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Synthesis and Anticancer Activity of Dimeric Polyether Ionophores

1
Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61–614 Poznań, Poland
2
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53–114 Wrocław, Poland
*
Author to whom correspondence should be addressed.
Biomolecules 2020, 10(7), 1039; https://doi.org/10.3390/biom10071039
Received: 8 June 2020 / Revised: 9 July 2020 / Accepted: 10 July 2020 / Published: 12 July 2020
(This article belongs to the Section Natural and Bio-inspired Molecules)
Polyether ionophores represent a group of natural lipid-soluble biomolecules with a broad spectrum of bioactivity, ranging from antibacterial to anticancer activity. Three seem to be particularly interesting in this context, namely lasalocid acid, monensin, and salinomycin, as they are able to selectively target cancer cells of various origin including cancer stem cells. Due to their potent biological activity and abundant availability, some research groups around the world have successfully followed semi-synthetic approaches to generate original derivatives of ionophores. However, a definitely less explored avenue is the synthesis and functional evaluation of their multivalent structures. Thus, in this paper, we describe the synthetic access to a series of original homo- and heterodimers of polyether ionophores, in which (i) two salinomycin molecules are joined through triazole linkers, or (ii) salinomycin is combined with lasalocid acid, monensin, or betulinic acid partners to form ‘mixed’ dimeric structures. Of note, all 11 products were tested in vitro for their antiproliferative activity against a panel of six cancer cell lines including the doxorubicin resistant colon adenocarcinoma LoVo/DX cell line; five dimers (1415, 1718 and 22) were identified to be more potent than the reference agents (i.e., both parent compound(s) and commonly used cytostatic drugs) in selective targeting of various types of cancer. Dimers 16 and 21 were also found to effectively overcome the resistance of the LoVo/DX cancer cell line. View Full-Text
Keywords: polyether ionophores; betulinic acid; stereoselective reactions; Huisgen 1,3-dipolar cycloaddition; ‘click’ chemistry; antiproliferative activity; in vitro assay; tumor-specificity; multi-drug resistance; SAR analysis polyether ionophores; betulinic acid; stereoselective reactions; Huisgen 1,3-dipolar cycloaddition; ‘click’ chemistry; antiproliferative activity; in vitro assay; tumor-specificity; multi-drug resistance; SAR analysis
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MDPI and ACS Style

Sulik, M.; Maj, E.; Wietrzyk, J.; Huczyński, A.; Antoszczak, M. Synthesis and Anticancer Activity of Dimeric Polyether Ionophores. Biomolecules 2020, 10, 1039. https://doi.org/10.3390/biom10071039

AMA Style

Sulik M, Maj E, Wietrzyk J, Huczyński A, Antoszczak M. Synthesis and Anticancer Activity of Dimeric Polyether Ionophores. Biomolecules. 2020; 10(7):1039. https://doi.org/10.3390/biom10071039

Chicago/Turabian Style

Sulik, Michał, Ewa Maj, Joanna Wietrzyk, Adam Huczyński, and Michał Antoszczak. 2020. "Synthesis and Anticancer Activity of Dimeric Polyether Ionophores" Biomolecules 10, no. 7: 1039. https://doi.org/10.3390/biom10071039

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