Adamantylsulfanyl- and N-adamantylcarboxamido-derivatives of heterocycles and phenols: synthesis, crystal structure, tumor necrosis factor-alpha production-enhancing properties, and theoretical considerations.

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 alpha (TNF-alpha) in genetically modified murine melanoma cells transduced with the gene for human TNF-alpha. 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-alpha 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.