Abstract
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 (14–15, 17–18 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.
Highlights
With more than 120 structures reported until now, naturally-occurring polyether ionophores constitute a group of products that are characterized by a very broad spectrum of bioactivity including antibacterial, antifungal, antiparasitic, and antiviral activity [1,2,3,4]
The synthesis of desired dimeric polyether ionophores began from the preparation of azide and the respective propargyl components (Scheme 1) as compatible partners for the CuAAC ‘click’ reactions
The terminal alkynes were synthesized from all polyether ionophores (i.e., lasalocid acid (LAS), monensin (MON), and salinomycin (SAL), and pentacyclic triterpenoid betulinic acid (BET)), and they included both N-propargyl amides and propargyl esters obtained through the chemical modification of carboxyl group of these biomolecules
Summary
With more than 120 structures reported until now, naturally-occurring polyether ionophores constitute a group of products that are characterized by a very broad spectrum of bioactivity including antibacterial, antifungal, antiparasitic, and antiviral activity [1,2,3,4]. Six of them have been approved for use in veterinary medicine, as they were found to effectively target Gram(+) bacterial strains in ruminants, and coccidial infections in poultry [2,5] In addition to their extensively explored antibiotic activity, recent studies have revealed that selected ionophores show significant anticancer properties. Interesting in this context seem to be the three multifunctional compounds lasalocid acid (LAS), monensin (MON), and salinomycin (SAL) (Figure 1a). The anticancer activity of SAL was originally reported in 2009, when this substance was identified as the most potent agent from ~16,000 compounds screened in the selective targeting of breast cancer stem cells (CSCs) [12]. Aside from its activity against breast cancer, SAL was found to be effective in destroying other drug-sensitive and drug-resistant cancer types [14]
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