Short and Efficient Synthesis of Alkyne‐Modified Amino Glycoside Building Blocks

Abstract

In the light of recent progress in RNA biology, the need for molecules that bind to RNA and thus may be suited to manipulating RNA-mediated processes is steadily increasing. We present a very short and efficient synthetic route to alkynemodified neamine and 2-deoxystreptamine derivatives on a half-gram scale. These derivatives are suitable for constructing a library of potential divalent RNA binders by cop-

The Tuberculosis Drug Streptomycin as a Potential Cancer Therapeutic: Inhibition of miR‐21 Function by Directly Targeting Its Precursor

“…Recently, Gumireddy et al [7] and Young et al reported the first use of small molecules as inhibitors of miRNA, specifically miR-21 and miR-122, function. [8] Independently, the group of Arenz has shown that kanamycin, [9,10] 2-deoxy-streptamine (2-DOS), and neamine [11] can block let-7 processing by binding to premiR and thus block Dicer activity. Lunse et al reported an aptamer that inhibits pri-miRNA processing by targeting the apical loop domain of pri-miRNA.…”

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

“…This latter was deprotected by using TFA in CH 2 Cl 2 to lead to final desired compound 6 a in 94 % yield. To obtain neamine‐ and 2‐DOS‐containing compounds, we prepared the alkyne derivatives of neamine and 2‐DOS, which had been previously described (i.e., 7 and 8 in Scheme B), and the azido derivative of nucleobase S (i.e., 9 in Scheme B). Again, a 1,3‐dipolar cycloaddition led to the desired protected compounds 6 b′ and 6 c′ in yields of 90 and 83 %, respectively.…”

Small-Molecule Approaches Toward the Targeting of Oncogenic Mirnas: Roadmap for the Discovery of Rna Modulators

“…By choosing DNA primers complementary to miRNAs, the production of miRNA resulting from pre-miRNAs after cleavage by Dicer is related to the induced polymerization reaction. This assay was applied to the same compounds described previously [57] confirming the IC 50 values found with the previous assay. Also, Maiti and co-workers succeeded in circumventing the possible interference of fluorescent labels on pre-miRNAs with Dicer processing by using a DNA beacon bearing the fluorophore and the quencher and complementary to the targeted miRNA sequence [62].…”

“…Aminoglycoside kanamycin B (15b), known to be a general RNA binder showed efficacy in inhibiting Dicer cleavage. This assay was then applied to a small set of aminoglycoside mimics with the most potent compound 21 (Figure 5) leading to inhibition of Dicermediated pre-let7-RNA maturation with an IC 50 of 0.65 μM [57]. Recently, our group has screened several classes of antibiotics (aminoglycosides, tetracyclines, macrolides, lincosamides as well as linezolid, chloramphenicol and puromycin) [58], as inhibitors of Dicer processing upon binding to four pre-miRNAs precursors of oncogenic miR-372, miR-373, miR-17 and miR-21 [59].…”

“…Cell-based HTS (luciferase reporter system) [54] 21 Let-7 Binding to pre-miRNA and inhibition of Dicer cleavage Cell-free assay (FRET-based assay) [57] …”