Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity
Open Access
- 20 March 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 63 (7), 3508-3521
- https://doi.org/10.1021/acs.jmedchem.9b01760
Abstract
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 sixteen 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, exhibit good solubility, metabolic (microsomal) stability, and promising cytotoxicity in three cancer cell lines (DU145, HeLa, A549). Compound 3f (ARN24139) is the most promising drug-like candidate, with a good pharmacokinetics profile in vivo. Our results indicate that this hybrid new chemical class of topoII poisons deserves further exploration, and that 3f is a favorable lead candidate as a topoII poison, meriting future studies to test its efficacy in in vivo tumor models.Funding Information
- Associazione Italiana per la Ricerca sul Cancro (23679)
This publication has 60 references indexed in Scilit:
- Mechanism of Generation of Therapy Related Leukemia in Response to Anti-Topoisomerase II AgentsInternational Journal of Environmental Research and Public Health, 2012
- Model for MLL translocations in therapy-related leukemia involving topoisomerase IIβ-mediated DNA strand breaks and gene proximityProceedings of the National Academy of Sciences, 2012
- Etoposide Quinone Is a Redox-Dependent Topoisomerase II PoisonBiochemistry, 2011
- Cleavage of Plasmid DNA by Eukaryotic Topoisomerase IIPublished by Springer Nature ,2009
- DNA topoisomerase II and its growing repertoire of biological functionsNature Reviews Cancer, 2009
- DNA topology and topoisomerasesBiochemistry and Molecular Biology Education, 2009
- The DNA cleavage reaction of topoisomerase II: wolf in sheep's clothingNucleic Acids Research, 2008
- Substituents on Etoposide That Interact with Human Topoisomerase IIα in the Binary Enzyme−Drug Complex: Contributions to Etoposide Binding and ActivityBiochemistry, 2008
- Roles of DNA topoisomerase II isozymes in chemotherapy and secondary malignanciesProceedings of the National Academy of Sciences, 2007
- Topoisomerase II−Drug Interaction Domains: Identification of Substituents on Etoposide That Interact with the EnzymeBiochemistry, 2007