Cargando…
Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors
[Image: see text] Chemical modifications of the mRNA cap structure can enhance the stability, translational properties, and half-life of mRNAs, thereby altering the therapeutic properties of synthetic mRNA. However, cap structure modification is challenging because of the instability of the 5′-5′-tr...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10242767/ https://www.ncbi.nlm.nih.gov/pubmed/37209102 http://dx.doi.org/10.1021/acs.joc.3c00126 |
_version_ | 1785054289817763840 |
---|---|
author | Wojtczak, Blazej A. Bednarczyk, Marcelina Sikorski, Pawel J. Wojtczak, Anna Surynt, Piotr Kowalska, Joanna Jemielity, Jacek |
author_facet | Wojtczak, Blazej A. Bednarczyk, Marcelina Sikorski, Pawel J. Wojtczak, Anna Surynt, Piotr Kowalska, Joanna Jemielity, Jacek |
author_sort | Wojtczak, Blazej A. |
collection | PubMed |
description | [Image: see text] Chemical modifications of the mRNA cap structure can enhance the stability, translational properties, and half-life of mRNAs, thereby altering the therapeutic properties of synthetic mRNA. However, cap structure modification is challenging because of the instability of the 5′-5′-triphosphate bridge and N7-methylguanosine. The Suzuki–Miyaura cross-coupling reaction between boronic acid and halogen compound is a mild, convenient, and potentially applicable approach for modifying biomolecules. Herein, we describe two methods to synthesize C8-modified cap structures using the Suzuki–Miyaura cross-coupling reaction. Both methods employed phosphorimidazolide chemistry to form the 5′,5′-triphosphate bridge. However, in the first method, the introduction of the modification via the Suzuki–Miyaura cross-coupling reaction at the C8 position occurs postsynthetically, at the dinucleotide level, whereas in the second method, the modification was introduced at the level of the nucleoside 5′-monophosphate, and later, the triphosphate bridge was formed. Both methods were successfully applied to incorporate six different groups (methyl, cyclopropyl, phenyl, 4-dimethylaminophenyl, 4-cyanophenyl, and 1-pyrene) into either the m(7)G or G moieties of the cap structure. Aromatic substituents at the C8-position of guanosine form a push–pull system that exhibits environment-sensitive fluorescence. We demonstrated that this phenomenon can be harnessed to study the interaction with cap-binding proteins, e.g., eIF4E, DcpS, Nudt16, and snurportin. |
format | Online Article Text |
id | pubmed-10242767 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-102427672023-06-07 Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors Wojtczak, Blazej A. Bednarczyk, Marcelina Sikorski, Pawel J. Wojtczak, Anna Surynt, Piotr Kowalska, Joanna Jemielity, Jacek J Org Chem [Image: see text] Chemical modifications of the mRNA cap structure can enhance the stability, translational properties, and half-life of mRNAs, thereby altering the therapeutic properties of synthetic mRNA. However, cap structure modification is challenging because of the instability of the 5′-5′-triphosphate bridge and N7-methylguanosine. The Suzuki–Miyaura cross-coupling reaction between boronic acid and halogen compound is a mild, convenient, and potentially applicable approach for modifying biomolecules. Herein, we describe two methods to synthesize C8-modified cap structures using the Suzuki–Miyaura cross-coupling reaction. Both methods employed phosphorimidazolide chemistry to form the 5′,5′-triphosphate bridge. However, in the first method, the introduction of the modification via the Suzuki–Miyaura cross-coupling reaction at the C8 position occurs postsynthetically, at the dinucleotide level, whereas in the second method, the modification was introduced at the level of the nucleoside 5′-monophosphate, and later, the triphosphate bridge was formed. Both methods were successfully applied to incorporate six different groups (methyl, cyclopropyl, phenyl, 4-dimethylaminophenyl, 4-cyanophenyl, and 1-pyrene) into either the m(7)G or G moieties of the cap structure. Aromatic substituents at the C8-position of guanosine form a push–pull system that exhibits environment-sensitive fluorescence. We demonstrated that this phenomenon can be harnessed to study the interaction with cap-binding proteins, e.g., eIF4E, DcpS, Nudt16, and snurportin. American Chemical Society 2023-05-20 /pmc/articles/PMC10242767/ /pubmed/37209102 http://dx.doi.org/10.1021/acs.joc.3c00126 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Wojtczak, Blazej A. Bednarczyk, Marcelina Sikorski, Pawel J. Wojtczak, Anna Surynt, Piotr Kowalska, Joanna Jemielity, Jacek Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors |
title | Synthesis and Evaluation
of Diguanosine Cap Analogs
Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling:
Discovery of 7-Methylguanosine-Based Molecular Rotors |
title_full | Synthesis and Evaluation
of Diguanosine Cap Analogs
Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling:
Discovery of 7-Methylguanosine-Based Molecular Rotors |
title_fullStr | Synthesis and Evaluation
of Diguanosine Cap Analogs
Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling:
Discovery of 7-Methylguanosine-Based Molecular Rotors |
title_full_unstemmed | Synthesis and Evaluation
of Diguanosine Cap Analogs
Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling:
Discovery of 7-Methylguanosine-Based Molecular Rotors |
title_short | Synthesis and Evaluation
of Diguanosine Cap Analogs
Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling:
Discovery of 7-Methylguanosine-Based Molecular Rotors |
title_sort | synthesis and evaluation
of diguanosine cap analogs
modified at the c8-position by suzuki–miyaura cross-coupling:
discovery of 7-methylguanosine-based molecular rotors |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10242767/ https://www.ncbi.nlm.nih.gov/pubmed/37209102 http://dx.doi.org/10.1021/acs.joc.3c00126 |
work_keys_str_mv | AT wojtczakblazeja synthesisandevaluationofdiguanosinecapanalogsmodifiedatthec8positionbysuzukimiyauracrosscouplingdiscoveryof7methylguanosinebasedmolecularrotors AT bednarczykmarcelina synthesisandevaluationofdiguanosinecapanalogsmodifiedatthec8positionbysuzukimiyauracrosscouplingdiscoveryof7methylguanosinebasedmolecularrotors AT sikorskipawelj synthesisandevaluationofdiguanosinecapanalogsmodifiedatthec8positionbysuzukimiyauracrosscouplingdiscoveryof7methylguanosinebasedmolecularrotors AT wojtczakanna synthesisandevaluationofdiguanosinecapanalogsmodifiedatthec8positionbysuzukimiyauracrosscouplingdiscoveryof7methylguanosinebasedmolecularrotors AT suryntpiotr synthesisandevaluationofdiguanosinecapanalogsmodifiedatthec8positionbysuzukimiyauracrosscouplingdiscoveryof7methylguanosinebasedmolecularrotors AT kowalskajoanna synthesisandevaluationofdiguanosinecapanalogsmodifiedatthec8positionbysuzukimiyauracrosscouplingdiscoveryof7methylguanosinebasedmolecularrotors AT jemielityjacek synthesisandevaluationofdiguanosinecapanalogsmodifiedatthec8positionbysuzukimiyauracrosscouplingdiscoveryof7methylguanosinebasedmolecularrotors |