Structural Optimization of Azacryptands for Targeting Three-Way DNA Junctions.

Autor: Pipier A; Institut de Chimie Moléculaire, ICMUB CNRS UMR6302, 9, Avenue Alain Savary, 21078, Dijon, France., Chetot T; Chemistry and Modelling for the Biology of Cancer (CMBC), CNRS UMR9187, INSERM U1196, Institut Curie, Université Paris Saclay, 91405, Orsay, France., Kalamatianou A; Chemistry and Modelling for the Biology of Cancer (CMBC), CNRS UMR9187, INSERM U1196, Institut Curie, Université Paris Saclay, 91405, Orsay, France., Martin N; Chemistry and Modelling for the Biology of Cancer (CMBC), CNRS UMR9187, INSERM U1196, Institut Curie, Université Paris Saclay, 91405, Orsay, France., Caroff M; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France., Britton S; Institut de Pharmacologie et de Biologie Structurale (IPBS), Université de Toulouse, CNRS, Université Toulouse III - Paul Sabatier (UT3), Toulouse, France., Chéron N; PASTEUR, Département de chimie, École Normale Supérieure (ENS), PSL University, Sorbonne Université, CNRS UMR8640, 75005, Paris, France., Trantírek L; Central European Institute of Technology, Masaryk University, Kamenice 753/5, 625 00, Brno, Czech Republic., Granzhan A; Chemistry and Modelling for the Biology of Cancer (CMBC), CNRS UMR9187, INSERM U1196, Institut Curie, Université Paris Saclay, 91405, Orsay, France., Monchaud D; Institut de Chimie Moléculaire, ICMUB CNRS UMR6302, 9, Avenue Alain Savary, 21078, Dijon, France.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Sep 02; Vol. 63 (36), pp. e202409780. Date of Electronic Publication: 2024 Aug 01.
DOI: 10.1002/anie.202409780
Abstrakt: Transient melting of the duplex-DNA (B-DNA) during DNA transactions allows repeated sequences to fold into non-B-DNA structures, including DNA junctions and G-quadruplexes. These noncanonical structures can act as impediments to DNA polymerase progression along the duplex, thereby triggering DNA damage and ultimately jeopardizing genomic stability. Their stabilization by ad hoc ligands is currently being explored as a putative anticancer strategy since it might represent an efficient way to inflict toxic DNA damage specifically to rapidly dividing cancer cells. The relevance of this strategy is only emerging for three-way DNA junctions (TWJs) and, to date, no molecule has been recognized as a reference TWJ ligand, featuring both high affinity and selectivity. Herein, we characterize such reference ligands through a combination of in vitro techniques comprising affinity and selectivity assays (competitive FRET-melting and TWJ Screen assays), functional tests (qPCR and Taq stop assays) and structural analyses (molecular dynamics and NMR investigations). We identify novel azacryptands TrisNP-amphi and TrisNP-ana as the most promising ligands, interacting with TWJs with high affinity and selectivity. These ligands represent new molecular tools to investigate the cellular roles of TWJs and explore how they can be exploited in innovative anticancer therapies.
(© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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