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A combined nanotherapeutic approach targeting farnesoid X receptor,ferroptosis,and fibrosis for nonalcoholic steatohepatitis treatment

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2228-2246页

作者： Jiangtao Fu Pingping Zhang Zhiguo Sun Guodong Lu Qi Cao Yiting Chen Wenbin Wu Jiabao Zhang Chunlin Zhuang chunquan sheng Jiajun Xu Ying Lu Pei Wang The Center for Basic Research and Innovation of Medicine and Pharmacy(MOE) School of PharmacyNaval Medical UniversityShanghai 200433China National Demonstration Center for Experimental Pharmaceutical Education Naval Medical University/Second Military Medical UniversityShanghai 200433China Department of Diving and Hyperbaric Medicine Naval Special Medical CenterNaval Medical UniversityShanghai 200433China

Obeticholic acid(OCA),a farnesoid X receptor(FXR)agonist with favorable effects on fatty and glucose metabolism,has been considered the leading candidate drug for nonalcoholic steatohepatitis(NASH)treatment.However,its limited effectiveness in resolving liver fibrosis and lipotoxicity-induced cell death remains a major drawback.Ferroptosis,a newly recognized form of cell death characterized by uncontrolled lipid peroxidation,is involved in the progression of NASH.Nitric oxide(NO)is a versatile biological molecule that can degrade extracellular matrix.In this study,we developed a PEGylated thiolated hollow mesoporous silica nanoparticles(MSN)loaded with OCA,as well as a ferroptosis inhibitor liproxsatin-1 and a NO donor S-nitrosothiol(ONL@MSN).Biochemical analyses,histology,multiplexed flow cytometry,bulk-tissue RNA sequencing,and fecal 16S ribosomal RNA sequencing were utilized to evaluate the effects of the combined nanoparticle(ONL@MSN)in a mouse NASH model.Compared with the OCA-loaded nanoparticles(O@MSN),ONL@MSN not only protected against hepatic steatosis but also greatly ameliorated fibrosis and ferroptosis.ONL@MSN also displayed enhanced therapeutic actions on the maintenance of intrahepatic macrophages/monocytes homeostasis,inhibition of immune response/lipid peroxidation,and correction of microbiota dysbiosis.These findings present a promising synergistic nanotherapeutic strategy for the treatment of NASH by simultaneously targeting FXR,ferroptosis,and fibrosis.

关键词： Nonalcoholic steatohepatitis Nanotherapy Farnesoid X receptor Ferroptosis Fibrosis Obeticholic acid S-Nitrosothiol Liproxstatin-1

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NAMPT-targeting PROTAC promotes antitumor immunity via suppressing myeloid-derived suppressor cell expansion

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2859-2868页

作者： Ying Wu Congying Pu Yixian Fu Guoqiang Dong Min Huang chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghai 201203China

Nicotinamide phosphoribosyl transferase(NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation.However,therapeutic benefit of NAMPT enzymatic inhibitors appears very limited,likely due to the failure to intervene nonenzymatic functions of NAMPT.Herein,we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells(MDSCs) via a mechanism independent of its enzymatic activity.Using proteolysis-targeting chimera(PROTAC) technology,PROTAC A7 is identified as a potent and selective degrader of NAMPT,which degrades intracellular NAMPT(iNAMPT) via the ubiquitin-proteasome system,and in turn decreases the secretion of extracellular NAMPT(eNAMPT),the major player of the non-enzymatic activity of NAMPT.In vivo,PROTAC A7 efficiently degrades NAMPT,inhibits tumor infiltrating MDSCs,and boosts antitumor efficacy.Of note,the anticancer activity of PROTAC A7 is superior to NAMPT enzymatic inhibitors that fail to achieve the same impact on MDSCs.Together,our findings uncover the new role of enzymatically-independent function of NAMPT in remodeling the immunosuppressive tumor microenvironment,and reports the first NAMPT PROTAC A7 that is able to block the pro-tumor function of both iNAMPT and eNAMPT,pointing out a new direction for the development of NAMPT-targeted therapies.

关键词： NAMPT Non-enzymatic function eNAMPT Cancer MDSC PROTAC Tumor immunity Immunotherapy

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Small molecules for combating multidrug-resistant superbug Candida auris infections

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Acta Pharmaceutica Sinica B 2022年第11期12卷 4056-4074页

作者： Jie Tu Na Liu Yahui Huang Wanzhen Yang chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China

Candida auris is emerging as a major global threat to human health. C. auris infections are associated with high mortality due to intrinsic multi-drug resistance. Currently, therapeutic options for the treatment of C. auris infections are rather limited. We aim to provide a comprehensive review of current strategies, drug candidates, and lead compounds in the discovery and development of novel therapeutic agents against C. auris. The drug resistance profiles and mechanisms are briefly summarized. The structures and activities of clinical candidates, drug combinations, antifungal chemosensitizers, repositioned drugs, new targets, and new types of compounds will be illustrated in detail, and perspectives for guiding future research will be provided. We hope that this review will be helpful to prompting the drug development process to combat this fungal pathogen.

关键词： Candidaauris Antifungal agents Drug resistance Virulence factors Antifungal targets

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Controlling antifungal activity with light:Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors

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药学学报:英文版 2023年第7期13卷 3080-3092页

作者： Zhuang Li Na Liu Wanzhen Yang Jie Tu Yahui Huang Wei Wang chunquan sheng State Key Laboratory of Bioengineering Reactor And Shanghai Key Laboratory of New Drug DesignSchool of PharmacyEast China University of Science&TechnologyShanghai 200237China School of Pharmacy Second Military Medical University(Naval Medical University)Shanghai 200433China Department of Pharmacology and Toxicology College of PharmacyAnd BIO5 InstituteUniversity of ArizonaTucsonAZ 85721USA

Invasive fungal infections(IFIs)have been associated with high mortality,highlighting the urgent need for developing novel antifungal strategies.Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14a-demethylase(CYP51)inhibitors.The photocaged triazoles completely shielded the CYP51inhibition.The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4%and 83.7%,respectively.Importantly,the shielded antifungal activity(MIC80≥64μg/m L)could be efficiently recovered(MIC80=0.5—8μg/m L)by light irradiation.The new chemical tools enable optical control of fungal growth arrest,morphological conversion and biofilm formation.The ability for highprecision antifungal treatment was validated by in vivo models.The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model.Overall,this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

关键词： Antifungal agents Ergosterol biosynthesis Triazoles Photocaged Optical control

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Discovery of novel KRAS-PDEδ inhibitors with potent activity in patient-derived human pancreatic tumor xenograft models

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Acta Pharmaceutica Sinica B 2022年第1期12卷 274-290页

作者： Long Chen Jing Zhang Xinjing Wang Yu Li Lu Zhou Xiongxiong Lu Guoqiang Dong chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China Department of Pathology Changzheng HospitalSecond Military Medical UniversityShanghai 200003China Department of General Surgery Pancreatic Disease CenterRuijin HospitalShanghai Jiao Tong UniversityShanghai 200025China Research Institute of Pancreatic Diseases Shanghai Jiao Tong University School of MedicineShanghai 200025China Department of Medicinal Chemistry School of PharmacyFudan UniversityShanghai 201203China

KRAS-PDEδ interaction is revealed as a promising target for suppressing the function of mutant KRAS. The bottleneck in clinical development of PDEδ inhibitors is the poor antitumor activity of known chemotypes. Here, we identified novel spiro-cyclic PDEδ inhibitors with potent antitumor activity both in vitro and in vivo. In particular, compound 36 l(KD= 127 ± 16 nmol/L) effectively bound to PDEδ and interfered with KRAS-PDEδ interaction. It influenced the distribution of KRAS in Mia PaCa-2 cells, downregulated the phosphorylation of t-ERK and t-AKT and promoted apoptosis of the cells. The novel inhibitor 36 l exhibited significant in vivo antitumor potency in pancreatic cancer patient-derived xenograft(PDX) models. It represents a promising lead compound for investigating the druggability of KRAS-PDEδ interaction.

关键词： KRAS-PDEδinteraction PDX Spiro-cyclic inhibitors Lead optimization SBDD Anti-pancreatic cancer activity

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A novel route for the synthesis of androgen receptor antagonist enzalutamide

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Chinese Chemical Letters 2023年第6期34卷 449-453页

作者： Xiangguo Meng Siju Bi Shixin Jin Kai Wu Shanchao Wu Lei Shao Pierre-Antoine Bonnet chunquan sheng College of Pharmacy Shanghai University of Medicine and Health SciencesShanghai 201318China Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai 200433China State Key Lab of Anti-Infectives Shanghai Institute of Pharmaceutical IndustryChina State Institute of Pharmaceutical IndustryShanghai 201203China IBMM Faculty of PharmacyMontpellier UniversityCNRSENSCM34093 Montpellier Cedex 5France

A novel route of enzalutamide was developed in five steps.Starting from 4-amino-2-(trifluoromethyl)benzonitrile(7)and Boc-2-aminoisobutyric acid(16),condensation,deprotection,Ullmann coupling,cyclization and amination provided enzalutamide in 41.0%total yield.This route avoids the using of toxic chemical,unstable intermediate and high-risk reaction.It is a potential efficient and economical procedure for industrialization.

关键词： Enzalutamide Condensation Deprotection Ullmann coupling Cyclization Amination

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Structural simplification: an efficient strategy in lead optimization

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Acta Pharmaceutica Sinica B 2019年第5期9卷 880-901页

作者： shengzheng Wang Guoqiang Dong chunquan sheng Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai200433China Department of Medicinal Chemistry and Pharmaceutical Analysis School of PharmacyFourth Military MedicalUniversityXi’an710032China

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding 'molecular obesity'. The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.

关键词： Structural simplification Lead optimization Drug discovery Drug design Reducing rings number Reducing chiral centers Structure-based simplification Pharmacophore-based simplification

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Targeting necroptosis in anticancer therapy:mechanisms and modulators

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Acta Pharmaceutica Sinica B 2020年第9期10卷 1601-1618页

作者： Ying Wu Guoqiang Dong chunquan sheng School of Pharmacy Second Military Medical UniversityShanghai 200433China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

Necroptosis,a genetically programmed form of necrotic cell death,serves as an important pathway in human diseases.As a critical cell-killing mechanism,necroptosis is associated with cancer progression,metastasis,and immunosurveillance.Targeting necroptosis pathway by small molecule modulators is emerging as an effective approach in cancer therapy,which has the advantage to bypass the apoptosis-resistance and maintain antitumor immunity.Therefore,a better understanding of the mechanism of necroptosis and necroptosis modulators is necessary to develop novel strategies for cancer therapy.This review will summarize recent progress of the mechanisms and detecting methods of necroptosis.In particular,the relationship between necroptosis and cancer therapy and medicinal chemistry of necroptosis modulators will be focused on.

关键词： Cell death Necroptosis Inducers Inhibitors Anticancer therapy

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Discovery of novel triple targeting G–quadruplex and topoisomerase 1/2 ligands from natural products evodiamine and rutaecarpine

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Chinese Chemical Letters 2023年第4期34卷 203-210页

作者： Haibo Wang Xuexin Bai Yahui Huang Yueru Chen Guoqiang Dong Tianmiao Ou Shanchao Wu Defeng Xu chunquan sheng National&Local Joint Engineering Research Center for High-efficiency Refining and High-quality Utilization of Biomass School of PharmacyChangzhou UniversityChangzhou 213164China Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai 200433China School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

Inspired by the indolopyridoquinazoline scaffold of natural products evodiamine and rutaecarpine, novel triple G4 and Top1/2 ligands were rationally designed and synthesized. Systematic structure–activity relationship(SAR) studies led to the discovery of compound 15g, which effectively induced and stabilized G4 and inhibited Top1/2 with potent antitumor activity. Compound 15g represents a valuable chemical tool or lead compound for antitumor drug discovery. This proof-of-concept study also validated the feasibility of using planar natural products scaffold as templates to design new G4 ligands.

关键词： Indolopyridoquinazoline G-quadruplex Topoisomerase Structure-activity relationship Antitumor activity

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Evodiamine-inspired dual inhibitors of histone deacetylase 1(HDAC1) and topoisomerase 2(TOP2) with potent antitumor activity

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Acta Pharmaceutica Sinica B 2020年第7期10卷 1294-1308页

作者： Yahui Huang Shuqiang Chen Shanchao Wu Guoqiang Dong chunquan sheng Department of Medicinal Chemistry School of PharmacySecond Military Medical UniversityShanghai 200433China School of Pharmaceutical Sciences Zhengzhou UniversityZhengzhou 450001China

A great challenge in multi-targetingdrug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations.Inspired by our previous efforts in designing antitumor evodiamine derivatives,herein selective histone deacetylase 1(HDAC1)and topoisomerase 2(TOP2)dual inhibitors were successfully identified,which showed potent in vitro and in vivo antitumor potency.Particularly,compound 30 a was orally active and possessed excellent in vivo antitumor activity in the HCT116 xenograft model(TGI=75.2%,150 mg/kg,p.o.)without significant toxicity,which was more potent than HDAC inhibitor vorinostat,TOP inhibitor evodiamine and their combination.Taken together,this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

关键词： Evodiamine Histone deacetylase Topoisomerase Dual inhibitors Antitumor activity

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