Tetrahydropyrido[4,3-d]pyrimidines as a new active scaffold for human topoisomerase II inhibitors

Human topoisomerase II (topoII) is a well-known and validated target for cancer treatment. We previously reported a first set of 6-amino-tetrahydroquinazoline derivatives as novel human topoII inhibitors. Here, we report on the expansion and this molecular scaffold and present 17 additional analogs centered on the tetrahydropyrido[4,3-d]pyrimidine heterocycle. Some of these compounds exhibit promising topoII inhibitory and antiproliferative activities. Compound 24 (ARN21929) shows good in vitro potency, with an IC50 of 4.5 ± 1.0 µM, excellent kinetic and thermodynamic solubility, and good metabolic stability. Our results indicate that this new chemical class of topoII inhibitors deserves further exploration and represents a promising starting point for developing novel and potentially safer topoII-targeted anticancer drugs.