Design, Synthesis, Dynamic Docking, Biochemical Characterization, and in Vivo Pharmacokinetics Studies of Novel Topoisomerase II Poisons with Promising Antiproliferative Activity | Zendy

José M. Arencibia | Zendy; Nicoletta Brindani | Zendy; Sebastián Franco-Ulloa | Zendy; Michela Nigro | Zendy; A. K. Jissy | Zendy; Giuliana Ottonello | Zendy; Sine Mandrup Bertozzi | Zendy; Maria Summa | Zendy; Stefania Girotto | Zendy; Rosalia Bertorelli | Zendy; Andrea Armirotti | Zendy; Marco De Vivo | Zendy

Open Access

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

Author(s) -

José M. Arencibia,

Nicoletta Brindani,

Sebastián Franco-Ulloa,

Michela Nigro,

A. K. Jissy,

Giuliana Ottonello,

Sine Mandrup Bertozzi,

Maria Summa,

Stefania Girotto,

Rosalia Bertorelli,

Andrea Armirotti,

Marco De Vivo

Publication year - 2020

Publication title -

journal of medicinal chemistry

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.01

H-Index - 261

eISSN - 1520-4804

pISSN - 0022-2623

DOI - 10.1021/acs.jmedchem.9b01760

Subject(s) - chemistry , in vivo , du145 , pharmacokinetics , etoposide , lipinski's rule of five , topoisomerase , docking (animal) , hela , combinatorial chemistry , pharmacology , in vitro , in silico , biochemistry , cancer cell , cancer , medicine , microbiology and biotechnology , surgery , nursing , chemotherapy , lncap , gene , biology

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 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.

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