Oncogenic MicroRNAs Biogenesis as a Drug Target: Structure–Activity Relationship Studies on New Aminoglycoside Conjugates

MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post‐transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers and that the inhibition of these oncogenic miRNAs could find application in the therapy of different types of cancer. Herein, we describe the synthesis and biological evaluation of new small‐molecule drugs that target oncogenic miRNAs production. In particular, we chose to target two miRNAs (i.e., miRNA‐372 and ‐373) implicated in various types of cancer, such as gastric cancer. Their precursors (pre‐miRNAs) are overexpressed in cancer cells and lead to mature miRNAs after cleavage of their stem‐loop structure by the enzyme Dicer in the cytoplasm. Some of the newly synthesized conjugates can inhibit Dicer processing of the targeted pre‐miRNAs in vitro with increased efficacy relative to our previous results (D.D. Vo et al., ACS Chem. Biol. 2014 , 9, 711–721) and, more importantly, to inhibit proliferations of adenocarcinoma gastric cancer (AGS) cells overexpressing these miRNAs, thus representing promising leads for future drug development.