title: Oncogenic MicroRNAs Biogenesis as a Drug Target: Structure-Activity Relationship Studies on New Aminoglycoside Conjugates.
abstract: 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.
authors.affiliation: University of Nice Sophia Antipolis, Institute of Chemistry of Nice, UMR7272 CNRS, Parc Valrose, 06100, Nice, France.
authors.forename: Duc Duy
authors.initials: DD
authors.lastname: Vo
authors.affiliation: University of Nice Sophia Antipolis, Institute of Chemistry of Nice, UMR7272 CNRS, Parc Valrose, 06100, Nice, France.
authors.forename: Thi Phuong Anh
authors.initials: TP
authors.lastname: Tran
authors.affiliation: University of Bordeaux, ARNA Laboratory, 33000, Bordeaux, France.|INSERM, U869, 33000, Bordeaux, France.
authors.forename: Cathy
authors.initials: C
authors.lastname: Staedel
authors.affiliation: University of Nice Sophia Antipolis, Institute of Chemistry of Nice, UMR7272 CNRS, Parc Valrose, 06100, Nice, France.
authors.forename: Rachid
authors.initials: R
authors.lastname: Benhida
authors.affiliation: University of Bordeaux, ARNA Laboratory, 33000, Bordeaux, France.|INSERM, U869, 33000, Bordeaux, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Darfeuille
authors.affiliation: University of Nice Sophia Antipolis, Institute of Chemistry of Nice, UMR7272 CNRS, Parc Valrose, 06100, Nice, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Di Giorgio
authors.affiliation: University of Nice Sophia Antipolis, Institute of Chemistry of Nice, UMR7272 CNRS, Parc Valrose, 06100, Nice, France. maria.duca@unice.fr.
authors.forename: Maria
authors.initials: M
authors.lastname: Duca
mesh_terms: D000617:Aminoglycosides / Q000737:chemistry*; D005075:Biological Evolution; D016503:Drug Delivery Systems; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D009328:Nebramycin / Q000031:analogs & derivatives / Q000737:chemistry; D009355:Neomycin / Q000737:chemistry; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000617:Aminoglycosides; D035683:MicroRNAs; D009328:Nebramycin; C011666:apramycin; D009355:Neomycin
keywords: RNA structures; biogenesis; cancer; inhibitors; microRNA