Design and Synthesis of <i>O</i>‐Dialkylaminoalkyl Substituted Urolithin Derivatives: DNA Topoisomerase IIα Inhibition With Promising Antiproliferative Activity

Based on the pharmacophore structural characteristics of topoisomerase II (TopoII) inhibitors: (i) planar polyaromatic skeleton; (ii) the cation core; (iii) a groove-binding side chain moiety, 16 urolithin derivatives with O-dialkylaminoalkyl substitutions were designed and synthesized. Most of the synthesized compounds showed improved TopoIIα inhibitory and antiproliferative activities. 20 with the best TopoIIα inhibitory activity also exhibited excellent antiproliferative activity with IC₅₀ values of 0.91 ± 0.01, 1.93 ± 0.04, and 2.84 ± 0.34 μM against the MDA-MB-231, HeLa, and A549 cell lines, being about 12.55, 3.95, and 2.17 times more active than VP-16 (IC₅₀ 11.42 ± 0.82, 7.63 ± 0.46, and 6.15 ± 0.43 μM, respectively). Meanwhile, 20 exhibited weak toxicity to normal cells. In addition, 20 exerted anti-migration and anti-invasion activity against MDA-MB-231 cells. Our results supported that 20 might act as TopoIIα inhibitor with the potential to become a new type of antitumor drug lead.