Design, Synthesis, Dynamic Docking, Biochemical Characterization, and Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity.

We previously reported a first set of hybrid topoisomerase II (topoII) poisons whose chemical core merges key pharmacophoric elements of etoposide and merbarone, which are two well-known topoII blockers. Here, we report on the expansion of this hybrid molecular scaffold and present 16 more hybrid derivatives that have been designed, synthesized, and characterized for their ability to block topoII and for their overall drug-like profile. Some of these compounds act as topoII poison and exhibit good solubility, metabolic (microsomal) stability, and promising cytotoxicity in three cancer cell lines (DU145, HeLa, A549). Compound (ARN24139) is the most promising drug-like candidate, with a good pharmacokinetics profile . Our results indicate that this hybrid new chemical class of topoII poisons deserves further exploration and that is a favorable lead candidate as a topoII poison, meriting future studies to test its efficacy in tumor models.