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Novel N7-Arylmethyl Substituted Dinucleotide mRNA 5′ cap Analogs: Synthesis and Evaluation as Modulators of Translation

Authors :
Radoslaw Wojcik
Marek R. Baranowski
Lukasz Markiewicz
Dorota Kubacka
Marcelina Bednarczyk
Natalia Baran
Anna Wojtczak
Pawel J. Sikorski
Joanna Zuberek
Joanna Kowalska
Jacek Jemielity
Source :
Pharmaceutics, Vol 13, Iss 11, p 1941 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

Dinucleotide analogs of the messenger RNA cap (m7GpppN) are useful research tools and have potential applications as translational inhibitors or reagents for modification of in vitro transcribed mRNAs. It has been previously reported that replacing the methyl group at the N7-position with benzyl (Bn) produces a dinucleotide cap with superior properties. Here, we followed up on this finding by synthesizing 17 novel Bn7GpppG analogs and determining their structure–activity relationship regarding translation and translational inhibition. The compounds were prepared in two steps, including selective N7-alkylation of guanosine 5′-monophosphate by arylmethyl bromide followed by coupling with imidazole-activated GDP, with total yields varying from 22% to 62%. The compounds were then evaluated by determining their affinity for eukaryotic translation initiation factor 4E (eIF4E), testing their susceptibility to decapping pyrophosphatase, DcpS—which is most likely the major cellular enzyme targeting this type of compound—and determining their translation inhibitory properties in vitro. We also synthesized mRNAs capped with the evaluated compounds and tested their translational properties in A549 cells. Our studies identified N7-(4-halogenbenzyl) substituents as promising modifications in the contexts of either mRNA translation or translational inhibition. Finally, to gain more insight into the consequences at the molecular level of N7-benzylation of the mRNA cap, we determined the crystal structures of three compounds with eIF4E.

Details

Language :
English
ISSN :
19994923
Volume :
13
Issue :
11
Database :
Directory of Open Access Journals
Journal :
Pharmaceutics
Publication Type :
Academic Journal
Accession number :
edsdoj.31081b992c5141aa820199bd8e43fc38
Document Type :
article
Full Text :
https://doi.org/10.3390/pharmaceutics13111941