Cargando…

Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis

The interaction between the series of berberine derivatives 1–5 (NAX071, NAX120, NAX075, NAX077 and NAX079) and human telomeric G-quadruplexes (G4), which are able to inhibit the Telomerase enzyme’s activity in malignant cells, was investigated. The derivatives bear a pyridine moiety connected by a...

Descripción completa

Detalles Bibliográficos
Autores principales: Bazzicalupi, Carla, Bonardi, Alessandro, Biver, Tarita, Ferraroni, Marta, Papi, Francesco, Savastano, Matteo, Lombardi, Paolo, Gratteri, Paola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693123/
https://www.ncbi.nlm.nih.gov/pubmed/36430540
http://dx.doi.org/10.3390/ijms232214061
_version_ 1784837456254730240
author Bazzicalupi, Carla
Bonardi, Alessandro
Biver, Tarita
Ferraroni, Marta
Papi, Francesco
Savastano, Matteo
Lombardi, Paolo
Gratteri, Paola
author_facet Bazzicalupi, Carla
Bonardi, Alessandro
Biver, Tarita
Ferraroni, Marta
Papi, Francesco
Savastano, Matteo
Lombardi, Paolo
Gratteri, Paola
author_sort Bazzicalupi, Carla
collection PubMed
description The interaction between the series of berberine derivatives 1–5 (NAX071, NAX120, NAX075, NAX077 and NAX079) and human telomeric G-quadruplexes (G4), which are able to inhibit the Telomerase enzyme’s activity in malignant cells, was investigated. The derivatives bear a pyridine moiety connected by a hydrocarbon linker of varying length (n = 1–5, with n number of aliphatic carbon atoms) to the C13 position of the parent berberine. As for the G4s, both bimolecular 5′-TAGGGTTAGGGT-3′ (Tel12) and monomolecular 5′-TAGGGTTAGGGTTAGGGTTAGGG-3′ (Tel23) DNA oligonucleotides were considered. Spectrophotometric titrations, melting tests, X-ray diffraction solid state analysis and in silico molecular dynamics (MD) simulations were used to describe the different systems. The results were compared in search of structure–activity relationships. The analysis pointed out the formation of 1:1 complexes between Tel12 and all ligands, whereas both 1:1 and 2:1 ligand/G4 stoichiometries were found for the adduct formed by NAX071 (n = 1). Tel12, with tetrads free from the hindrance by the loop, showed a higher affinity. The details of the different binding geometries were discussed, highlighting the importance of H-bonds given by the berberine benzodioxole group and a correlation between the strength of binding and the hydrocarbon linker length. Theoretical (MD) and experimental (X-ray) structural studies evidence the possibility for the berberine core to interact with one or both G4 strands, depending on the constraints given by the linker length, thus affecting the G4 stabilization effect.
format Online
Article
Text
id pubmed-9693123
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-96931232022-11-26 Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis Bazzicalupi, Carla Bonardi, Alessandro Biver, Tarita Ferraroni, Marta Papi, Francesco Savastano, Matteo Lombardi, Paolo Gratteri, Paola Int J Mol Sci Article The interaction between the series of berberine derivatives 1–5 (NAX071, NAX120, NAX075, NAX077 and NAX079) and human telomeric G-quadruplexes (G4), which are able to inhibit the Telomerase enzyme’s activity in malignant cells, was investigated. The derivatives bear a pyridine moiety connected by a hydrocarbon linker of varying length (n = 1–5, with n number of aliphatic carbon atoms) to the C13 position of the parent berberine. As for the G4s, both bimolecular 5′-TAGGGTTAGGGT-3′ (Tel12) and monomolecular 5′-TAGGGTTAGGGTTAGGGTTAGGG-3′ (Tel23) DNA oligonucleotides were considered. Spectrophotometric titrations, melting tests, X-ray diffraction solid state analysis and in silico molecular dynamics (MD) simulations were used to describe the different systems. The results were compared in search of structure–activity relationships. The analysis pointed out the formation of 1:1 complexes between Tel12 and all ligands, whereas both 1:1 and 2:1 ligand/G4 stoichiometries were found for the adduct formed by NAX071 (n = 1). Tel12, with tetrads free from the hindrance by the loop, showed a higher affinity. The details of the different binding geometries were discussed, highlighting the importance of H-bonds given by the berberine benzodioxole group and a correlation between the strength of binding and the hydrocarbon linker length. Theoretical (MD) and experimental (X-ray) structural studies evidence the possibility for the berberine core to interact with one or both G4 strands, depending on the constraints given by the linker length, thus affecting the G4 stabilization effect. MDPI 2022-11-14 /pmc/articles/PMC9693123/ /pubmed/36430540 http://dx.doi.org/10.3390/ijms232214061 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bazzicalupi, Carla
Bonardi, Alessandro
Biver, Tarita
Ferraroni, Marta
Papi, Francesco
Savastano, Matteo
Lombardi, Paolo
Gratteri, Paola
Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis
title Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis
title_full Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis
title_fullStr Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis
title_full_unstemmed Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis
title_short Probing the Efficiency of 13-Pyridylalkyl Berberine Derivatives to Human Telomeric G-Quadruplexes Binding: Spectroscopic, Solid State and In Silico Analysis
title_sort probing the efficiency of 13-pyridylalkyl berberine derivatives to human telomeric g-quadruplexes binding: spectroscopic, solid state and in silico analysis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9693123/
https://www.ncbi.nlm.nih.gov/pubmed/36430540
http://dx.doi.org/10.3390/ijms232214061
work_keys_str_mv AT bazzicalupicarla probingtheefficiencyof13pyridylalkylberberinederivativestohumantelomericgquadruplexesbindingspectroscopicsolidstateandinsilicoanalysis
AT bonardialessandro probingtheefficiencyof13pyridylalkylberberinederivativestohumantelomericgquadruplexesbindingspectroscopicsolidstateandinsilicoanalysis
AT bivertarita probingtheefficiencyof13pyridylalkylberberinederivativestohumantelomericgquadruplexesbindingspectroscopicsolidstateandinsilicoanalysis
AT ferraronimarta probingtheefficiencyof13pyridylalkylberberinederivativestohumantelomericgquadruplexesbindingspectroscopicsolidstateandinsilicoanalysis
AT papifrancesco probingtheefficiencyof13pyridylalkylberberinederivativestohumantelomericgquadruplexesbindingspectroscopicsolidstateandinsilicoanalysis
AT savastanomatteo probingtheefficiencyof13pyridylalkylberberinederivativestohumantelomericgquadruplexesbindingspectroscopicsolidstateandinsilicoanalysis
AT lombardipaolo probingtheefficiencyof13pyridylalkylberberinederivativestohumantelomericgquadruplexesbindingspectroscopicsolidstateandinsilicoanalysis
AT gratteripaola probingtheefficiencyof13pyridylalkylberberinederivativestohumantelomericgquadruplexesbindingspectroscopicsolidstateandinsilicoanalysis