The Synergistic Effect of N2 and N7 Modifications on the Inhibitory Efficacy of mRNA Cap Analogues

Abstract

In the fight against cancer, researchers have turned their attention to the eukaryotic initiation factor eIF4E, a protein whose increased level is strongly correlated with the development and progression of various types of cancer. Among the numerous strategies devised to tackle eIF4E overexpression, the use of 5′ end mRNA cap analogues has emerged as a promising approach. Here, we present new candidates as potent m7GMP analogues for inhibiting translation and interfacing with eIF4E. By employing an appropriate strategy, we synthesized doubly modified mono- and dinucleotide cap analogues, introducing simultaneous substituents at both the N7 and N2 positions of the guanine ring. This approach was identified as an effective and promising combination. Our findings reveal that these dual modifications increase the potency of the dinucleotide analogue, marking a significant advancement in the development of cancer therapeutics targeting the eIF4E pathway.