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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, three compounds (iso-TOxaPy, iso-TOxaPy-1, and iso-TOxabiPy) exhibited high antiproliferative activity toward a tumor panel of cancer cell lines. However, these compounds do not behave as typical G-quadruplex (G4) 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.