Article
Immunology
Melanie A. Whitmore, Hong Li, Wentao Lyu, Sharmily Khanam, Guolong Zhang
Summary: The combination of HDACi and DNMTi/HMTi showed a strong synergy in inducing HDP gene expression, and also regulated the expression of tight junction proteins.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Yusuke Ano, Masaya Higashino, Yuki Yamada, Naoto Chatani
Summary: The Pd-catalyzed transformation of N-phthaloyl hydrazones into nitriles involving the cleavage of an N-N bond is reported. The use of N-heterocyclic carbene as a ligand is crucial for the success of the reaction. N-Phthaloyl hydrazones prepared from aromatic aldehydes or cyclobutanones can be applied to this transformation, yielding aryl or alkenyl nitriles, respectively.
CHEMICAL COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Guang-Jing Feng, Yang-Fan Guo, Yuming Tang, Min Li, Yufei Jia, Zhimeng Li, Shuangshuang Wang, Hongmei Liu, Yuzhou Wu, Hai Dong
Summary: The potential of thioglucoside analogues as antidiabetic drugs was investigated in this study. The analogues showed good stability, low toxicity, and high inhibitory activity, making them promising candidates for new gliflozin drugs. Additionally, the synthesis of these analogues is simple, efficient, and cost-effective.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Arindam Talukdar, Ayan Mukherjee, Debomita Bhattacharya
Summary: The abnormal expression of protein methyltransferase (PMT) is related to various diseases, and the focus of current research is on the evolution from nucleoside inhibitors to selective competitive non-nucleoside inhibitors to solve the inherent problems of nucleoside analogues.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Multidisciplinary
Yoshihiro Sohtome, Tadahiro Shimazu, Yoichi Shinkai, Mikiko Sodeoka
Summary: Developing synthetic strategies to construct covalent bonds is a common research topic among synthetic chemists. The success of such strategies relies on the tunability of conditions such as catalysts, reagents, solvents, and reaction temperature. However, controlling chemical reactions in living cells poses challenges due to a smaller number of hit substrates and a complex and inflexible environment. The use of chemical methylome analysis serves as an example of bridging the gap between chemistry and biology in this context.
ACCOUNTS OF CHEMICAL RESEARCH
(2021)
Article
Chemistry, Multidisciplinary
Iredia D. Iyamu, Jonah Z. Vilseck, Ravi Yadav, Nicholas Noinaj, Rong Huang
Summary: The study reports the first cell-potent NNMT bisubstrate inhibitor II399, which demonstrates strong binding affinity and selectivity for NNMT. The inhibition mechanism and crystal structure analysis reveal the interactions between II399 and both the substrate and cofactor binding pockets. This research provides a valuable probe for studying NNMT biology and introduces a strategy for developing cell-potent inhibitors for SAM-dependent methyltransferases.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Karolina Dzedulionyte, Nina Fuxreiter, Ekaterina Schreiber-Brynzak, Asta Zukauskaite, Algirdas Sackus, Verena Pichler, Egle Arbaciauskiene
Summary: A library of pyrazole-based lamellarin O analogues was synthesized via modification of easily accessible 3(5)-aryl-1H-pyrazole-5(3)-carboxylates using bromination, N-alkylation, and Pd-catalysed Suzuki cross-coupling reactions. The synthesized compounds were evaluated for their physicochemical properties and cytotoxicity against colorectal cancer cell lines. The most active compounds exhibited cell proliferation inhibition in the low micromolar range and triggered cell death through G2/M-phase arrest.
Article
Plant Sciences
Shi-Xing Miao, Lin-Xi Wan, Zhen-Xiang He, Xian-Li Zhou, Xiaohuan Li, Feng Gao
Summary: The first systematic direct diversification of a complex natural product by metal-catalyzed N-H functionalization was conducted, resulting in the synthesis of a new series of N-aryl-huperzine A analogues with good AChE inhibitory activity. Compound 30 showed the most potent AChE inhibition activity and could be a promising lead compound for Alzheimer's disease drug development.
JOURNAL OF NATURAL PRODUCTS
(2021)
Article
Chemistry, Organic
Mohammad Z. Abidin, Thangavelu Saravanan, Laura Bothof, Pieter G. Tepper, Andy-Mark W. H. Thunnissen, Gerrit J. Poelarends
Summary: The study presents the asymmetric synthesis of N-arylalkyl-substituted l-aspartic acids using EDDS lyase as a biocatalyst, resulting in products with good enantioselectivity and high yields. This demonstrates that C-N lyases can serve as a powerful synthetic tool for preparing difficult noncanonical amino acids.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Kishanpal Singh, Neetu Singh, Harvinder Singh Sohal, Baljit Singh, Fohad Mabood Husain, Mohammed Arshad, Mohd Adil
Summary: This study reports a synthetic route for generating N-phenyl amino acid derivatives using CO(2) through a C-C coupling reaction in an undivided cell with Mg-Pt electrodes. The synthesis is efficient, simple, and produces no side products. The newly prepared compounds' structures were determined using advanced spectroscopic techniques. The derivatives exhibited good to excellent activity against bacterial and fungal strains. Interestingly, compounds with polar groups capable of forming hydrogen bonds showed activity equivalent to standard drugs.
Article
Chemistry, Multidisciplinary
Louise Eagling, Daniel J. Leonard, Maria Schwarz, Inaki Urruzuno, Grace Boden, J. Steven Wailes, John W. Ward, Jonathan Clayden
Summary: l-Arogenate is a key metabolite in the synthesis of plant secondary metabolites, with a practical synthesis method involving carboxylative dearomatization by intramolecular electrophilic capture to generate a versatile intermediate for further functionalization.
Article
Chemistry, Multidisciplinary
Jianbo Liu, Matthew F. L. Parker, Sinan Wang, Robert R. Flavell, F. Dean Toste, David M. Wilson
Summary: The synthesis of N-trifluoromethyl amides from carboxylic acid halides and esters under mild conditions via isothiocyanates in the presence of silver fluoride at room temperature has been reported. This method desulfurizes isothiocyanates with AgF and then acylates the formed derivative to afford N-trifluoromethyl amides, including previously inaccessible structures. The strategy provides a platform for rapidly generating N-trifluoromethyl amides by virtue of the diversity and availability of both reaction partners and could find application in the modification of advanced intermediates.
Article
Chemistry, Organic
James M. Fordham, Paolo Piacentini, Marco Santagostino
Summary: We report a Pd-catalyzed reaction sequence that allows the modular synthesis of isocytosine analogues through ring-opening/arylation/cyclization reactions between 2-aminothiazoles and aryl (pseudo)halides. The reaction shows broad scope in terms of coupling partners and is tolerant of various functional groups, as demonstrated by a robustness test. Visual kinetic analysis suggests that the product may inhibit catalyst turnover for some substrates.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Lin-Xi Wan, Shi-Xing Miao, Zhen-Xiang He, Xiaohuan Li, Xian-Li Zhou, Feng Gao
Summary: Efficient catalysis by Palladium/BuAd(2)P led to the synthesis of 15 aryldonepezil analogues with high selective AChE inhibition, among which the 3-methylpridinyl analogue (12) showed lower toxicity compared to donepezil and remarkable neuroprotective activity. Docking results of compound 12 provided insights into the selective inhibition mechanism between AChE and BuChE.
Article
Chemistry, Organic
Xiaozheng Dou, Bhargav A. Patel, Terin D'Amico, Chitra Subramanian, Eric Cousineau, Yi Yi, Mark Cohen, Brian S. J. Blagg
Summary: Hsp90 is a molecular chaperone involved in regulating protein folding and stability, and it plays a significant role in cancer development and progression. Inhibition of Hsp90 has emerged as a promising approach for cancer treatment, but currently available inhibitors have demonstrated toxic side effects. Cruentaren A, a natural product, shows potent anticancer activity by disrupting the interactions between Hsp90 alpha and F1FO ATP synthase without inducing the pro-survival heat shock response. However, the complex structure of Cruentaren A has hindered its development as an anticancer agent.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Mathieu Carlier, Emilie Lesur, Aurelie Baron, Aurelie Lemetais, Karine Guitot, Loic Roupnel, Christiane Dietrich, Gilles Doisneau, Dominique Urban, Nicolas Bayan, Jean-Marie Beau, Dominique Guianvarc'h, Boris Vauzeilles, Yann Bourdreux
Summary: Trehalose-based probes are useful tools for detecting the mycomembrane of mycobacteria through metabolic labeling. This study simplified the synthesis of trehalose analogues and demonstrated their application in one-step and two-step labeling methods for studying the mycomembrane in live mycobacteria.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2022)
Article
Biology
Sabrina Adam, Julia Bracker, Viviane Klingel, Bernd Osteresch, Nicole E. Radde, Jens Brockmeyer, Pavel Bashtrykov, Albert Jeltsch
Summary: This study reveals that the catalytic activities of TET1 and TET2 are influenced by the flanking sequences of DNA substrates, and this influence is related to 5mC and 5hmC. Furthermore, enhanced flanking sequence preferences and profound effects on the specificity of TET2 are observed at non-CpG sites. The flanking sequence preferences of TET are reflected in genome-wide and local patterns of 5hmC and DNA demethylation.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Alexandra Mack, Max Emperle, Philipp Schnee, Sabrina Adam, Juergen Pleiss, Pavel Bashtrykov, Albert Jeltsch
Summary: Somatic R882H DNMT3A mutations are common in AML, but their pathogenic mechanism is unclear. R882H mutations affect the sequence preferences of DNMT3A and have a dominant effect on its catalytic properties in samples containing WT and R882H subunits.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biology
Alexander Broehm, Tabea Schoch, Michael Dukatz, Nora Graf, Franziska Dorscht, Evelin Mantai, Sabrina Adam, Pavel Bashtrykov, Albert Jeltsch
Summary: DNMT3A efficiently methylates recombinant mononucleosome linker DNA, and H3K36me3 stimulates linker DNA methylation independent of its interaction with the PWWP domain.
COMMUNICATIONS BIOLOGY
(2022)
Article
Chemistry, Multidisciplinary
Blaise Gatin-Fraudet, Mathilde Pucher, Thomas Le Saux, Gilles Doisneau, Yann Bourdreux, Ludovic Jullien, Boris Vauzeilles, Dominique Guianvarc'h, Dominique Urban
Summary: Arylborinic acids are a new, efficient, and underexplored hydrogen peroxide-responsive triggers. This study investigated the factors that could selectively guide their oxidative rearrangement and found that the o-CF3 substituent is an excellent directing group for complete regioselectivity. This research successfully applied the findings to synthesize borinic acid-based fluorogenic probes that exclusively release the fluorescent moiety upon H2O2 treatment, maintaining their superior kinetic properties compared to boronic acids.
CHEMISTRY-A EUROPEAN JOURNAL
(2022)
Article
Chemistry, Organic
D. Liu, O. Monfret, Y. Bourdreux, D. Urban, D. Guianvarc'h, G. Doisneau
Summary: 5-Hydroxymethyl derivatives of pyrimidine nucleosides are biologically relevant compounds. A method for the O-5 chemoselective transformation of unprotected 5-(hydroxymethyl)-2'-deoxyuridine through selective etherification in the presence of an alcohol promoted by acidic Amberlyst 15 resin at room temperature is reported. This method provides a fast, economical, and efficient access to 5-hydroxymethylated derivatives and has a broad substrate scope. It can be used to prepare useful building blocks, natural hypermodified thymidines and analogues, and cyanethyl-protected 5hmdU for solid-phase oligonucleotide syntheses.
Article
Biochemistry & Molecular Biology
Stefan Kunert, Max Emperle, Sabrina Adam, Julia Bracker, Jens Bracker, Arumugam Rajavelu, Albert Jeltsch
Summary: The DNMT3A DNA methyltransferase is frequently mutated in cancers, especially in AML. The R736H mutation in the FF-interface of the enzyme leads to a moderate reduction in catalytic activity but no changes in CpG specificity or sub-nuclear localization. DNMT3L strongly stimulates the activity of R736H, and mixed interfaces involving R736H also enhance the activity.
Article
Biochemistry & Molecular Biology
Dimitri Graf, Laura Laistner, Viviane Klingel, Nicole E. Radde, Sara Weirich, Albert Jeltsch
Summary: A DNA methylation-based epigenetic memory system was developed to detect environmental signals and trigger phenotypic switches in bacteria. The system's reversible reset was achieved by adding ZnSO4, and the long-term stability of the ON-state was studied, showing a gradual loss of signal over time.
Article
Biology
Julian Broche, Anja R. R. Koehler, Fiona Kuehnel, Bernd Osteresch, Thyagarajan T. T. Chandrasekaran, Sabrina Adam, Jens Brockmeyer, Albert Jeltsch
Summary: Although cytosine-C5 methylation of DNA is essential in higher eukaryotes, the presence and importance of 6-methyladenine (m6dA) in human cells are controversial. We introduced m6dA in human cells and observed reductions in cell viability, particularly after global GANTC methylation. Genes directly regulated by m6dA in a GANTC context showed changes in H3K27me3 and JUN family transcription factor binding, indicating an inhibitory effect on the PRC2 complex and reduced recruitment of JUN transcription factors. Our study demonstrates the physiological effects of m6dA introduction in human DNA and identifies target genes and molecular pathways that affect gene expression and cell phenotypes.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Leeroy Baron, Justine Hadjerci, Leishemba Thoidingjam, Marina Plays, Romain Bucci, Nolwenn Morris, Sebastian Muller, Fabien Sindikubwabo, Stephanie Solier, Tatiana Caneque, Ludovic Colombeau, Cedric M. Blouin, Christophe Lamaze, Alain Puisieux, Yannick Bono, Christine Gaillet, Luca Laraia, Boris Vauzeilles, Frederic Taran, Sebastien Papot, Philippe Karoyan, Romain Duval, Florence Mahuteau-Betzer, Paola Arimondo, Kevin Cariou, Gilles Guichard, Laurent Micouin, Melanie Etheve-Quelquejeu, Daniela Verga, Antoine Versini, Gilles Gasser, Cong Tang, Philippe Belmont, Andreas Linkermann, Claudia Bonfio, Dennis Gillingham, Thomas Poulsen, Marco Di Antonio, Marie Lopez, Dominique Guianvarc'h, Christophe Thomas, Geraldine Masson, Arnaud Gautier, Ludger Johannes, Raphael Rodriguez
Summary: This symposium is the third PSL Chemical Biology meeting held at Institut Curie. It originated from the Institut de Chimie des Substances Naturelles (ICSN) in Gif-sur-Yvette and expanded its scope at Institut Curie before becoming the official PSL Chemical Biology meeting. The pandemic allowed for additional speakers and the inclusion of online participants.
Article
Chemistry, Organic
Oceane Monfret, Dan Liu, Paulin Rollando, Yann Bourdreux, Dominique Urban, Gilles Doisneau, Dominique Guianvarc'h
Summary: In recent years, there has been a focus on 5-hydroxymethyl-pyrimidine-based nucleobases due to their significance in gene regulation. Several approaches have been used to synthesize properly protected 5-hydroxymethyl-pyrimidine based nucleosides, including hydroxymethylation, radical bromination, or carbonylative coupling. This study reviews these approaches, reinvestigates some of them, and proposes an alternative route based on methyl oxidation and reduction. Examples of applications, such as the synthesis of base J and 5-azidomethyl-2'-deoxyuridine, are also presented.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Sabrina Adam, Viviane Klingel, Nicole E. Radde, Pavel Bashtrykov, Albert Jeltsch
Summary: The specificity of DNMT1 for hemimethylated DNA is strongly influenced by the flanking sequence, with an average specificity of 80-fold. This preference is enhanced on long hemimethylated DNA substrates. The presence of a single methyl group in the DNA changes the conformation of the DNMT1-DNA complex, leading to an active conformation by steric repulsion. Passive DNA demethylation by 5hmC generation is not efficient in many flanking contexts.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemical Research Methods
Alexandra Bristiel, Manon Cadinot, Mathieu Pizzonero, Frederic Taran, Dominique Urban, Raphael Guignard, Dominique Guianvarc'h
Summary: The researchers developed a facile method for conjugating relevant probes, ligands, or delivery agents onto oligonucleotides (ONs), which is important for both fundamental studies in chemical biology and improving the pharmacology of ONs in medicinal chemistry. They introduced novel 2'-functionalized nucleoside phosphoramidite monomers that contain bioorthogonal methylcyclopropene or sydnone moieties for the first time to ON solid-phase synthesis, allowing traceless ON postsynthetic modifications with reactive complementary probes through inverse electron-demand Diels-Alder reactions or strain-promoted sydnone-alkyne cycloaddition. These findings expand the bioorthogonal phosphoramidite building blocks and provide a new method for generating labeled ONs.
BIOCONJUGATE CHEMISTRY
(2023)
Article
Genetics & Heredity
Nivethika Rajaram, Alexandra G. Kouroukli, Susanne Bens, Pavel Bashtrykov, Albert Jeltsch
Summary: Specific allele-specific targeted DNA methylation was achieved at multiple gene loci using epigenome editing, which can be potentially applied in the treatment of diseases caused by dominant mutations with minimal side effects.
EPIGENETICS & CHROMATIN
(2023)
Editorial Material
Multidisciplinary Sciences
Sara Weirich, Albert Jeltsch
Summary: Protein lysine methylation is important but lacks suitable mimetics for experimental characterization. This limits biochemical and cellular studies. We summarize the challenges and propose alternative approaches.
NATURE COMMUNICATIONS
(2023)