Ferrocenyl 2,5-Piperazinediones as Tubulin-Binding Organometallic ABCB1 and ABCG2 Inhibitors Active against MDR Cells.
The tubulin-microtubule system is a common target of many anticancer drugs. However, the use of chemotherapeutics frequently leads to the development of a clinically relevant phenomenon of multidrug resistance (MDR). One of the basic mechanisms involved in MDR involves elevated expression and/or activity of several ATP-binding cassette superfamily members (ABC transporters) which are normally responsible for the efflux of xenobiotics or secondary metabolites outside the cell. Here we present the synthesis and biological characteristics of ferrocenyl analogues of plinabulin, i.e. one of the so-called "spindle poisons". We found that replacement of the phenyl group of plinabulin by the ferrocenyl moiety turns this compound into a potent inhibitor of ABCB1 and ABCG2, thus making it possible to overcome the multidrug resistance phenomenon. We also demonstrated that the alkyl group attached to the imidazole moiety of ferrocenyl analogues of plinabulin strongly affects their potency to inhibit tubulin polymerization.
Department of Organic Chemistry, Faculty of Chemistry, University of Łódź, Tamka 12, 91-403 Łódź, Poland; Cytometry Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź, Pomorska 141/143, 90-236 Łódź, Poland.
Anna
A
Wieczorek
Cytometry Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź , Pomorska 141/143, 90-236 Łódź, Poland.
Andrzej
A
Błauż
Department of Organic Chemistry, Faculty of Chemistry, University of Łódź , Tamka 12, 91-403 Łódź, Poland.
Janusz
J
Zakrzewski
Cytometry Lab, Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Łódź , Pomorska 141/143, 90-236 Łódź, Poland.
Błażej
B
Rychlik
Department of Organic Chemistry, Faculty of Chemistry, University of Łódź , Tamka 12, 91-403 Łódź, Poland.
Damian
D
Plażuk
ABCB1 inhibitor; ABCG2 inhibitor; Ferrocene; bioorganometallic chemistry; cancer; multidrug resistance