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Development of non-nucleoside reverse transcriptase inhibitors(NNRTIs):our past twenty years

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Acta Pharmaceutica Sinica B 2020年第6期10卷 961-978页

作者： Chunlin Zhuang Christophe Pannecouque Erik De Clercq fener chen Engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs Shanghai 200433China Institute of Pharmaceutical Science and Technology Zhejiang University of TechnologyHangzhou 310014China Rega Institute for Medical Research KU LeuvenLeuven B-3000Belgium

Human immunodeficiency virus(HIV)is the primary infectious agent of acquired immunodeficiency syndrome(AIDS),and non-nucleoside reverse transcriptase inhibitors(NNRTIs)are the cornerstone of HIV *** the last 20 years,our medicinal chemistry group has made great strides in developing several distinct novel NNRTIs,including 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine(HEPT),thio-dihydro-alkoxy-benzyl-oxopyrimidine(S-DABO),diaryltriazine(DATA),diarylpyrimidine(DAPY)analogues,and their hybrid *** of integrated modern medicinal strategies,including structure-based drug design,fragment-based optimization,scaffold/fragment hopping,molecular/fragment hybridization,and bioisosterism,led to the development of several highly potent analogues for further *** this paper,we review the development of NNRTIs in the last two decades using the above optimization strategies,including their structure-activity relationships,molecular modeling,and their binding modes with HIV-1 reverse transcriptase(RT).Future directions and perspectives on the design and associated challenges are also discussed.

关键词： HIV-1 NNRTIs HENTs S-DABOs DATAs DAPYs Structure-based optimization Fragment-based drug design Molecular hybridization Bioisosterism

Concise syntheses of 13-methylprotoberberine and 13-methyltetrahydroprotoberberine alkaloids

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Chinese Chemical Letters 2022年第12期33卷 5080-5083页

作者： Wenchang chen Xiaofen Yi Hongmin Qu Yu chen Pei Tang fener chen Sichuan Research Center for Drug Precision Industrial Technology West China School of PharmacySichuan UniversityChengdu 610041China Engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China hanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs Shanghai 200433China

The concise syntheses of eight 13-methylprotoberberine(13-MePB)and eight enantioenriched 13-methyltetrahydroprotoberberine(13-MeTHPB)alkaloids have been achieved in a tactically modular *** synthetic work features a one-pot metal-free Pictet-Spengler/Friedel-Crafts hydroxyalkylation/dehydration/oxidation sequence and a following highly enantioselective Ir-catalyzed *** such brevity and modularity,our developed synthetic route would be greatly beneficial to the efficient syntheses of existing natural products and new fully synthetic variants of 13-MePB and 13-MeTHPB family.

关键词： 13-Methylprotoberberine 13-Methyltetrahydroprotoberberine One-pot metal-free sequence Asymmetric hydrogenation

Palladium-catalyzed base-and solvent-controlled chemoselective allylation of amino acids with allylic carbonates

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Chinese Chemical Letters 2022年第11期33卷 4850-4855页

作者： Yang Zhou Hang chen Panpan Lei Chunming Gui Haifeng Wang Qiongjiao Yan Wei Wang fener chen Pharmaceutical Research Institute Wuhan Institute of TechnologyWuhan 430205China Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province China West Normal UniversityNanchong 637009China Engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai Engineering Center of Industrial Catalysis for Chiral Drugs Shanghai 200433China

The utilization of readily available amino acids,which is not only an oxygen nucleophile but also a nitrogen nucleophile,in palladium-catalyzed allylic substitution is realized under mild *** chemoselectivity and multiple allylation are controlled by adjusting the reaction *** represents the first example of this convenient access to valuable N,O-diallylated amino *** the title conditions,a range of amino acids(α-,β-,γ-)and dipeptides can be readily converted in to the corresponding allylic products with excellent yields(67 examples,up to 99%yield)as well as good functional group tolerance.

关键词： Allylation Amino acid Carbonates Chemoselectivity Palladium

Linker optimization of HEPT derivatives as potent non-nucleoside HIV-1 reverse transcriptase inhibitors: From S=O to CHOR

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Chinese Chemical Letters 2023年第4期34卷 188-192页

作者： Qingqing Hao Xu Ling Christophe Pannecouque Erik De Clercq fener chen Sichuan Research Center for Drug Precision Industrial Technology West China School of PharmacySichuan UniversityChengdu 610041China Department of Chemistry Engineering Center of Catalysis and Synthesis for Chiral MoleculesFudan UniversityShanghai 200433China Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs Shanghai 200433China Rega Institute for Medical Research KU LeuvenHerestraat 49Leuven B-3000Belgium

A novel series of CHOR-HEPT non-nucleoside HIV-1 reverse transcriptase inhibitors were developed by means of structure-based design strategy based on compound 6 reported previously by our group. Most of these compounds showed moderate to good activity toward wild-type HIV-1 strain with EC50values in the range of 0.18–51.88 μmol/L and SI values in the range of 4–907. The compound 14aj with a CHOH linker and compound 13i with a CHOTMS linker in this series exhibited improved anti-HIV-1 activity(EC50= 0.18 μmol/L, and 0.20 μmol/L) with higher selectivity(SI = 907, and 665) as comparison with the lead compound 6(EC50= 0.59 μmol/L, SI = 9). These two compounds 14aj and 13i were more sensitive than 6 toward clinically relevant mutant L100I, K103N and E138K viruses, which were further evaluated for their activity against wild-type reverse transcriptase and displayed a good correlation with the cell-based activity. Preliminary molecular modeling investigations provided insight for further structural optimization of HEPT.

关键词： HIV NNRTIs HEPTs RT Optimization

Intramolecularly lactam stapled oxyntomodulin analogues inhibit cancer cell proliferation in vitro

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Chinese Chemical Letters 2023年第4期34卷 222-225页

作者： Junli Wang Cen Liu Hongliu Yang Tao Ma Yonggang Liu fener chen Engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Institute of Materia Medica Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100050China School of Chinese Materia Medica Beijing University of Chinese MedicineLiangxiang CampusBeijing 102488China

As a glucagon(GCG) receptor(GCGR) and glucagon-like peptide 1(GLP-1) receptor(GLP-1R) dual agonist, oxyntomodulin(OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasing energy expenditure, and inducing body weight loss in obese humans. Based on the scaffold of native OXM, specific helix-favoring amino acids substitutions and the consequent salt bridge formations were believed to offer enhanced and balanced GCGR/GLP-1R activations through increasing α-helical conformation. Novel OXM analogues are obtained by intramolecular lactam stapling of positions[Glu16 & Lys20] or [Lys17 & Glu21] to further strengthen conformationally constrained stabilization. Even though the lactam staple does not provide additional dual GCGR/GLP-1R activations in vitro, the stapled OXM analogues are firstly reported to have higher or lower anti-PANC-1 cell proliferation activity, meanwhile which has no obvious inhibitory effect on the proliferation of He La cells. Therefore, it is speculated that the stapled analogues may have the potential to inhibit the proliferation of specific cancer cell *** the stapled peptides as well as their precursors, analogue 6 has the most prominent anti-PANC-1 proliferation activity with the IC50value of 115.1 μmol/L. Its mechanism of actions including effective signal pathways should be worth further investigations in future.

关键词： Oxyntomodulin analogues Intramolecular lactam Dual GCGR/GLP-1R activations Anti-PANC-1 proliferation

Asymmetric synthesis of syn-aryl-(2S,3R)-2-chloro-3-hydroxy esters via an engineered ketoreductase-catalyzed dynamic reductive kinetic resolution

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Chinese Chemical Letters 2023年第9期34卷 156-159页

作者： Xiaoping Yue Yitong Li Di Sang Yuan Tao Zedu Huang fener chen Sichuan Research Center for Drug Precision Industrial Technology West China School of PharmacySichuan UniversityChengdu 610041China Engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs Shanghai 200433China

We report here a generic,green synthesis of 17 valuable syn-aryl-(2S,3R)-2–chloro-3–hydroxy esters(syn-(2S,3R)-1)in 73%-99%isolated yields along with 6.1:1–83:1 dr and 31%~>99%ee,through dynamic reductive kinetic resolution of racemic arylα–chloroβ-keto esters(2)catalyzed by an engineered ketoreductase which was obtained via ep PCR-based directed *** hectogram scale synthesis of syn-(2S,3R)-1b at a substrate concentration of 120 g/L showcased the application potential of the biocatalytic method developed presently.

关键词： (2S,3R)-2-Chloro-3-hydroxy esters Dynamic reductive kinetic resolution Ketoreductase Directed evolution Asymmetric synthesis

Characterization of HpnG as a Purine Nucleoside Phosphorylase in Bacteriohopanepolyol Biosynthesis

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Chinese Journal of Chemistry 2024年第19期42卷 2351-2356页

作者： Xinhui Li Xiaoyu Zhu Yuting Zhong Wei Zhang fener chen Wenning Wang Wei Ding Qi Zhang Department of Chemistry Fudan UniversityShanghai 200433China State Key Laboratory of Microbial Metabolism School of Life Sciences&BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China Key Laboratory of Extreme Environmental Microbial Resources and Engineering of Gansu Province Northwest Institute of Eco-Environment and ResourcesChinese Academy of SciencesLanzhouGansu 73000China

Comprehensive Summary HpnG plays a crucial role in the production of ribosylhopane,a key intermediate in the biosynthesis of *** early extensive studies,the precise function of HpnG has remained ***,we report functional characterization of HpnG as a purine nucleoside phosphorylase,which converts adenosylhopane to phosphoribosylhopane in the presence of *** demonstrates broad substrate specificity and impressive stability,making it a valuable enzymatic tool for applications in nucleoside processing and related biotechnology.

关键词： Enzymes Enzyme catalysis Nucleosides Biosynthesis Natural products Lipids Phosphorolysis Biotransformations

Improving the positional adaptability:structurebased design of biphenyl-substituted diaryltriazines as novel non-nucleoside HIV-1 reverse transcriptase inhibitors

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Acta Pharmaceutica Sinica B 2020年第2期10卷 344-357页

作者： Kaijun Jin Minjie Liu Chunlin Zhuang Erik De Clercq Christophe Pannecouque Ge Meng fener chen Engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs Shanghai 200433China Rega Institute for Medical Research KU LeuvenLeuven B-3000Belgium

In order to improve the positional adaptability of our previously reported naphthyl diaryltriazines(NP-DATAs),synthesis of a series of novel biphenyl-substituted diaryltriazines(BP-DATAs)with a flexible side chain attached at the C-6 position is *** compounds exhibited excellent potency against wild-type(WT)HIV-1 with EC50 values ranging from 2.6 to 39 nmol/L and most of them showed low nanomolar anti-viral potency against a panel of HIV-1 mutant *** 5 j and 6 k had the best activity against WT,single and double HIV-1 mutants and reverse transcriptase(RT)enzyme comparable to two reference drugs(EFV and ETR)and our lead compound NP-DATA(1).Molecular modeling disclosed that the side chain at the C-6 position of DATAs occupied the entrance channel of the HIV-1 reverse transcriptase non-nucleoside binding pocket(NNIBP)attributing to the improved *** preliminary structure-activity relationship and PK profiles were also discussed.

关键词： HIV-1 NNRTIs NP-DATAs BP-DATAs Positional adaptability Molecular modeling

Fragment-based discovery of sulfur-containing diarylbenzopyrimidines as novel nonnucleoside reverse transcriptase inhibitors

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Chinese Chemical Letters 2020年第3期31卷 764-768页

作者： Sheng Han Yuan Lei Christophe Pannecouque Erik De Clercq Chunlin Zhuang fener chen Engineering Center of Catalysis and Synthesis for Chiral Molecules Department of ChemistryFudan UniversityShanghai 200433China Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs Shanghai 200433China Sichuan Research Center for Drug Precision Industrial Technology West China School of PharmacySichuan UniversityChengdu 610041China Institute of Pharmaceutical Science and Technology Zhejiang University of TechnologyHangzhou 310014China Rega Institute for Medical Research KU LeuvenHerestraat 49B-3000 LeuvenBelgium

Two series of sulfur-containing diarylbenzopyrimidines are designed by the fragment combination of a thioacetamide with our previous disclosed DABP 3 and further *** best compound 6 e with a sulfonyl scaffold displayed EC(50)values of 0.0356μmol/L against WT and 0.0228μmol/L against HIV K103 N mutant *** pronounced,it had a lower cytotoxicity(CC(50)=99.6μmol/L),higher selectivity index(SIWT=2799,SIK103 N=4375)and better calculated logarithm of the octanol-water partition coefficient(cLogP)than the lead compound *** docking and dynamics provided the binding modes of these compounds with reve rse transcriptase,explaining their ***,the new compounds could be candidates for anti-HIV drug discovery.

关键词： HIV-1 NNRTIs DAPY Sulfur-containing DABPs FBDD