Biotinylated selenocyanates: Potent and selective cytostatic agents

Roldán-Peña, Jesús M.; Puerta, Adrián; Dinić, Jelena; Jovanović Stojanov, Sofija; González-Bakker, Aday; Hicke, Francisco J.; Mishra, Atreyee; Piyasaengthong, Akkharadet; Maya, Inés; Walton, James W.; Pešić, Milica; Padrón, José M.; Fernández-Bolaños, José G.; López, Óscar

Abstract

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 B7), 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 GI50 values in the low nM range for most of the tested cancer cells; moreover, it was featured with an outstanding selectivity, with GI50 > 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.

Citation

Roldán-Peña, J. M., Puerta, A., Dinić, J., Jovanović Stojanov, S., González-Bakker, A., Hicke, F. J., Mishra, A., Piyasaengthong, A., Maya, I., Walton, J. W., Pešić, M., Padrón, J. M., Fernández-Bolaños, J. G., & López, Ó. (2023). Biotinylated selenocyanates: Potent and selective cytostatic agents. Bioorganic Chemistry, 133, Article 106410. https://doi.org/10.1016/j.bioorg.2023.106410

• Journal Article Type: Article
• Acceptance Date: Feb 2, 2023
• Online Publication Date: Feb 8, 2023
• Publication Date: 2023-04
• Deposit Date: Mar 27, 2023
• Publicly Available Date: Feb 9, 2024
• Journal: Bioorganic Chemistry
• Print ISSN: 0045-2068
• Electronic ISSN: 1090-2120
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 133
• Article Number: 106410
• DOI: https://doi.org/10.1016/j.bioorg.2023.106410
• Public URL: https://durham-repository.worktribe.com/output/1177414