2. Academic Validation
  3. N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H3 receptor and cancer resistance proteins

N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H3 receptor and cancer resistance proteins

  • Bioorg Med Chem Lett. 2020 Nov 15;30(22):127522. doi: 10.1016/j.bmcl.2020.127522.
Katarzyna Szczepańska 1,  Annamária Kincses 2,  Klaudia Vincze 2,  Ewa Szymańska 1,  Gniewomir Latacz 1,  Kamil J Kuder 1,  Holger Stark 3,  Gabriella Spengler 2,  Jadwiga Handzlik 4,  Katarzyna Kieć-Kononowicz 1
Affiliations

Affiliations

  • 1 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland.
  • 2 Department of Medical Microbiology and Immunobiology, Faculty of Medicine, University of Szeged, Dóm tér 10, 6720 Szeged, Hungary.
  • 3 Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-University Düsseldorf, Universitaetsstr. 1, 40225 Düsseldorf, Germany.
  • 4 Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, Kraków 30-688, Poland. Electronic address: j.handzlik@uj.edu.pl.
PMID: 32871268 DOI: 10.1016/j.bmcl.2020.127522
Abstract

Taking into account that multidrug resistance (MDR) is the main cause for chemotherapeutic failure in Cancer treatment, the ability of novel histamine H3 receptor ligands to reverse the Cancer MDR was evaluated, using the ABCB1 efflux pump inhibition assay in mouse MDR T-lymphoma cells. The most active compounds displayed significant cytotoxic and antiproliferative effects as well as a very potent MDR efflux pump inhibitory action, 3-5-fold stronger than that of reference inhibitor verapamil. Although these compounds possess weak antagonistic properties against histamine H3 receptors, they are valuable pharmacological tools in the search for novel Anticancer molecules. Furthermore, for the most active compounds, an insight into mechanisms of action using either, the luminescent Pgp-Glo™ Assay in vitro or docking studies to human Pgp, was performed.

Keywords

ABCB1; Antiproliferative; Cancer; Histamine H(3) receptor ligands; MDR efflux pumps; Piperazine; T-Lymphoma.

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