Kinetic Target-Guided Synthesis of Small-Molecule G-Quadruplex Stabilizers

0537196 - ÚOCHB 2021 RIV DE eng J - Journal Article
Pomeislová, Alice - Vrzal, Lukáš - Kozák, Jaroslav - Dobiaš, Juraj - Hubálek, Martin - Dvořáková, H. - Reyes Gutierrez, Paul Eduardo - Teplý, Filip - Veverka, Václav
Kinetic Target-Guided Synthesis of Small-Molecule G-Quadruplex Stabilizers.
ChemistryOpen. Roč. 9, č. 12 (2020), s. 1236-1250. ISSN 2191-1363. E-ISSN 2191-1363
R&D Projects: GA ČR(CZ) GA17-04393S; GA MŠMT(CZ) LO1304; GA MŠMT(CZ) LK11205; GA MŠMT(CZ) EF16_019/0000729
Institutional support: RVO:61388963
Keywords : anticancer therapy * click chemistry * G-quadruplex * NMR * secondary structures
OECD category: Organic chemistry
Impact factor: 2.911, year: 2020
Method of publishing: Open access
https://doi.org/10.1002/open.202000261

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.
Permanent Link: http://hdl.handle.net/11104/0316292