently deliver DOX into cancer cells. The triple combination of ROS generation, GSH elimination, and chemotherapy dramatically improved antitumor efficiency relative to each of them alone in vitro and in vivo .
研究领域:
癌症治疗
·
纳米医学
·
药物递送系统
·
生物医学工程
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL RESEARCH IN TOXICOLOGY
·
2022
·
IF 3.973
Mingyu Zhang,Yaodong Hu,Wei Li,Chen Sun,Chunjing Guan,Ying Peng,Jiang Zheng
2,6-Dimethylphenol (2,6-DMP) is an environmental pollutant found in industrial wastewater. Exposure to 2,6-DMP is of increasing concern as it endangered reportedly some aquatic animals. In this study, we investigated the metabolic activation and hepatotoxicity of 2,6-DMP. 2,6-DMP was metabolized to an o-quinone methide intermediate in vitro and in vivo. The electrophilic metabolite was reactive to the sulfhydryl groups of glutathione, N-acetyl cysteine, and cysteine. NADPH was required for the formation of the reactive metabolite. The quinone methide intermediate reacted with cysteine residues to form hepatic protein adduction. A single dose of 2,6-DMP induced marked elevation of serum ALT and AST in mice. Both the protein adduction and hepatotoxicity of 2,6-DMP showed dose dependency.
研究领域:
毒理学
·
环境科学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2014
·
IF 2.982
Qi Shen,Minjuan Zuo,Li Ma,Ye Tian,Lu Wang,Huidi Jiang,Quan Zhou,Hui Zhou,Lushan Yu,Su Zeng
Neferine is a bisbenzylisoquinoline alkaloid isolated from the seed embryos of Nelumbo nucifera Gaertn (Lotus) with various potent pharmacological effects. Recently, neferine has attracted attention for its anti-tumor activities. Our study explored its metabolism and cytotoxicity mechanism. Approaches using chemical inhibitors and recombinant human enzymes to characterize the involved enzymes and kinetic studies indicated that the demethylation of neferine by cytochrome P450 (CYP) 2D6 and CYP3A4 fitted a biphasic kinetic profile. Glutathione (GSH) was used as a trapping agent to identify reactive metabolites of neferine, and four novel GSH conjugates were detected with [M+H] + ions at m / z 902.4, 916.2, 916.1, and 930.4. Based on its structure containing para -methylene phenol and results from a product ion scan, GSH tends to conjugate with C9’ after undergoing oxidative metabolism to form the binding site predominated by CYP3A4. Furthermore, the addition of recombinant human GSTA1, GSTT1, and GSTP1 had little effect on the production of the GSH conjugates. In a 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide assay, combined with the GSH modulators l -buthionine sulfoximine or N -acetyl- l -cysteine, neferine treatment of MDCK-hCYP3A4 and HepG2 cells revealed that CYP3A4 expression and cellular GSH content could cause an EC 50 shift. Metabolic activation mediated by CYP3A4 and GSH depletion significantly enhanced neferine-induced cytotoxicity.
研究领域:
药理学
·
毒理学
·
生物化学
·
肿瘤学
·
酶学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF COLLOID AND INTERFACE SCIENCE
·
2024
·
IF 9.4
Xinlu Zhang,Xu Zhang,Shutong Chen,Yongxin Liu,Chen Cao,Guohui Cheng,Sheng Wang
Nanomedicines that combine reactive oxygen species (ROS)-responsive polyprodrug and photodynamic therapy have shown great potential for improving treatment efficacy. However, the consumption of ROS by overexpressed glutathione in tumor cells is a major obstacle for achieving effective ROS amplification and prodrug activation. Herein, we report a polyprodrug-based nanoparticle that can realize ROS amplification and cascaded drug release. The nanoparticle can respond to the high level of hydrogen peroxide in tumor microenvironment, achieving self-destruction and release of quinone methide. The quinone methide depletes intracellular glutathione and thus decreases the antioxidant capacity of cancer cells. Under laser irradiation, a large amount of ROS will be generated to induce cell damage and prodrug activation. Therefore, the glutathione-depleting polyprodrug nanoparticles can efficiently inhibit tumor growth by enhanced photodynamic therapy and cascaded locoregional chemotherapy.
研究领域:
纳米技术
·
药学
·
癌症研究
·
治疗学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICO-BIOLOGICAL INTERACTIONS
·
2016
·
IF 2.618
Huina Yao,Ying Peng,Jiang Zheng
Methyleugenol (ME), an alkenylbenzene compound, is a constituent of many foods and is used as flavoring agent in foodstuffs and as fragrance in cosmetics. It has been reported that exposure to ME can cause carcinogenicity , cytotoxicity, and genotoxicity . Metabolic activation is suggested to play an important role in ME-induced toxicities. Electrophilic metabolites of ME have been reported to covalently bind to proteins and nucleic acids . The objective of this study was to identify GSH and related cysteine conjugates derived from these reactive metabolites in vivo . Five biliary GSH (M1-M5) and four urinary cysteine conjugates (M6-M9) were detected in rats given ME. M1 and M2 were GSH conjugates derived from the epoxide of ME. M3, M4, and M5 were GSH conjugates possibly generated from the corresponding α,β -unsaturated aldehyde, carbonium ion , and quinone methide, respectively. The structures of the GSH conjugates were verified by chemical synthesis. Cysteine conjugates M6, M7, M8, and M9 were found to correspond to the respective M1/M2, M3, M4, and M5. The data obtained from the present in vivo work facilitate the understanding of mechanism action of ME toxicities and may provide information suitable for use as biomarkers of exposure to ME.
研究领域:
毒理学
·
药理学
·
生物化学
·
代谢学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）