Adamantylsulfanyl- and N-Adamantylcarboxamido-Derivatives of Heterocycles and Phenoles: Synthesis, Crystal Structure, Tumor Necrosis Factor-α Production-Enhancing Properties, and Theoretical Considerations
✍ Scribed by Jan Krzysztof Maurin; Witold Lasek; Agata Górska; Tomasz Świtaj; Anna Beata Jakubowska; Zygmunt Kazimierczuk
- Publisher
- John Wiley and Sons
- Year
- 2004
- Tongue
- English
- Weight
- 500 KB
- Volume
- 1
- Category
- Article
- ISSN
- 1612-1872
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✦ Synopsis
Abstract
The synthesis of several adamantylthio heterocycles and S‐adamantylated thiocresols is reported. The attack of the adamantyl cation formed from 1‐adamantan‐1‐ol in refluxing trifluoroacetic acid provides the corresponding adamantylsulfanyl compounds. The use of the adamantyl cation in the Ritter reaction gave the number of N‐adamantylcarboxamide derivatives of heterocyclic and phenolic compounds. Adamantylsulfanyl heterocycles, contrary to N‐adamantylcarboxamido compounds, enhanced the production of tumor necrosis factor α (TNF‐α) in genetically modified murine melanoma cells transduced with the gene for human TNF‐α. The highest activity, comparable to that of the most‐active previously described for 6‐methyl‐2‐[(adamantyl)amino]pyridine, showed 2‐thioadamantyl derivatives of pyridine and 6‐methylpyridine. The crystal structures of carboxamido and sulfanyl analogues of 2‐(1‐adamantylamino)pyridine have been studied, and consecutive quantum‐chemical calculations have been performed. The low TNF‐α production stimulatory activity of N‐adamantylcarboxamido‐pyridine compared to the sulfanyl and amino analogues is postulated to be linked to the conformational rigidity of the former one enhanced by the formation of the intramolecular H‐bond. The comparison of the activity of 2‐(1‐adamantylsulfanyl)‐6‐methylpyridine and (1‐adamantylsulfanyl)‐2‐methylbenzene proved the importance of the ring N‐atom, whereas the differences in activity between bromo and methyl analogues pointed at electronic rather than steric influence of __ortho‐__substituents on the biological activity.