Structure-antimicrobial activity relationships among the sesquiterpene lactones and related compounds

Thirty-six sesquiterpene lactones and related compounds were evaluated for antimicrobial activity against six strains of bacteria. The results obtained show that the beta unsubstituted cyclopentenone ring moiety contributes to moderate antimicrobial activity against Gram positive bacteria. The corresponding saturated compounds gave a more than ten-fold decrease in activity. The significant antimicrobial activity appears to be independent of the presence or absence of an α-methylene-γ-lactone moiety. A more than ten-fold diminution in antimicrobial activity was also observed when the beta position of the cyclopentenone ring was substituted. A similar result was found when the beta unsubstituted enone system was present in a six-membered ring. Enhanced activity was obtained by esterification of the hydroxyl group of helenalin as well as epoxidation of mexicanin-A.     

Selective inactivation of rabbit reticulocyte initiation factor eIF-3 by helenalin

Helenalin, a sesquiterpene lactone which reacts primarily with exposed sulfhydryl groups, was shown to be an effective inhibitor of protein synthesis in rabbit reticulocyte lysates. Optimal inhibition required a 30 min preincubation in the absence of any added thiol compound. β-Mercaptoethanol was more effective than reduced glutathione in protecting enzyme sulfhydryl groups from inactivation by helenalin. Using partially fractionated systems, it was possible to show that helenalin had no effect on the elongation reactions or on the formation of the ternary initiation complex. However, the conversion of the ternary complex to the 48 S initiation complex was strongly inhibited. In this assay, only the initiation factor(s) were sensitive to helenalin. Using an assay system which requires all the initiation factors for optimal activity it was possible to show that the 0–40% ammonium sulfate cut of intiation factors (containing eIF-3 and eIF-4B) was sensitive to helenalin, while the 40–50% ammonium sulfate cut (containing eIF-2 and eIF-5) was not. Both ammonium sulfate cuts were equally sensitive to inhibition by the sulfhydryl reagent N-ethylmaleimide. Three purified rabbit reticulocyte initiation factors were then tested in the same assay system. Only eIF-3 showed appreciable sensitivity to helenalin, while eIF-2, eIF-3 and eIF-4B were all sensitive to inactivation by N-ethylmaleimide. These data suggest that helenalin may possess a relatively high degree of specificity as a sulfhydryl reagent.