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Abietane diterpenoids and iridoids from Caryopteris mongolica

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Chinese Journal of Natural Medicines 2023年第12期21卷 927-937页

作者： ZHANG Shanshan MAO Xudong XU Hongtao WEI Xiaohui CHOU Guixin Institute of Chinese Materia Medica Shanghai University of Traditional Chinese MedicineShanghai 201203China Shanghai R&D Center for Standardization of Chinese Medicines Shanghai 201203China state key lab of new drug and pharmaceutical process Shanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 201203China

Six new abietane diterpenoids(1−6)and five undescribed iridoids(7−11)have been isolated from the aerial parts of Caryopteris *** intricate structural characterization of these compounds was meticulously undertaken using an array of advanced spectroscopic *** process was further enhanced by the application of DP4+probability analyses and electronic circular dichroism(ECD)*** isolation and structural elucidation,the cytotoxicity of these compounds was *** them,compound 3 stood out,displaying significant cytotoxic activity against HeLa cells with an IC50 value of 7.83±1.28μmol·L^(−1).Additionally,compounds 1,2,4,9,and 10 manifested moderate cytotoxic effects on specific cell lines,with IC50 values ranging from 11.7 to 20.9μmol·L^(−1).

关键词： Caryopteris mongolica Abietane diterpenoids Spectroscopic analysis Cytotoxicity

Discovery of proqodine A derivatives with antitumor activity targeting NAD(P)H:quinone oxidoreductase 1 and nicotinamide phosphoribosyltransferase

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Chinese Journal of Natural Medicines 2024年第1期22卷 75-88页

作者： SONG Jiangzhou ZOU Guiqing ZHAO Zhou ZHU Ya XUE Jiayu AO Lanjia SUN Huiyong HAO Haiping ZHANG Bo XU Xiaowei state key laboratory of Natural Medicines Key Lab of Drug Metabolism and PharmacokineticsChina Pharmaceutical UniversityNanjing 210009China state key laboratory of Natural Medicines China Pharmaceutical UniversityNanjing 210009China

NAD(P)H:quinone oxidoreductase 1(NQO1)is a flavin protease highly expressed in various cancer ***1 catalyzes a futile redox cycle in substrates,leading to substantial reactive oxygen species(ROS)*** ROS generation results in extensive DNA damage and elevated poly(ADP-ribose)polymerase 1(PARP1)-mediated consumption of nicotinamide adenine dinucleotide(NAD^(+)),ultimately causing cell *** phosphoribosyltransferase(NAMPT),the rate-limiting enzyme in the NAD^(+)salvage synthesis pathway,emerges as a critical target in cancer *** concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD+*** this study,we designed,synthesized,and assessed a novel series of proqodine A derivatives targeting both NQO1 and *** these,compound T8 demonstrated potent antitumor ***,T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and *** discovery offers a promising new molecular entity for advancing anticancer research.

关键词： NQO1 ROS NAMPT NAD^(+) T8

Recent progress in tumor photodynamic immunotherapy

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Chinese Chemical Letters 2020年第7期31卷 1709-1716页

作者： Lijun Shen Tianjiao Zhou Yatong Fan Xin Chang Yi Wang Jianguo Sun Lei Xing Hulin Jiang state key laboratory of Natural Medicines Department of PharmaceuticsChina Pharmaceutical UniversityNanjing 210009China Jiangsu key laboratory of druggability of Biopharmaceuticals China Pharmaceutical UniversityNanjing 210009China Jiangsu key laboratory of drug Screening China Pharmaceutical UniversityNanjing 210009China Jiangsu key laboratory of drug Discovery for Metabolic Diseases China Pharmaceutical UniversityNanjing 210009China key lab of drug Metabolism and Pharmacokinetics State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 210009China

Photodynamic therapy(PDT)is a promising alternative approach for effective cancer treatment,which can directly destroy local tumor cells due to the generation of cytotoxic singlet oxygen and reactive oxygen species(ROS)in the tumor ***,PDT-mediated cell death is also associated with anti-tumor immune *** r,immunosuppre s sion of tumor microe nvironment is able to limit the immune response induced by PDT,it is therefore necessary to combine with immunocheckpoint inhibitor and immunoadjuvant for synergistic treatment of ***,the recent advances of PDT,immunotherapy,and photodynamic immunotherapy are reviewed.

关键词： Cancer therapy Photodynamic therapy Immunotherapy Reactive oxygen species Singlet oxygen

A novel inhibitor of ARfl and ARv7 induces protein degradation to overcome enzalutamide resistance in advanced prostate cancer

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4165-4179页

作者： Yan Li Ya Chu Guangjiang Shi Xiaobin Wang Wanli Ye Chun Shan Dajia Wang Di Zhang Wei He Jingwei Jiang Shuqian Ma Yuhong Han Zhili Zhao Shijia Du Zhen Chen Zhiyu Li Yong Yang Chen Wang Xi Xu Hongxi Wu Center for new drug Safety Evaluation and Research State Key Laboratory of Natural MedicinesChina Pharmaceutical UniversityNanjing 211198China School of Life Science and Technology China Pharmaceutical UniversityNanjing 211198China School of Pharmacy China Pharmaceutical UniversityNanjing 211198China Jiangsu key lab of drug Screening China Pharmaceutical UniversityNanjing 211198China

Enzalutamide(ENZ) is a second-generation androgen receptor(AR) antagonist used for the treatment of castration-resistant prostate cancer(CRPC) and reportedly prolongs survival time within a year of starting therapy. However, CRPC patients can develop ENZ resistance(ENZR), mainly driven by abnormal reactivation of AR signaling, involving increased expression of the full-length AR(ARfl)or dominantly active androgen receptor splice variant 7(ARv7) and ARfl/ARv7 heterodimers. There is currently no efficient treatment for ENZR in CRPC. Herein, a small molecule LLU-206 was rationally designed based on the ENZ structure and exhibited potent inhibition of both ARfl and constitutively active ARv7 to inhibit PCa proliferation and suppress ENZR in CRPC. Mechanically, LLU-206 promoted ARfl/ARv7 protein degradation and decreased ARfl/ARv7 heterodimers through mouse double minute 2-mediated ubiquitination. Finally, LLU-206 exhibited favorable pharmacokinetic properties with poor permeability across the blood-brain barrier, leading to a lower prevalence of adverse effects, including seizure and neurotoxicity, than ENZ-based therapies. In a nutshell, our findings demonstrated that LLU-206 could effectively inhibit ARfl/ARv7-driven CRPC by dual-targeting of ARfl/ARv7 heterodimers and protein degradation, providing new insights for the design of new-generation AR inhibitors to overcome ARfl/ARv7-driven CRPC.

关键词： drug resistance Enzalutamide Castration-resistant prostate cancer Androgen receptorsplice variant7 Heterodimers Degradation

Two symmetrical unsaturated acids isolated from Viscum album

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Chinese Journal of Natural Medicines 2019年第2期17卷 145-148页

作者： CAO Duo WANG Li-Qing HAN Xiao-Min GUAN Hui-Rui LEI Meng WEI Ya-Hui CHENG Liang YANG Pei-Ming SUN Zheng-Liang GAO Wen DAI Jia-Kun College of Life Science Northwest University state key laboratory of new drug and pharmaceutical process Shanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical Industry Shanghai University of Medicine&Health Sciences Affiliated Sixth People's Hospital South Campus Shineway pharmaceutical Group Co. Ltd. Bio-Agricultue Institute of Shaanxi

In the present study,two new acetylene conjugate compounds,dibutyl(2Z,6Z)-octa-2,6-dien-4-yne dioate(1),and dibutyl(2E,6E)-octa-2,6-dien-4-yne dioate(2),were isolated from the dry stem leaves of Viscum album,along with nine known compounds(3–11).Their structures were confirmed on the basis of spectroscopic *** 1 and 8 showed antioxidant activity against xanthine oxidase(XOD)and 1,1-diphenyl-2-picrylhydrazyl radical 2,2-diphenyl-1-(2,4,6-trinitrophenyl)hydroxyl(DPPH),with the IC_(50) of 1.22 and 1.33μmol·L^(–1),and the SC_(50 )of 4.34 and 8.22μmol·L^(–1),respectively.

关键词： Viscum album Symmetrical unsaturated acid Antioxidant activity

Antiviral effects of Reduning injection against Enterovirus 71 and possible mechanisms of action

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Chinese Journal of Natural Medicines 2015年第12期13卷 881-888页

作者： CAO Ze-Yu CHANG Xiu-Juan ZHAO Zhong-Peng CAO Liang XIAO Wei Jiangsu Kanion pharmaceutical Co. Ltd. state key laboratory of new-tech for Chinese Medicine pharmaceutical process Department of Immunology Institute of Microbiology and EpidemiologyAcademy of Military Medical Sciences

The present study was designed to evaluate the protective effects of Reduning injection against Enterovirus 71(EV71) in Vero cells and in mice. The Vero cells were infected with 100 and 50 TCID50(50% tissue culture infective dose) of EV71, respectively. The inhibition of Reduning injection on cytopathic effect(CPE) was detected. Meanwhile, a mouse model produced by intraperitoneal EV71-infection(106 TCID50), was used to investigate the protective effects of Reduning injection. The total survival rate, living time, daily survival rate, weight ratio, and score for symptoms were examined. The viral loads in Vero cells and muscle tissues were detected using real-time PCR. Finally, the content of cytokines was analyzed by ELISA. In the Vero cells, 2.5 mg crude drug·m L-1 of Reduning injection inhibited CPE induced by EV71 infection. In the mice, 1.3 g crude drug·kg-1 of Reduning injection rescued death triggered by infection, in comparison with model group. Moreover, the survival rate, weight ratio, and clinical scores were also improved. The viral RNA copies in the Vero cells and the mice muscle tissues were reduced. Besides, the steep EV71-induced accumulations of TNF-α and MCP-1 were decreased by Reduning injection. In conclusion, Reduning injection showed promising protective effects against EV71 in Vero cells and in mice.

关键词： Reduning injection EV71 Vero cell Mice Antiviral

A hepatoprotection study of Radix Bupleuri on acetaminophen-induced liver injury based on CYP450 inhibition

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Chinese Journal of Natural Medicines 2019年第7期17卷 517-524页

作者： WANG Yu-Xin DU Yi LIU Xia-Fei YANG Fang-Xiu WU Xiao TAN Li LU Yi-Hong ZHANG Jing-Wei ZHOU Fang WANG Guang-Ji key lab of drug Metabolism and Pharmacokinetics China Pharmaceutical University Nanjing 210009 China key laboratory of new drug Research and Clinical Pharmacy Xuzhou Medical University Xuzhou 221004 China Jiangsu Institute for Food and drug Control Nanjing 210019 China

We investigated the potential hepatoprotective effect of Radix Bupleuri(RB) by inducing acute liver injury(ALI) in an animal model using acetaminophen(APAP) after pretreatment with RB aqueous extract for three consecutive days. Compared to those of the APAP group, the biochemical and histological results of the RB pretreatment group showed lower serum aspartate transaminase(AST) and alanine transaminase(ALT) levels as well as less liver damage. Pharmacokinetic study of the toxicity related marker acetaminophen-cysteine(APC) revealed a lower exposure level in rats, suggesting that RB alleviated APAP-induced liver damage by preventing glutathione(GSH) depletion. The results of cocktail approach showed significant inhibition of CYP2 E1 and CYP3 A activity. Further investigation revealed the increasing of CYP2 E1 and CYP3 A protein was significantly inhibited in pretreatment group,while no obvious effect on gene expression was found. Therefore, this study clearly demonstrates that RB exhibited significant protective action against APAP-induced acute live injury via pretreatment, and which is partly through inhibiting the increase of activity and translation of cytochrome P450 enzymes, rather than gene transcription.

关键词： Hepatoprotection Radix Bupleuri Acetaminophen Acute liver injury Cytochrome P450 enzymes

Effect of Guizhi Fuling capsule and its extracts on human breast cancer cells proliferation

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中国药理学与毒理学杂志 2017年第10期31卷 1013-1014页

作者： Zi-ru YU Li LI Jin-hua WANG Zhen-zhong WANG Wei XIAO Guan-hua DU Beijing key laboratory of drug Targets Identification and drug Screening Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical College state key laboratory of new-tech for Chinese Medicine pharmaceutical process Jiangsu Kanion Pharmaceutical CoLtd

OBJECTIVE To evaluate the effect of Guizhi Fuling Capsule active pharmaceutical ingredient(API)and its fractions on human breast cancer cells proliferation by high-throughput screening *** The crude fractions were obtained from the extraction and elution of the API of Guizhi Fuling Capsule,and 929 standard fractions were obtained by the optimal separation *** B(SRB)method was used to evaluate the effects of the Guizhi Fuling capsule API and929 kinds of fractions on the proliferation of human breast cancer cells MCF-7 and *** The Guizhi Fuling capsule API had a strong ability to inhibit the proliferation of MCF-7 cells at high concentration and the ability to inhibit MDA-MB-231 cells' proliferate at low concentration following 72 h treatment;some samples of 929 fractions(5μg·mL^(-1))was found to have a breast cancer cell growth inhibition rate above 50%,without toxicity on HUVECs *** The API of Guizhi Fuling capsule had significant cytotoxicity effects on these two human breast cancer cells,with significant concentration-and time-dependent manner.

关键词： high throughput screening Guizhi Fuling capsule breast cancer MCF-7 cell MDA-MB-231 cell sulforhodamine B

NAMPT inhibition synergizes with NQO1-targeting agents in inducing apoptotic cell death in non-small cell lung cancer cells

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Chinese Journal of Natural Medicines 2016年第8期14卷 582-589页

作者： LIU Hui-Ying LI Qing-Ran CHENG Xue-Fang WANG Guang-Ji HAO Hai-Ping state key laboratory of Natural Medicines Key Lab of Drug Metabolism and Pharmacokinetics China Pharmaceutical University Department of Physiology and Pathophysiology School of Basic Medical Sciences Peking University

Nicotinamide phosphoribosyltransferase(NAMPT) catalyzes the first rate-limiting step in converting nicotinamide to NAD^+, essential for a number of enzymes and regulatory proteins involved in a variety of cellular processes, including deacetylation enzyme SIRT1 which modulates several tumor suppressors such as p53 and FOXO. Herein we report that NQO1 substrates Tanshione IIA(TSA) and β-lapachone(β-lap) induced a rapid depletion of NAD^+ pool but adaptively a significant upregulation of NAMPT. NAMPT inhibition by FK866 at a nontoxic dose significantly enhanced NQO1-targeting agent-induced apoptotic cell death. Compared with TSA or β-lap treatment alone, co-treatment with FK866 induced a more dramatic depletion of NAD^+, repression of SIRT1 activity, and thereby the increased accumulation of acetylated FOXO1 and the activation of apoptotic pathway. In conclusion, the results from the present study support that NAMPT inhibition can synergize with NQO1 activation to induce apoptotic cell death, thereby providing a new rationale for the development of combinative therapeutic drugs in combating non-small lung cancer.

关键词： FK866 NQOl-targeting agents Synergy NAD+ SIRT1