Kinetics of the Imidazolium Ring-Opening of mRNA 5'-cap Analogs in Aqueous Alkali

Stachelska, Alicja; Wieczorek, Z; Stępiński, Janusz; Jankowska-Anyszka, Marzena; Lönnberg, Harri; Darżynkiewicz, Edward

doi:10.1135/cccc20060567

Cited by 3 publications

(1 citation statement)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 17 However, there have been no examples of modified cap analogs, most likely because of their limited chemical stability. The positively charged N7-methylguanosine increases the rate of depurination reaction, 20 and it undergoes an imidazolium ring-opening side reaction 21 at high pH. In addition, decomposition of the 5′-5′-triphosphate bridge in alkaline or acidic environment limits its use for modification.…”

Section: Introductionmentioning

confidence: 99%

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,

Bednarczyk,

Sikorski

et al. 2023

J. Org. Chem.

View full text Add to dashboard Cite

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 m7G 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.

show abstract

Section: Introductionmentioning

confidence: 99%

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,

Bednarczyk,

Sikorski

et al. 2023

J. Org. Chem.

View full text Add to dashboard Cite

show abstract

Hydrolysis of 5′,5′-Tri- or Tetraphosphate-mRNA 5′-cap Analogs Promoted by Cu²⁺or Zn²⁺Metal Ions

Stachelska-Wierzchowska

Wieczorek

2011

Nucleosides, Nucleotides and Nucleic Acids

View full text Add to dashboard Cite

Kinetics of the hydrolysis of a P(1)-(7-methylguanosinyl-5') P(3)-(guanosinyl-5') triphosphate (m(7)GpppG), P(1)-(7-methylguanosinyl-5') P(4)- (guanosinyl-5') tetraphosphate (m(7)GppppG), diadenosine-5',5'''-P(1),P(3)-triphosphate (ApppA), and diadenosine-5',5'''-P(1),P(4)-tetraphosphate (AppppA) promoted by Cu(2+) or Zn(2+) has been investigated. Time-dependent products distributions at various metal ion concentrations have been determined by CZE and HPLC-RP. The results show that in acidic conditions, in the presence of metal ion, the predominant hydrolytic reaction is the cleavage of 5',5'-oligophosphate bridge. The 5',5'-oligophosphate bridge of the dinucleotides studied is hydrolyzed by Cu(2+) more efficiently than by Zn(2+). At the catalyst concentration of 2 mM the cleavage of the 5',5'-triphosphate bridge of m(7)GpppG was ∼3.6 times faster, and that of the tetraphosphate bridge of m(7)GppppG ∼2.3-fold faster in the presence of Cu(2+) compared to the Zn(2+) ion, applied as catalysts. Dependence of the rates of hydrolysis on the catalyst concentration was in some instances not linear, interpreted as evidence for participation of more than one metal ion in the transition complex.

show abstract

The Hydrolysis of 5′-CAP Dinucleotide Analogs: Catalysis by Bi- and Terpyridine Complexes of Cu²⁺and Zn²⁺Ions

Stachelska-Wierzchowska

Wieczorek

Wierzchowski

2012

Nucleosides, Nucleotides and Nucleic Acids

View full text Add to dashboard Cite

The kinetics of the hydrolysis of P(1)-(7-methylguanosinyl-5') P(3)-(guanosinyl-5') triphosphate (m(7)GpppG), P(1)-(7-methylguanosinyl-5') P(4)-(guanosinyl-5') tetraphosphate (m(7)GppppG), and diadenosine 5', 5'( ')-P(1),P(3) -triphosphate (ApppA) in the presence of several Cu(2+) or Zn(2+) ions complexed with bi- or terpyridine has been studied at pH 8.0 and 60 °C. Time-dependent product distributions at various metal complex concentrations have been determined by capillary zone electrophoresis and reversed-phase high performance liquid chromatography. The results show that the predominant hydrolytic reaction is the cleavage of 5',5'-oligophosphate bridge, with Cu(2+) complexes being approximately 15-fold more efficient catalysts than Zn(2+) chelates. In addition, the effect of metal ions complexes at pH 7.0 and 8.0 on the imidazole ring opening in m(7)Gua mononucleotides has been studied. The influence of Cu(2+) complexes on imidazole ring cleavage of mononucleotides is modest, whereas Zn(2+) complexes are almost inactive.

show abstract

Kinetics of the Imidazolium Ring-Opening of mRNA 5'-cap Analogs in Aqueous Alkali

Cited by 3 publications

References 27 publications

Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors

Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors

Hydrolysis of 5′,5′-Tri- or Tetraphosphate-mRNA 5′-cap Analogs Promoted by Cu²⁺or Zn²⁺Metal Ions

The Hydrolysis of 5′-CAP Dinucleotide Analogs: Catalysis by Bi- and Terpyridine Complexes of Cu²⁺and Zn²⁺Ions

Contact Info

Product

Resources

About

Kinetics of the Imidazolium Ring-Opening of mRNA 5'-cap Analogs in Aqueous Alkali

Cited by 3 publications

References 27 publications

Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors

Synthesis and Evaluation of Diguanosine Cap Analogs Modified at the C8-Position by Suzuki–Miyaura Cross-Coupling: Discovery of 7-Methylguanosine-Based Molecular Rotors

Hydrolysis of 5′,5′-Tri- or Tetraphosphate-mRNA 5′-cap Analogs Promoted by Cu2+or Zn2+Metal Ions

The Hydrolysis of 5′-CAP Dinucleotide Analogs: Catalysis by Bi- and Terpyridine Complexes of Cu2+and Zn2+Ions

Contact Info

Product

Resources

About

Hydrolysis of 5′,5′-Tri- or Tetraphosphate-mRNA 5′-cap Analogs Promoted by Cu²⁺or Zn²⁺Metal Ions

The Hydrolysis of 5′-CAP Dinucleotide Analogs: Catalysis by Bi- and Terpyridine Complexes of Cu²⁺and Zn²⁺Ions