Guided Antitumoural Drugs: (Imidazol‐2‐ylidene)(L)gold(I) Complexes Seeking Cellular Targets Controlled by the Nature of Ligand L
| Autor: | Lucas R. Carnell, Leonhard Köhler, Madeleine Gold, Tobias Rehm, Bernhard Biersack, Sebastian W. Schleser, Alexander Bär, Sofia I. Bär, Rainer Schobert |
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| Rok vydání: | 2021 |
| Předmět: |
Stereochemistry
Thioredoxin reductase Antineoplastic Agents Mitochondrion Ligands 010402 general chemistry 01 natural sciences Catalysis drug discovery chemistry.chemical_compound Coordination Complexes Cell Line Tumor cancer Ligand Effects Cytotoxicity chemistry.chemical_classification Reactive oxygen species Full Paper subcellular localisation 010405 organic chemistry Chemistry Ligand Organic Chemistry General Chemistry Full Papers gold 0104 chemical sciences Pharmaceutical Preparations metallodrugs Cancer cell Drug Screening Assays Antitumor Carbene DNA |
| Zdroj: | Chemistry (Weinheim an Der Bergstrasse, Germany) |
| ISSN: | 1521-3765 0947-6539 |
| DOI: | 10.1002/chem.202005451 |
| Popis: | Three [1,3‐diethyl‐4‐(p‐methoxyphenyl)‐5‐(3,4,5‐trimethoxyphenyl)imidazol‐2‐ylidene](L)gold(I) complexes, 4 a (L=Cl), 5 a (L=PPh3), and 6 a (L=same N‐heterocyclic carbene (NHC)), and their fluorescent [4‐(anthracen‐9‐yl)‐1,3‐diethyl‐5‐phenylimidazol‐2‐ylidene](L)gold(I) analogues, 4 b, 5 b, and 6 b, respectively, were studied for their localisation and effects in cancer cells. Despite their identical NHC ligands, the last three accumulated in different compartments of melanoma cells, namely, the nucleus (4 b), mitochondria (5 b), or lysosomes (6 b). Ligand L was also more decisive for the site of accumulation than the NHC ligand because the couples 4 a/4 b, 5 a/5 b, and 6 a/6 b, carrying different NHC ligands, afforded similar results in cytotoxicity tests, and tests on targets typically found at their sites of accumulation, such as DNA in nuclei, reactive oxygen species and thioredoxin reductase in mitochondria, and lysosomal membranes. Regardless of the site of accumulation, cancer cell apoptosis was eventually induced. The concept of guiding a bioactive complex fragment to a particular subcellular target by secondary ligand L could reduce unwanted side effects. Striking gold: Through the choice of their secondary ligand L, a series of [4,5‐diarylimidazol‐2‐ylidene](L)gold(I) complexes targeted different cancer cell organelles (nuclei, mitochondria or lysosomes) where they interfered beneficially with molecular targets, such as DNA, thioredoxin reductase, or lysosomal membranes, to elicit p53‐independent apoptosis. Such guided metallodrugs will help to minimise unwanted side effects by addressing limited arrays of targets. |
| Databáze: | OpenAIRE |
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