Synthesis and Anticancer Activity of Dimeric Polyether Ionophores

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.

Keywords: Huisgen 1,3-dipolar cycloaddition; SAR analysis; antiproliferative activity; betulinic acid; in vitro assay; multi-drug resistance; polyether ionophores; stereoselective reactions; tumor-specificity; ‘click’ chemistry.

Figure 1

(a) Structures of polyether ionophores studied in this work, and (b) the literature-known salinomycin homodimers conjugated via the C20 hydroxyl [29,30].

Scheme 1

Synthesis of precursors of (a) lasalocid acid, monensin, (b) betulinic acid, and (c) salinomycin, as the partners for further CuAAC reactions.

Scheme 2

Synthetic access to novel dimeric polyether ionophores.

Figure 2

Antiproliferative activity of tested compounds against (a) cancer cell lines, and (b) non-tumor cell lines, where LAS, MON, and SAL = sodium salt of lasalocid acid, monensin, and salinomycin, respectively, BET = betulinic acid, CIS = cisplatin, and DX = doxorubicin. Data are given as IC₅₀ in µM (mean ± SD).

Figure 3

The calculated values of the (a) selectivity indexes (SI) for BALB/3T3 (left side) and MCF10A (right side) non-tumor cell lines, and (b) resistance indexes (RI) of the tested compounds.