Synthesis and Anticancer Activity of Dimeric Polyether Ionophores
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 selec...
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MDPI AG
2020-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/10/7/1039 |
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| author | Michał Sulik Ewa Maj Joanna Wietrzyk Adam Huczyński Michał Antoszczak |
| author_facet | Michał Sulik Ewa Maj Joanna Wietrzyk Adam Huczyński Michał Antoszczak |
| author_sort | Michał Sulik |
| collection | DOAJ |
| description | 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 (<b>14</b>–<b>15</b>, <b>17</b>–<b>18</b> and <b>22</b>) 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 <b>16</b> and <b>21</b> were also found to effectively overcome the resistance of the LoVo/DX cancer cell line. |
| first_indexed | 2024-03-10T18:31:54Z |
| format | Article |
| id | doaj.art-bb06d2a205dc41d6a231e38ab2b864b5 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-10T18:31:54Z |
| publishDate | 2020-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-bb06d2a205dc41d6a231e38ab2b864b52023-11-20T06:34:11ZengMDPI AGBiomolecules2218-273X2020-07-01107103910.3390/biom10071039Synthesis and Anticancer Activity of Dimeric Polyether IonophoresMichał Sulik0Ewa Maj1Joanna Wietrzyk2Adam Huczyński3Michał Antoszczak4Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61–614 Poznań, PolandHirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53–114 Wrocław, PolandHirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53–114 Wrocław, PolandDepartment of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61–614 Poznań, PolandDepartment of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61–614 Poznań, PolandPolyether 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 (<b>14</b>–<b>15</b>, <b>17</b>–<b>18</b> and <b>22</b>) 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 <b>16</b> and <b>21</b> were also found to effectively overcome the resistance of the LoVo/DX cancer cell line.https://www.mdpi.com/2218-273X/10/7/1039polyether ionophoresbetulinic acidstereoselective reactionsHuisgen 1,3-dipolar cycloaddition‘click’ chemistryantiproliferative activity |
| spellingShingle | Michał Sulik Ewa Maj Joanna Wietrzyk Adam Huczyński Michał Antoszczak Synthesis and Anticancer Activity of Dimeric Polyether Ionophores Biomolecules polyether ionophores betulinic acid stereoselective reactions Huisgen 1,3-dipolar cycloaddition ‘click’ chemistry antiproliferative activity |
| title | Synthesis and Anticancer Activity of Dimeric Polyether Ionophores |
| title_full | Synthesis and Anticancer Activity of Dimeric Polyether Ionophores |
| title_fullStr | Synthesis and Anticancer Activity of Dimeric Polyether Ionophores |
| title_full_unstemmed | Synthesis and Anticancer Activity of Dimeric Polyether Ionophores |
| title_short | Synthesis and Anticancer Activity of Dimeric Polyether Ionophores |
| title_sort | synthesis and anticancer activity of dimeric polyether ionophores |
| topic | polyether ionophores betulinic acid stereoselective reactions Huisgen 1,3-dipolar cycloaddition ‘click’ chemistry antiproliferative activity |
| url | https://www.mdpi.com/2218-273X/10/7/1039 |
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