STRUCTURE - CYTOTOXICITY RELATIONSHIPS OF SOME HELENANOLIDE-TYPE SESQUITERPENE LACTONES

This study deals with the cytotoxicity of helenanolide-type (10 alpha- methylpseudoguaianolide) sesquiterpene lactones. We determined the inf luence of substitution patterns on the toxicity of 21 helenanolides to a cloned Ehrlich ascites tumor cell line, EN2. Within a series of hel enalin esters, the acetate (2) and isobutyrate (3) were more toxic tha n helenalin itself (1). Esters with larger acyl groups (tiglate 4 and isovalerate 5) exhibited a decreased toxicity compared with the parent alcohol (1). Similar relationships were observed between the 6,8-dias tereomer of helenalin, mexicanin I (6) and its acetate (7) and isovale rate (8). In contrast, cytotoxicity within a series of 11 alpha,13-dih ydrohelenalin esters (9-12) was shown to be directly related to the si ze and lipophilicity of the ester side chain, dihydrohelenalin (9) bei ng the least toxic compound in this group. Investigation of several 2, 3-dihydrohelenalin derivatives (13-21) with 2 alpha-hydroxy-4-oxo- and 2 alpha,4 alpha-dihydroxy- or -O-acyl-substituted cyclopentane rings (arnifolins and chamissonolides, respectively), for which no pharmacol ogical data have been reported so far, revealed further interesting in fluences of the substitution pattern on cytotoxicity. The results may be interpreted in terms of lipophilicity and steric effects on the acc essibility of the reactive sites considered responsible for biological activity.