Institution: | 1. Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences Flemingovo nam. 2, Prague, Czech Republic
Department of Organic Chemistry, Charles University, Prague, Czech Republic
These authors contributed equally to this work;2. Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences Flemingovo nam. 2, Prague, Czech Republic
NMR laboratory, University of Chemistry and Technology, Prague, Czech Republic
These authors contributed equally to this work;3. Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences Flemingovo nam. 2, Prague, Czech Republic;4. NMR laboratory, University of Chemistry and Technology, Prague, Czech Republic |
Abstract: | The formation of a G-quadruplex motif in the promoter region of the c-MYC protooncogene prevents its expression. Accordingly, G-quadruplex stabilization by a suitable ligand may be a viable approach for anticancer therapy. In our study, we used the 4-(4-methylpiperazin-1-yl)aniline molecule, previously identified as a fragment library screen hit, as a template for the SAR-guided design of a new small library of clickable fragments and subjected them to click reactions, including kinetic target-guided synthesis in the presence of a G-quadruplex forming oligonucleotide Pu24. We tested the clickable fragments and products of click reactions for their G-quadruplex stabilizing activity and determined their mode of binding to the c-MYC G-quadruplex by NMR spectroscopy. The enhanced stabilizing potency of click products in biology assays (FRET, Polymerase extension assay) matched the increased yields of in situ click reactions. In conclusion, we identified the newly synthesized click products of bis-amino derivatives of 4-(4-methylpiperazin-1-yl)aniline as potent stabilizers of c-MYC G-quadruplex, and their further evolution may lead to the development of an efficient tool for cancer treatment. |