Induction of lymphoproliferative popliteal lymph node reaction by hydantoin derivatives: structure-activity relationships.

We evaluated the ability of a series of 3-phenylhydantoin derivatives to induce a lymphoproliferative popliteal lymph node reaction in C57B1/6 mice. 5-Aryl-3-phenylhydantoins induced a significant lymphoproliferative reaction, whereas the 5-alkyl-substituted and the unsubstituted 3-phenylhydantoins did not. 5-Alkyl-3-phenylhydantoins were unable to induce a lymphoproliferative reaction, unlike the corresponding 5-alkyl-3-phenyl-2-thiohydantoins, which have been reported to induce a significant lymphoproliferative reaction in the same strain of mice. Based on these results, we suggest that, to induce a lymphoproliferative popliteal lymph node reaction, hydantoins have to bind covalently to proteins through the N-atoms if they are activated by electrophilic groups bound to the hydantoin ring. We also suggest that 2-thiohydantoins can bind through their S-atom, whereas hydantoins cannot do so through their O-atoms.