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J Med Chem. 2018 Nov 20. doi: 10.1021/acs.jmedchem.8b01023. [Epub ahead of print]

Polyheteroaryl Oxazole/Pyridine-based compounds selected in vitro as G-quadruplex ligands inhibit Rock kinase and exhibit antiproliferative activity.


Heptaheteroaryl compounds comprised of oxazole and pyridine units (TOxaPy) are quadruplex DNA (G4)-interactive compounds. Herein, we report on the synthesis of parent compounds bearing either amino side chains (TOxaPy-1-5) or featuring an isomeric oxazole-pyridine central connectivity (iso-TOxapy, iso-TOxapy 1-3) or a bipyridine core (iso-TOxabiPy). The new isomeric series showed significant G4-binding activity in vitro and remarkably 3 compounds (iso-TOxaPy, iso-TOxaPy-1, iso-TOxabiPy) exhibited high antiproliferative activity towards a tumor panel of cancer cell lines. However, these compounds do not behave as typical G-quadruplex binders and the kinase profiling assay revealed that the best antiproliferative molecule iso-TOxaPy selectively inhibited Rock-2. The targeting of Rock kinase was confirmed in cells by the dephosphorylation of Rock-2 substrates, the decrease of stress fibers and peripheral focal adhesions, as well as the induction of long neurite-like extensions. Remarkably two of these molecules were able to inhibit the growth of cells organized as spheroids.

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