Optimization of G‐Quadruplex Ligands through a SAR Study Combining Parallel Synthesis and Screening of Cationic Bis(acylhydrazones)
| Autor: | Oksana Reznichenko, Denis Leclercq, Jaime Franco Pinto, Liliane Mouawad, Valérie Gabelica, Anton Granzhan |
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| Přispěvatelé: | Chimie et modélisation pour la biologie du cancer (CMBC), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Acides Nucléiques : Régulations Naturelle et Artificielle (ARNA), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut Européen de Chimie et Biologie (IECB), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French Ministry of Higher Education, Research and Innovation (PhD fellowship, to OR), European Union's Horizon 2020 Framework Programme(Marie Skłodowska-Curie Grant Agreement No. 666003 through an IC-3i international PhD programme, to JFP), and benefited from access to Plateforme de BioPhysico-Chimie Structurale of the IECB (Univ. Bordeaux, CNRS UMS3033, Inserm US001) for native mass spectrometry., ANR-17-CE07-0004,DYCONAS,Chimie dynamique constitutionnelle pour les structures d'acides nucléiques(2017), GRANZHAN, Anton, Chimie dynamique constitutionnelle pour les structures d'acides nucléiques - - DYCONAS2017 - ANR-17-CE07-0004 - AAPG2017 - VALID |
| Rok vydání: | 2022 |
| Předmět: |
G4 ligands
[CHIM.ORGA]Chemical Sciences/Organic chemistry Nitrogen heterocycles [CHIM.THER] Chemical Sciences/Medicinal Chemistry Organic Chemistry Combinatorial chemistry [CHIM.THER]Chemical Sciences/Medicinal Chemistry General Chemistry [CHIM.ORGA] Chemical Sciences/Organic chemistry G-quadruplexes N-acylhydrazones Catalysis |
| Zdroj: | Chemistry-A European Journal Chemistry-A European Journal, 2022, ⟨10.1002/chem.202202427⟩ |
| ISSN: | 1521-3765 0947-6539 |
| DOI: | 10.1002/chem.202202427 |
| Popis: | International audience; G-quadruplexes (G4s), secondary structures adopted by guanine-rich DNA and RNA sequences, are implicated in numerous biological processes and have been suggested as potential drug targets. Accordingly, there is an increasing interest in developing high-throughput methods allowing the generation of congeneric series of G4-targeting molecules (“ligands”) and investigation of their interaction with the targets. Here, we developed an operationally simple method of parallel synthesis to generate “ready-to-screen” libraries of cationic acylhydrazones, a motif that we have previously identified as a promising scaffold for potent, biologically active G4 ligands. Combined with well-established screening techniques, such as fluorescence melting, this method enables rapid synthesis and screening of combinatorial libraries of potential G4 ligands. Following this protocol, we synthesized a combinatorial library of 90 bis(acylhydrazones) and screened it against five different nucleic acid structures. This way, we were able to analyze the structure-activity relationships within this series of G4 ligands, and identified three novel promising ligands whose interaction with G4-DNA of different topologies was carefully studied by a combination of several biophysical techniques, including native mass spectrometry, and molecular modeling. |
| Databáze: | OpenAIRE |
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