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Exploration of 5-cyano-6-phenylpyrimidin derivatives containing an 1,2,3-triazole moiety as potent FAD-based LSD1 inhibitors

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Acta Pharmaceutica Sinica B 2020年第9期10卷 1658-1668页

作者： Liying May Haojie Wangy Yinghua You Chaoya Ma Yuejiao Liu Feifei Yang Yichao Zheng Hongmin Liu Collaborative Innovation Center of new drug Research and Safety evaluation Henan ProvinceKey Laboratory of Technology of Drug Preparation(Zhengzhou University)Ministry of Education of ChinaKey Laboratory of Henan Province for Drug Quality and EvaluationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhou 450001China

Histone lysine specific demethylase 1(LSD1)has become a potential therapeutic target for the treatment of cancer.Discovery and develop novel and potent LSD1 inhibitors is a challenge,although several of them have already entered into clinical trials.Herein,for the first time,we reported the discovery of a series of 5-cyano-6-phenylpyrimidine derivatives as LSD1 inhibitors using flavin adenine dinucleotide(FAD)similarity-based designing strategy,of which compound 14 q was finally identified to repress LSD1 with IC50=183 nmol/L.Docking analysis suggested that compound 14 q fitted well into the FAD-binding pocket.Further mechanism studies showed that compound 14 q may inhibit LSD1 activity competitively by occupying the FAD binding sites of LSD1 and inhibit cell migration and invasion by reversing epithelial to mesenchymal transition(EMT).Overall,these findings showed that compound14 q is a suitable candidate for further development of novel FAD similarity-based LSD1 inhibitors.

关键词： LSD1 inhibitors Pyrimidine Anticancer Flavin adenine dinucleotide(FAD) Gastric cancer

The poly(ADP-ribosyl)ation of BRD4 mediated by PARP1 promoted pathological cardiac hypertrophy

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Acta Pharmaceutica Sinica B 2021年第5期11卷 1286-1299页

作者： Zhenzhen Li Zhen Guo Rui Lan Sidong Cai Zhirong Lin Jingyan Li Junjian Wang Zhuoming Li Peiqing Liu department of Pharmacology and Toxicology School of Pharmaceutical SciencesNational and Local United Engineering Lab of Druggability and New Drugs EvaluationGuangdong Engineering Laboratory of Druggability and New Drug EvaluationGuangdong Provincial Key Laboratory of New Drug Design and EvaluationSun Yat-sen UniversityGuangzhou 510006China Center for Cardiovascular Research and Division of Cardiology Washington University School of MedicineSt.LouisMO 63101USA International Institute for Translational Chinese Medicine School of Pharmaceutical SciencesGuangzhou University of Chinese MedicineGuangzhou 510006China

The bromodomain and extraterminal(BET)family member BRD4 is pivotal in the pathogenesis of cardiac hypertrophy.BRD4 induces hypertrophic gene expression by binding to the acetylated chromatin,facilitating the phosphorylation of RNA polymerases II(Pol II)and leading to transcription elongation.The present study identified a novel post-translational modification of BRD4:poly(ADPribosyl)ation(PARylation),that was mediated by poly(ADP-ribose)polymerase-1(PARP1)in cardiac hypertrophy.BRD4 silencing or BET inhibitors JQ1 and MS417 prevented cardiac hypertrophic responses induced by isoproterenol(ISO),whereas overexpression of BRD4 promoted cardiac hypertrophy,confirming the critical role of BRD4 in pathological cardiac hypertrophy.PARP1 was activated in ISOinduced cardiac hypertrophy and facilitated the development of cardiac hypertrophy.BRD4 was involved in the prohypertrophic effect of PARP1,as implied by the observations that BRD4 inhibition or silencing reversed PARP1-induced hypertrophic responses,and that BRD4 overexpression suppressed the antihypertrophic effect of PARP1 inhibitors.Interactions of BRD4 and PARP1 were observed by coimmunoprecipitation and immunofluorescence.PARylation of BRD4 induced by PARP1 was investigated by PARylation assays.In response to hypertrophic stimuli like ISO,PARylation level of BRD4 was elevated,along with enhanced interactions between BRD4 and PARP1.By investigating the PARylation of truncation mutants of BRD4,the C-terminal domain(CTD)was identified as the PARylation modification sites of BRD4.PARylation of BRD4 facilitated its binding to the transcription start sites(TSS)of hypertrophic genes,resulting in enhanced phosphorylation of RNA Pol II and transcription activation of hypertrophic genes.The present findings suggest that strategies targeting inhibition of PARP1-BRD4 might have therapeutic potential for pathological cardiac hypertrophy.

关键词： BRD4 PARP1 PARylation Isoproterenol Cardiac hypertrophy RNA Pol II Transcription activation Hypertrophic genes

Oridonin restores hepatic lipid homeostasis in an LXRa-ATGL/EPT1 axis-dependent manner

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Journal of Pharmaceutical Analysis 2023年第11期13卷 1281-1295页

作者： Yulian Chen Huanguo Jiang Zhikun Zhan Jindi Lu Tanwei Gu Ping Yu Weimin Liang Xi Zhang Shilong Zhong Lan Tang NMPA Key Laboratory for Research and evaluation of drug Metabolism Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou510515China department of Pharmacy Guangdong Provincial People's Hospital(Guangdong Academy of Medical Sciences)Southern Medical UniversityGuangzhou510515China

Hepatosteatosis is characterized by abnormal accumulation of triglycerides(TG),leading to prolonged and chronic inflammatory infiltration.To date,there is still a lack of effective and economical therapies for hepatosteatosis.Oridonin(ORI)is a major bioactive component extracted from the traditional Chinese medicinal herb Rabdosia rubescens.In this paper,we showed that ORI exerted significant protective effects against hepatic steatosis,inflammation and fibrosis,which was dependent on LXRa signaling.It is reported that LXRa regulated lipid homeostasis between triglyceride(TG)and phosphatidylethanolamine(PE)by promoting ATGL and EPT1 expression.Therefore,we implemented the lipidomic strategy and luciferase reporter assay to verify that ORI contributed to the homeostasis of lipids via the regulation of the ATGL gene associated with TG hydrolysis and the EPT1 gene related to PE synthesis in a LXRadependent manner,and the results showed the TG reduction and PE elevation.In detail,hepatic TG overload and lipotoxicity were reversed after ORI treatment by modulating the ATGL and EPT1 genes,respectively.Taken together,the data provide mechanistic insights to explain the bioactivity of ORI in attenuating TG accumulation and cytotoxicity and introduce exciting opportunities for developing novel natural activators of the LXRa-ATGL/EPT1 axis for pharmacologically treating hepatosteatosis and metabolic disorders.

关键词： Oridonin Lipid homeostasis TG reduction PE elevation LXRa-ATGL/EPT1 axis

APOBEC3B and IL-6 form a positive feedback loop in hepatocellular carcinoma cells

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Science China(Life Sciences) 2017年第6期60卷 617-626页

作者： Shuran Li Xueyang Bao Duowei Wang Linjun You Xianjing Li Hongbao Yang Jinsong Bian Yun Wang Yong Yang State Key Laboratory of Natural Medicines Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease Center for New Drug Safety Evaluation and Research China Pharmaceutical University department of Pharmacology Yong Loo Lin School of Medicine National University of Singapore

APOBEC3 protein families, a DNA cytidine deaminase, were up-regulated in multiple tumors. However, the relationship between Hepatocellular carcinoma(HCC) and APOBEC3B(A3B) remains unknown. It has been confirmed that interleukin-6(IL-6)has significant impacts on oncogenesis of HCC. Here, we reported that the expression of IL-6 was substantially up-regulated by A3 B in HepG2 cells. A3 B induced IL-6 expression through relocating HuR to enhance the IL-6 mRNA stability. Further analysis indicated that IL-6 also increased the expression of A3 B through JAK1/STAT3 signaling pathway, which formed a positive feedback to maintain the continuous expression of A3 B and IL-6, and thereby promoted the prolonged non-resolving inflammation. Collectively, these findings suggest that A3 B is essential for oncogenesis of HCC, and is a potential target for preventive intervention.

关键词： IL-6 肝细胞癌反馈回路白细胞介素-6 胞嘧啶脱氨酶 mRNA 信号通路 DNA

Sensitive detection of microRNAs using polyadenine-mediated fluorescent spherical nucleic acids and a microfluidic electrokinetic signal amplification chip

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Journal of Pharmaceutical Analysis 2022年第5期12卷 808-813页

作者： Jun Xu Qing Tang Runhui Zhang Haoyi Chen Bee Luan Khoo Xinguo Zhang Yue Chen Hong Yan Jincheng Li Huaze Shao Lihong Liu NMPA Key Laboratory for Research and evaluation of drug Metabolism Guangdong Provincial Key Laboratory of New Drug ScreeningSchool of Pharmaceutical SciencesSouthern Medical UniversityGuangzhou510515China The Second Clinical Medical School Southern Medical UniversityGuangzhou510515China department of Biomedical Engineering City University of Hong KongHong Kong999077China

The identification of tumor-related microRNAs(miRNAs)exhibits excellent promise for the early diagnosis of cancer and other bioanalytical applications.Therefore,we developed a sensitive and efficient biosensor using polyadenine(polyA)-mediated fluorescent spherical nucleic acid(FSNA)for miRNA analysis based on strand displacement reactions on gold nanoparticle(AuNP)surfaces and electrokinetic signal amplification(ESA)on a microfluidic chip.In this FSNA,polyA-DNA biosensor was anchored on AuNP surfaces via intrinsic affinity between adenine and Au.The upright conformational polyA-DNA recognition block hybridized with 6-carboxyfluorescein-labeled reporter-DNA,resulting in fluorescence quenching of FSNA probes induced by AuNP-based resonance energy transfer.Reporter DNA was replaced in the presence of target miRNA,leading to the recovery of reporter-DNA fluorescence.Subsequently,reporter-DNAs were accumulated and detected in the front of with Nafion membrane in the microchannel by ESA.Our method showed high selectivity and sensitivity with a limit of detection of 1.3 pM.This method could also be used to detect miRNA-21 in human serum and urine samples,with recoveries of 104.0%-113.3% and 104.9%-108.0%,respectively.Furthermore,we constructed a chip with three parallel channels for the simultaneous detection of multiple tumor-related miRNAs(miRNA-21,miRNA-141,and miRNA-375),which increased the detection efficiency.Our universal method can be applied to other DNA/RNA analyses by altering recognition sequences.

关键词： MicroRNAs Microfluidic chip Electrokinetic signal amplification Polyadenine-DNA Gold nanoparticle

Pharmacokinetics of Jiaotai pill self-microemulsion in insomnia rats

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Journal of Hainan Medical University 2022年第21期28卷 14-21页

作者： BAI Dan-ni WEI Xi-hong SHEN Meng-ting WANG Qing-wei SU Jin Heilongjiang Provincial Key Laboratory of new drug Development and Pharmacotoxicological evaluation Department of PharmacyJiamusi UniversityHeilongjiang ProvinceJiamusi 154007China

Objective:The pharmacokinetics and relative bioavailability of Jiaotai pill self-microemulsion were evaluated by investigating the blood concentration of Berberine,Coptisine,Palmatine and Jatrorrhizine in insomnia rats.Methods:Insomnia rat model was established by intraperitoneal injection of p-chlorophenylalanine(PCPA).The model rats were given Jiaotai pill self-microemulsion and Jiaotai pill suspension.The contents of Berberine,Coptisine,Palmatine and Jatrorrhizine in plasma at different times after administration were determined by UPLC-MS/MS,and calculate pharmacokinetic parameters.Results:Under the set chromatographic conditions,the linear relationship of the four components was good,and the precision,accuracy and stability meet the requirements of biological samples.After intragastric administration of Jiaotai pill self-microemulsion,The C_(max) of Berberine,Coptisine,Palmatine and Jatrorrhizine were(412.68±28.45),(68.65±3.92),(34.06±3.13),(40.60±1.22)ng/mL,and AUC_(0-∞)were(672.70±72.55),(146.04±25.01),(71.49±18.67),(72.25±9.54)ng·mL^(-1)·h^(-1),respectively.Compared with Jiaotai pill suspension,the Cmax,AUC_(0-t) and AUC_(0-∞)of the four components in insomnia rats were significantly increased(P<0.01).Conclusion:Jiaotai pill self-microemulsionl can promote the absorption of effective components in insomnia rats and improve its bioavailability.

关键词： Jiaotai pill Self-microemulsion Insomnia rat Pharmacokinetics Bioavailability

A temporo-spatial pharmacometabolomics method to characterize pharmacokinetics and pharmacodynamics in the brain microregions by using ambient mass spectrometry imaging

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Acta Pharmaceutica Sinica B 2022年第8期12卷 3341-3353页

作者： Dan Liu Jianpeng Huang Shanshan Gao Hongtao Jin Jiuming He State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China department of Clinical Pharmacy First People’s Hospital of HuaihuaHuaihua 418000China new drug Safety evaluation Center Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100050China NMPA Key Laboratory for Safety Research and evaluation of Innovative drug Beijing 100050China

The brain is the most advanced organ with various complex structural and functional microregions. It is often challenging to understand what and where the molecular events would occur for a given drug treatment in the brain. Herein, a temporo-spatial pharmacometabolomics method was proposed based on ambient mass spectrometry imaging and was applied to evaluate the microregional effect of olanzapine(OLZ) on brain tissue and demonstrate its effectiveness in characterizing the microregional pharmacokinetics and pharmacodynamics of OLZ for improved understanding of the molecular mechanism of drugs acting on the microregions of the brain. It accurately and simultaneously illustrated the levels dynamics and microregional distribution of various substances, including exogenous drugs and its metabolites, as well as endogenous functional metabolites from complicated brain tissue. The targeted imaging analysis of the prototype drug and its metabolites presented the absorption, distribution, metabolism, and excretion characteristics of the drug itself. Moreover, the endogenous functional metabolites were identified along with the associated therapeutic and adverse effects of the drug, which can reflect the pharmacodynamics effect on the microregional brain. Therefore, this method is significant in elucidating and understanding the molecular mechanism of central nervous system drugs at the temporo and spatial metabolic level of system biology.

关键词： Pharmacometabolomics Pharmacokinetics Pharmacodynamics Mass spectrometry imaging Antipsychotic drug

Detailed resume of RNA m^(6)A demethylases

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2193-2205页

作者： Dandan Shen Bo Wang Ya Gao Lijuan Zhao Yaping Bi Jinge Zhang Ning Wang Huiqin Kang Jingru Pang Ying Liu Luping Pang Zhe-Sheng Chen Yi-Chao Zheng Hong-Min Liu Key Laboratory of Advanced drug Preparation Technologies Ministry of Education of ChinaCollaborative Innovation Center of New Drug Research and Safety EvaluationZhengzhou UniversityZhengzhou 450052China Key Laboratory of Henan Province for drug Quality and evaluation Institute of Drug Discovery and DevelopmentSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhou 450052China State Key Laboratory of Esophageal Cancer Prevention&Treatment Academy of Medical SciencesZhengzhou UniversityZhengzhou 450052China department of Pharmaceutical Sciences College of Pharmacy and Health SciencesSt.John’s UniversityQueensNY 11439USA The School of Chinese Medicine The University of Hong KongPokfulamHong KongChina

N6-Methyladenosine(m^(6)A) is the most abundant internal modification in eukaryotic mRNA,playing critical role in various bioprocesses. Like other epigenetic modifications, m^(6)A modification can be catalyzed by the methyltransferase complex and erased dynamically to maintain cells homeostasis. Up to now, only two m^(6)A demethylases have been reported, fat mass and obesity-associated protein(FTO)and alkylation protein AlkB homolog 5(ALKBH5), involving in a wide range of mRNA biological progress, including mRNA shearing, export, metabolism and stability. Furthermore, they participate in many significantly biological signaling pathway, and contribute to the progress and development of cancer along with other diseases. In this review, we focus on the studies about structure, inhibitors development and biological function of FTO and ALKBH5.

关键词： FTO ALKBH5 RNA demethylation Diseases Inhibitors Screening

evaluation of repeated exposure systemic toxicity test of PVC with new plasticizer on rats via dual parenteral routes

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Regenerative Biomaterials 2018年第1期5卷 9-14页

作者： Li Hou Chunguang Fan Chenghu Liu Qiujin Qu ChunrenWang Yanping Shi department of Biological evaluation Key Lab of Biological Evaluation of Medical DevicesShandong Provincial Inspection Center for Medical DevicesJinan 250101China department of Biomaterials and Tissue Engineering National Institutes for Food and Drug Control of ChinaBeijing 100050China

Systemic toxicity caused by repeated exposure to both polar and nonpolar leachables of di(2-ethylhexyl)-1,2-cyclohexane plasticized polyvinyl chloride(PVC)was evaluated with dual routes of parenteral administration method on rats in the study.Experimental group and control group were designed by researchers.Tail intravenous injection with 0.9%sodium chloride injection extracts and intraperitoneal injection with corn oil extracts were conducted to the experimental rats while tail intravenous injection with 0.9%sodium chloride Injection and intraperitoneal injection with corn oil were conducted to the control rats.After 14 days,blood specimens were collected for clinical pathology(hematology and clinical chemistry)analysis.Selected organs were weighed and a histopathological examination was conducted.As a result,compared with the control animals,there were no toxicity-related changes on the parameters above.The results show that the rats do not show obvious systemic toxicity reaction caused by repeated exposure with dual routes of parenteral administration method on rats after administration with both polar and nonpolar exacts of di(2-ethylhexyl)-1,2-cyclohexane plasticized PVC simultaneously up for 14 days.

关键词： plasticized PVC repeated exposure systemic toxicity test dual routes of parenteral administration method