The ability of hydroxy-thiol compounds, typified by 2-mercaptoethanol, to activate murine splenic lymphocytes was studied with respect to functional correlates of molecular structure. It was found that both the hydroxyl and sulfhydryl groups needed to be present on the same molecule in order to activate lymphocytes or to enhance activation by other substances. Oxidation of the thiol to a disulfide allowed the retention of lymphocyte activating properties, but eliminated the ability of the compound to enhance the responses to other agents. Replacement of the disulfide linkage with a carbon-carbon linkage, however, totally eliminated any biological activity of this compound. When the sulfhydryl and hydroxyl groups were separated by two intervening carbon atoms, the compound became effective at lower concentrations than when these groups were located on adjacent carbon atoms. This may indicate that the former molecule fits the activating site more closely, or that it passes through the membrane to arrive at that site more easily. In contrast, separation of the two functional groups by intervening carbon atoms decreased the ability of these compounds to enhance the response to other stimulants. In general, hydroxy-thiol compounds which are capable of activating lymphocytes in and of themselves, are toxic at high doses. Compounds which are not capable of such activation generally are not toxic at high concentrations.
