Synthesis of Bleomycin-Inspired RNA Ligands Targeting the Biogenesis of Oncogenic miRNAs

Noncoding RNAs (ncRNAs) play pivotal roles in the regulation
of
gene expression and represent a promising target for the development
of new therapeutic approaches. Among these ncRNAs, microRNAs (miRNAs
or miRs) are involved in the regulation of gene expression, and their
dysregulation has been linked to several diseases such as cancers.
Indeed, oncogenic miRNAs are overexpressed in cancer cells, thus promoting
tumorigenesis and maintenance of cancer stem cells that are resistant
to chemotherapy and often responsible for therapeutic failure. Here,
we describe the design and synthesis of new small-molecule RNA binders
able to inhibit the biogenesis of oncogenic miRNAs and target efficiently
cancer stem cells. Through the biochemical study of their interaction
with the target and thanks to intracellular assays, we describe the
structure–activity relationships for this new series of RNA
ligands, and we identify compounds bearing a very promising antiproliferative
activity against cancer stem cells.