Synthetic approaches to bis-adenosine derivatives as potential bisubstrates of RNA methyltransferases

The development of bisubstrate molecules mimicking the transition state of RNA methylation offers a promising approach for modulating post-transcriptional processes. In this study, five SAM-adenosine conjugates were synthesized, each incorporating a SAM cofactor analog linked to the <i>N</i>1 position of adenosine <i>via</i> triazole- and amide-based connectors. Cellular assays demonstrate that these compounds were not cytotoxic at 10 μM on SW620 and MCF-7 human cancer cell lines. Notably, one conjugate significantly affected several mRNA methylation processes in colorectal SW620 cells at this concentration. Furthermore, four compounds inhibited sphere formation in both cancer cell lines, underscoring their potential as tools to modulate RNA methylation in oncogenic contexts and guide the design of new therapeutic agents.