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A new tetracyclic triterpenoid from endophytic fungus Fusarium sporotrichioides

Chinese Herbal Medicines 2024年第2期16卷 231-234页

作者： Yajing Wang Chunyue Liu Yihui Yang Chang Li Yuehu Pei department of medicinal chemistry and Natural Medicine chemistry College of PharmacyHarbin Medical UniversityHarbin 150081China

Objective: To isolate bioactive compounds from the endophytic fungus Fusarium sporotrichioides isolated from Rauwolfia yunnanensis, and investigate their pharmacological activities.Methods: The chemical constituents were isolated and purified by combining with ODS column chromatography, silica gel column chromatography and by performing semipreparative HPLC. Their structures were established on the basis of 1D NMR(1H-NMR and13C-NMR) and 2D NMR(1H–1H COSY,HSQC, HMBC and NOESY), as well as HRESIMS and comparison with literature data. In addition, the absolute configuration of compound 1 was determined by calculated ECD data.Results: One previously undescribed tetracyclic triterpenoid derivative, named as integracide L(1), 12aacetoxy-4,4-dimethyl-24-methylene-5a-cholesta-8,14-diene-2a,3β,11β-triol(2), 12a-acetoxy-4,4-dime thyl-24-methylene-5a-cholesta-8-momoene-2a,3β,11β-triol(3), 12a-acetoxy-4,4-dimethyl-24-methy lene-5a-cholesta-8,14-diene-3β,11β-triol(4), and 12a-acetoxy-4,4-dimethyl-24-methylene-5acholesta-8-momoene-3β,11β-triol(5) were isolated from F. sporotrichioide. Moreover, compound 1 was rare tetracyclic triterpenoid with single methyl replacement at C-4 position.Conclusion: Compound 1 was a new tetracyclic triterpenoid isolated from the endophytic fungus F.sporotrichioides. In addition, compound 2 could inhibit the growth of three different human cancer cells significantly. Compounds 3 and 5 were found to possess better cytotoxic activities on Hep G-2 cells than the other compounds, with IC50values of(2.8 ± 0.1) and(6.3 ± 0.3) μmol/L respectively.

关键词： antitumor Fusarium sporotrichioides integracide L tetracyclic triterpenoid 12a-acetoxy-4,4-dimethyl-24-methylene5a-cholesta-814-diene-2a,3b,11b-triol 12a-acetoxy-4,4-dimethyl-24-methylene5a-cholesta-8-momoene-2a,3b,11b-triol 12a-acetoxy-4,4-dimethyl-24-methylene5a-cholesta-8-momoene-3b,11b-triol

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Emerging structures and dynamic mechanisms ofγ-secretase for Alzheimer’s disease

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Neural Regeneration Research 2025年第1期20卷 174-180页

作者： Yinglong Miao Michael S.Wolfe Computational Medicine Program and department of pharmacology University of North Carolina–Chapel HillChapel HillNCUSA department of medicinal chemistry University of KansasLawrenceKSUSA

γ-Secretase,called“the proteasome of the membrane,”is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations inγ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer’s disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer’s disease and the more common late-onset Alzheimer’s disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer’s disease mutations,and allosteric modulation of substrate cleavage byγ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms ofγ-secretase.Different mechanisms,including the“Fit-Stay-Trim,”“Sliding-Unwinding,”and“Tilting-Unwinding,”have been proposed for substrate proteolysis of amyloid precursor protein byγ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-boundγ-secretase,molecular dynamics simulations on a resolved model of Notch1-boundγ-secretase that was reconstructed using the amyloid precursor protein-boundγ-secretase as a template successfully capturedγ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates byγ-secretase.In addition,controversy over the effects of familial Alzheimer’s disease mutations,particularly the issue of whether they stabilize or destabilizeγ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies ofγ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer’s disease mutations of theγ-secretase-substrate complexes.Comprehen

关键词： Alzheimer’s disease amyloid precursor protein cryo-EM structures drug design intramembrane proteolysis molecular dynamics Notch

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Discovery of GluN2A subtype-selective N-methyl-d-aspartate(NMDA)receptor ligands

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Acta Pharmaceutica Sinica B 2024年第5期14卷 1987-2005页

作者： Liyang Jiang Na Liu Fabao Zhao Boshi Huang Dongwei Kang Peng Zhan Xinyong Liu department of medicinal chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China

The N-methyl-d-aspartate(NMDA)receptors,which belong to the ionotropic Glutamate receptors,constitute a family of ligand-gated ion channels.Within the various subtypes of NMDA receptors,the GluN1/2A subtype plays a significant role in central nervous system(CNS)disorders.The present article aims to provide a comprehensive review of ligands targeting GluN2A-containing NMDA receptors,encompassing negative allosteric modulators(NAMs),positive allosteric modulators(PAMs)and competitive antagonists.Moreover,the ligands’structure–activity relationships(SARs)and the binding models of representative ligands are also discussed,providing valuable insights for the clinical rational design of effective drugs targeting CNS diseases.

关键词： NMDA receptors GluN2A subtype Subtype-selective ligands SARs Protein ligand interactions

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1,6-Conjugate addition of para-quinone methides using gem-diborylcarbanions: Practical access to gem-diborylalkanes bearing vicinal tertiary/quaternary stereocenters

Green Synthesis and Catalysis

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Green Synthesis and Catalysis 2024年第1期5卷 68-72页

作者： Pu-Zhang Zi Xing-Bang Liu Quan-Hong Zhao Min He Yuan Huang department of medicinal chemistry School of PharmacyXi'an Jiaotong UniversityXi'an710061China

A novel,efficient and pragmatic method to prepare gem-diboron products with vicinal tertiary/quaternary stereocenters using LiTMP-mediated 1,6-conjugate addition of gem-diborylalkanes to para-quinone methides was described for the first time.The results showed that various gem-diboron products with vicinal tertiary and quaternary stereocenters could be formed within 15 min at ambient temperature.This simple protocol has also been applied for the efficient synthesis of the analogue of Bedaquiline.

关键词： gem-Diborylalkanes Quaternary stereocenter Conjugate addition para-Quinone methides Organoboron compounds

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Deciphering the Shared and Specific Drug Resistance Mechanisms of Anaplastic Lymphoma Kinase via Binding Free Energy Computation

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Research 2024年第1期2023卷 663-674页

作者： Yang Yu Zhe Wang Lingling Wang Qinghua Wang Rongfan Tang Sutong Xiang Qirui Deng Tingjun Hou Huiyong Sun department of medicinal chemistry China Pharmaceutical UniversityNanjing 210009JiangsuP.R.China Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University College of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058ZhejiangP.R.China

Anaplastic lymphoma kinase(ALK),a tyrosine receptor kinase,has been proven to be associated with the occurrence of numerous malignancies.Although there have been already at least 3 generations of ALK inhibitors approved by FDA or in clinical trials,the occurrence of various mutations seriously attenuates the effectiveness of the drugs.Unfortunately,most of the drug resistance mechanisms still remain obscure.Therefore,it is necessary to reveal the bottom reasons of the drug resistance mechanisms caused by the mutations.In this work,on the basis of verifying the accuracy of 2 main kinds of binding free energy calculation methodologies[end-point method of Molecular Mechanics with Poisson-Boltzmann/Generalized Born and Surface Area(MM/PB(GB)SA)and alchemical method of Thermodynamic Integration(TI)],we performed a systematic analysis on the ALK systems to explore the underlying shared and specific drug resistance mechanisms,covering the one-drug-multiple-mutation and multiple-drug-onemutation cases.

关键词： drugs Anaplastic clinical

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MKK4 inhibitor:the hope for liver failure prevention and potential small liver graft transplantation

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Chinese Journal of Natural Medicines 2024年第6期22卷 483-485页

作者： ZHANG Yanqiu ZHANG Hao Jiangsu Key Laboratory of Bioactive Natural Product Research Department of Natural Medicinal ChemistryChina Pharmaceutical UniversityNanjing 210009China

Liver regeneration represents a fascinating concept that spans from ancient mythology to modern medical science.In Greek mythology,Prometheus,a hero who defied Zeus by stealing fire and giving it to humanity,was subjected to a severe punishment.He was bound to a rock where,each day,an eagle would feast on his liver,which would then miracu-lously regenerate overnight.This myth underscores the liver’s unique regenerative abilities,a feature that is not just le-gendary but also scientifically recognized.

关键词： Liver regeneration Partial hepatectomy MKK4 Drug discovery and development First-in-human phase I trial

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CRABP1-mediated non-canonical retinoic acid signaling in motor neurons and neural stem cells

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Neural Regeneration Research 2024年第6期19卷 1169-1170页

作者： Li-Na Wei department of pharmacology University of Minnesota Medical School

Retinoic acid(RA), the active metabolite of vitamin A(the retinoids), elicits a wide spectrum of biological activities critical to the development and health of most of the organ systems including the nervous systems(Corcoran et al., 2002). The effects of RA are mediated by two very distinct pathways; the first is manifested in the nucleus by binding to a large family of nuclear RA receptors(RARs) to regulate proper expression of RAtargeted genes,

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Modular Synthesis of Multi-substituted Cyclobutanones Enabled by Oxyallyl Cations

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Chinese Journal of chemistry 2024年第5期42卷 459-463页

作者： Meng Wang Zhonggui Wang Ping Lu Research Center for Molecular Recognition and Synthesis Department of ChemistryFudan University220 Handan LuShanghai200433 China Present address: department of Cancer Biology Dana-Farber Cancer Institute department of Biological chemistry and Molecular pharmacology Harvard Medical SchoolBostonMA 02115USA

Stereoselective synthesis of multi-substituted cyclobutanes with different substituents is still a daunting challenge in organic synthesis.We report here a practical and facile approach to synthesizing all-trans 2,3,4-trisubstituted cyclobutanones from readily available dichlorocyclobutanones.The substitution reaction proceeds smoothly via oxyallyl cation intermediates under mild basic conditions.Further transformation to the synthesis of 1,2,3,4-tetrasubstituted cyclobutanes was also explored.

关键词： Diastereoselectivity Modular synthesis Nucleophilic substitution Organohalides Oxyallyl cation Precision functionalization Strained molecules 1,2,3,4-Tetrasubstituted cyclobutanes

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Development of a potent benzonitrile-based inhibitor of glutaminyl-peptide cyclotransferase-like protein(QPCTL)with antitumor efficacy

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Signal Transduction and Targeted Therapy 2024年第1期9卷 44-46页

作者： Lei Yu Pengcheng Zhao Yaoliang Sun Zening Zheng Wenhao Du Lishan Zhang Yaxu Li Longyan Xie Shilin Xu Ping Wang Tongji University Cancer Center Shanghai Tenth People’s HospitalSchool of MedicineTongji UniversityShanghaiChina department of medicinal chemistry Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghaiChina

Dear Editor,Immune checkpoint therapies manipulating the immune system to eliminate tumor cells have shown remarkable clinical efficacy in treating various cancers.CD47,an emerging efficient immune checkpoint,is crucial for cancer cells to evade macrophagemediated phagocytosis by interaction with signal-regulatory proteinα(SIRPα).Antibodies blocking the CD47/SIRPαinteraction have been effective to promote macrophage-mediated phagocytosis in various types of cancer in mice and humans.CD47 is not only highly expressed in tumor cells,but also normal cells,such as red blood cells(RBCs).Thus,during clinical trials involving cancer patients,anti-CD47 antibodies may promote the macrophagesmediated phagocytosis of RBCs,ultimately inducing undesirable anemia side effects.In contrast,small molecule inhibitors interrupting CD47/SIRPαaxis have shown potential to overcome the anemia,possibly due to their lower immunogenicity and shorter half-life compared to antibodies.1 Hence,developing the novel strategies,especially those without the anemia side effect,to intervene in CD47/SIRPαinteraction will benefit cancer immunotherapy.

关键词： anemia overcome eliminate

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Development of an active-site titrant for SARS-CoV-2 main protease as an indispensable tool for evaluating enzyme kinetics

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2349-2357页

作者： Rabea Voget Julian Breidenbach Tobias Claff Alexandra Hingst Katharina Sylvester Christian Steinebach Lan Phuong Vu Renato H.Weiße Ulrike Bartz Norbert Sträter Christa E.Müller Michael Gütschow Pharmaceutical Institute Pharmaceutical&Medicinal ChemistryUniversity of BonnBonn 53121Germany Institute of Bioanalytical chemistry Center for Biotechnology and BiomedicineLeipzig UniversityLeipzig 04103Germany department of Natural Sciences University of Applied Sciences Bonn-Rhein-SiegRheinbach 53359Germany

A titrant for the SARS-CoV-2 main protease(M^(pro))was developed that enables,for the first time,the exact determination of the concentration of the enzymatically active M^(pro) by active-site titration.The covalent binding mode of the tetrapeptidic titrant was elucidated by the determination of the crystal structure of the enzyme–titrant complex.Four fluorogenic substrates of M^(pro),including a prototypical,internally quenched Dabcyl-EDANS peptide,were compared in terms of solubility under typical assay conditions.By exploiting the new titrant,key kinetic parameters for the M^(pro)-catalyzed cleavage of these substrates were determined.

关键词： COVID-19 SARS-CoV-2 Main protease Peptide nitriles Fluorogenic substrates Active-site titration X-ray crystallography Inner filter effect

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