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Synthesis and Cytotoxic Activity of Lepidilines A–D: Comparison with Some 4,5-Diphenyl Analogues and Related Imidazole-2-thiones
[Image: see text] 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-...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society and American Society of Pharmacognosy
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8713287/ https://www.ncbi.nlm.nih.gov/pubmed/34808062 http://dx.doi.org/10.1021/acs.jnatprod.1c00797 |
Sumario: | [Image: see text] 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 Cs(2)CO(3) 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 PF(6) 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. |
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