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

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

  • Sci Rep. 2025 Jun 4;15(1):19618. doi: 10.1038/s41598-025-04773-z.
Nicoletta Brindani 1,  Maria Antonietta La Serra 2,  Jose Antonio Ortega 2,  Jose M Arencibia 2,  Michela Nigro 2,  Sine Mandrup Bertozzi 3,  Andrea Armirotti 2,  Marco Borgogno 2,  Claudia Sissi 4,  Marco De Vivo 5
Affiliations

Affiliations

  • 1 Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, via Morego 30, Genova, 16163, Italy. nicoletta.brindani@iit.it.
  • 2 Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, via Morego 30, Genova, 16163, Italy.
  • 3 Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego 30, Genova, 16163, Italy.
  • 4 Department of Pharmaceutical and Pharmacological Sciences, University of Padova, via F. Marzolo 5, Padova, 35131, Italy. claudia.sissi@unipd.it.
  • 5 Molecular Modeling and Drug Discovery Lab, Istituto Italiano di Tecnologia, via Morego 30, Genova, 16163, Italy. marco.devivo@iit.it.
PMID: 40467713 DOI: 10.1038/s41598-025-04773-z
Abstract

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.

Keywords

Cancer treatment; Tetrahydropyridopyrimidines derivatives.; Topoisomerase II inhibitors.

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