Synthesis and Cytotoxic Activity of Lepidilines A–D: Comparison with Some 4,5-Diphenyl Analogues and Related Imidazole-2-thiones
| Autor: | Mateusz Kowalczyk, Katarzyna Gach-Janczak, Anna Janecka, Marcin Jasiński, Małgorzata Celeda, Grzegorz Mlostoń |
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| Rok vydání: | 2021 |
| Předmět: |
Base (chemistry)
Pharmaceutical Science Salt (chemistry) Crystallography X-Ray Medicinal chemistry Article Analytical Chemistry Structure-Activity Relationship chemistry.chemical_compound Bromide Hexafluorophosphate Drug Discovery Pyridine Humans Imidazole Deoxygenation Pharmacology chemistry.chemical_classification Biological Products Molecular Structure Organic Chemistry Imidazoles Thiones Complementary and alternative medicine chemistry MCF-7 Cells Molecular Medicine Counterion |
| Zdroj: | Journal of Natural Products |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.1c00797 |
| Popis: | A straightforward access to 2-unsubstituted imidazole N-oxides with subsequent deoxygenation by treatment with Raney-nickel followed by N-benzylation opens up a convenient route to lepidilines A and C. Both imidazolium salts were used to generate in situ the corresponding imidazol-2-ylidenes, which smoothly reacted with elemental sulfur, yielding imidazole-2-thiones. These reactions were performed either under classical conditions in pyridine solutions or mechanochemically using solid Cs2CO3 as a base. The structure of lepidiline C was unambiguously confirmed by X-ray analysis of its hexafluorophosphate. An analogous protocol toward lepidilines B and D and their 4,5-diphenyl analogues is less efficient due to observed instability of the key precursors, i.e., the respective 2-methylimidazole N-oxides. Comparison of cytotoxic activity against HL-60 and MCF-7 cell lines of all lepidilines, as well as their selected structural analogues (e.g., 4,5-diphenyl derivatives and PF6 salts), revealed slightly more potent activity of the 2-methylated series, irrespectively of the type of counterion present in the imidazolium salt. Remarkably, the well-known 1,3-diadamantylimidazolium bromide (the “Arduengo salt”), known as the precursor of the first, shelf-stable NHC representative, and its adamantyloxy analogue displayed the most significant cytotoxic activity in the studied series. |
| Databáze: | OpenAIRE |
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