Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznań, Poland.
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland.
Biomolecules. 2020 Jul 12;10(7):1039. doi: 10.3390/biom10071039.
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 (-, - and ) 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 and were also found to effectively overcome the resistance of the LoVo/DX cancer cell line.
聚醚离子载体是一组具有广泛生物活性的天然脂溶性生物分子，具有抗菌、抗癌等活性。在这方面，有三种似乎特别有趣，即拉沙洛西酸、莫能菌素和盐霉素，因为它们能够选择性地靶向各种来源的癌细胞，包括癌症干细胞。由于其强大的生物学活性和丰富的可用性，世界各地的一些研究小组已经成功地采用半合成方法生成了离子载体的原始衍生物。然而，一个研究得相对较少的途径是合成和功能评估它们的多价结构。因此，在本文中，我们描述了一系列聚醚离子载体的同型和异型二聚体的合成方法，其中（i）通过三唑键将两个盐霉素分子连接起来，或（ii）将盐霉素与拉沙洛西酸、莫能菌素或白桦脂酸结合形成“混合”二聚体结构。值得注意的是，所有 11 种产物都在体外针对六种癌细胞系（包括多柔比星耐药结肠腺癌 LoVo/DX 细胞系）进行了抗增殖活性测试；五种二聚体（-、-和-）被鉴定为比参考试剂（即母体化合物和常用的细胞毒性药物）更有效地针对各种类型的癌症进行选择性靶向。二聚体-和-也被发现能够有效地克服 LoVo/DX 癌细胞系的耐药性。
