Biotinylated selenocyanates: Potent and selective cytostatic agents.

Autor: Roldán-Peña JM; Organic Chemistry Department, Faculty of Chemistry, University of Seville, PO box 1203, E-41071 Seville, Spain., Puerta A; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain., Dinić J; Institute for Biological Research 'Siniša Stanković', National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia., Jovanović Stojanov S; Institute for Biological Research 'Siniša Stanković', National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia., González-Bakker A; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain., Hicke FJ; Organic Chemistry Department, Faculty of Chemistry, University of Seville, PO box 1203, E-41071 Seville, Spain., Mishra A; Department of Chemistry, Durham University, Lower Mountjoy, South Road, Durham DH1 3LE, UK., Piyasaengthong A; Department of Chemistry, Durham University, Lower Mountjoy, South Road, Durham DH1 3LE, UK; Bioscience Program, Faculty of Science, Kasetsart University, Bangkok 10900, Chatuchak, Thailand., Maya I; Organic Chemistry Department, Faculty of Chemistry, University of Seville, PO box 1203, E-41071 Seville, Spain., Walton JW; Department of Chemistry, Durham University, Lower Mountjoy, South Road, Durham DH1 3LE, UK., Pešić M; Institute for Biological Research 'Siniša Stanković', National Institute of the Republic of Serbia, University of Belgrade, Despota Stefana 142, 11060 Belgrade, Serbia. Electronic address: camala@ibiss.bg.ac.rs., Padrón JM; BioLab, Instituto Universitario de Bio-Orgánica 'Antonio González' (IUBO-AG), Universidad de La Laguna, Astrofísico Francisco Sánchez 2, E-38206 La Laguna, Spain. Electronic address: jmpadron@ull.es., Fernández-Bolaños JG; Organic Chemistry Department, Faculty of Chemistry, University of Seville, PO box 1203, E-41071 Seville, Spain. Electronic address: bolanos@us.es., López Ó; Organic Chemistry Department, Faculty of Chemistry, University of Seville, PO box 1203, E-41071 Seville, Spain. Electronic address: osc-lopez@us.es.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2023 Apr; Vol. 133, pp. 106410. Date of Electronic Publication: 2023 Feb 08.
DOI: 10.1016/j.bioorg.2023.106410
Abstrakt: Most of the currently available cytotoxic agents for tackling cancer are devoid of selectivity, thus causing severe side-effects. This situation stimulated us to develop new antiproliferative agents with enhanced affinity towards tumour cells. We focused our attention on novel chalcogen-containing compounds (thiosemicarbazones, disulfides, selenoureas, thio- and selenocyanates), and particularly on selenium derivatives, as it has been documented that this kind of compounds might act as prodrugs releasing selenium-based reactive species on tumour cells. Particularly interesting in terms of potency and selectivity was a pharmacophore comprised by a selenocyanato-alkyl fragment connected to a p-phenylenediamine residue, where the nature of the second amino moiety (free, Boc-protected, enamine-protected) provided a wide variety of antiproliferative activities, ranging from the low micromolar to the nanomolar values. The optimized structure was in turn conjugated through a peptide linkage with biotin (vitamin B 7 ), a cellular growth promoter, whose receptor is overexpressed in numerous cancer cells; the purpose was to develop a selective vector towards malignant cells. Such biotinylated derivative behaved as a very strong antiproliferative agent, achieving GI 50 values in the low nM range for most of the tested cancer cells; moreover, it was featured with an outstanding selectivity, with GI 50  > 100 µM against human fibroblasts. Mechanistic studies on the mode of inhibition of the biotinylated selenocyanate revealed (Annexin-V assay) a remarkable increase in the number of apoptotic cells compared to the control experiment; moreover, depolarization of the mitochondrial membrane was detected by flow cytometry analysis, and with fluorescent microscopy, what supports the apoptotic cell death. Prior to the apoptotic events, cytostatic effects were observed against SW1573 cells using label-free cell-living imaging; therefore, tumour cell division was prevented. Multidrug resistant cell lines exhibited a reduced sensitivity towards the biotinylated selenocyanate, probably due to its P-gp-mediated efflux. Remarkably, antiproliferative levels could be restored by co-administration with tariquidar, a P-gp inhibitor; this approach can, therefore, overcome multidrug resistance mediated by the P-gp efflux system.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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