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Adamantylsulfanyl‐ and N ‐Adamantylcarboxamido‐Derivatives of Heterocycles and Phenoles: Synthesis, Crystal Structure, Tumor Necrosis Factor‐ α Production‐Enhancing Properties, and Theoretical Considerations
Author(s) -
Maurin Jan Krzysztof,
Lasek Witold,
Górska Agata,
Świtaj Tomasz,
Jakubowska Anna Beata,
Kazimierczuk Zygmunt
Publication year - 2004
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200490110
Subject(s) - chemistry , pyridine , trifluoroacetic acid , steric effects , intramolecular force , stereochemistry , sulfanyl , crystal structure , medicinal chemistry , organic chemistry
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.