Carborane derivatives of 1,2,3-triazole depolarize mitochondria by transferring protons through the lipid part of membranes
| Autor: | Alexei V. Shunaev, Yuri N. Antonenko, Valentina A. Ol'shevskaya, Alexander A. Shtil, Tatyana I. Rokitskaya, Victor V. Tatarskiy, Anton V. Makarenkov, Khailova Ls |
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| Rok vydání: | 2019 |
| Předmět: |
Boron Compounds
Protonophore Biophysics Triazole Mitochondria Liver 01 natural sciences Biochemistry Membrane Lipids 03 medical and health sciences chemistry.chemical_compound Animals Humans 030304 developmental biology Membrane Potential Mitochondrial Membrane potential 0303 health sciences Liposome Ion Transport Uncoupling Agents 010405 organic chemistry Biological membrane Biological activity Cell Biology Triazoles HCT116 Cells Mitochondria Rats 0104 chemical sciences Membrane chemistry Mitochondrial Membranes Carborane Protons K562 Cells |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Biomembranes. 1861:573-583 |
| ISSN: | 0005-2736 |
| Popis: | Boron containing polyhedra (carboranes) are three-dimensional delocalized aromatic systems. These structures have been shown to transport protons through lipid membranes and mitochondria. Conjugation of carboranes to various organic moieties is aimed at obtaining biologically active compounds with novel properties. Taking advantage of 1,2,3-triazoles as the scaffolds valuable in medicinal chemistry, we synthesized 1-(o-carboranylmethyl)-4-pentyl-1,2,3-triazole (c-triazole) and 1-(o-carboranylmethyl)-4-pentyl-1,2,3-triazolium iodide (c-triazolium). Both compounds interacted with model lipid membranes and exhibited a proton carrying activity in planar bilayers and liposomes in a concentration- and pH-dependent manner. Importantly, mechanisms of the protonophoric activity differed; namely, protonation-deprotonation reactions of the triazole and the o-carborane moieties were involved in the transport cycles of c-triazole and c-triazolium, respectively. At micromolar concentrations, c-triazole and c-triazolium stimulated respiration of isolated rat liver mitochondria and depolarized their membrane potential, with c-triazole being more potent. In living K562 (human chronic myelogenous leukemia) cells, both c-triazolium and c-triazole altered the mitochondrial membrane potential as determined by a decreased intracellular accumulation of the potential-dependent dye tetramethylrhodamine ethyl ester. Finally, cell viability testing demonstrated a cytotoxic potency of c-triazolium and, to a lesser extent, of c-triazole against K562 cells, whereas non-malignant fibroblasts were much less sensitive. In all tests, the reference boron-free benzyl-4-pentyl-1,2,3-triazole showed little-to-no effects. These results demonstrated that carboranyltriazoles carry protons across biological membranes, a property potentially important in anticancer drug design. |
| Databáze: | OpenAIRE |
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