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<p>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 <b>24</b> (ARN21929) shows good in vitro potency, with an IC<sub>50</sub> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月4日

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  • Nicoletta Brindani,
  • Maria Antonietta La Serra,
  • Jose Antonio Ortega,
  • Jose M. Arencibia,
  • Michela Nigro,
  • Sine Mandrup Bertozzi,
  • Andrea Armirotti,
  • Marco Borgogno,
  • Claudia Sissi,
  • Marco De Vivo

摘要

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.