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 influence of substitution patterns on the toxicity of 21 helenanolides to a cloned Ehrlich ascites tumor cell line, EN2. Within a series of helenalin esters, the acetate (2) and isobutyrate (3) were more toxic than 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-diastereomer of helenalin, mexicanin I (6) and its acetate (7) and isovalerate (8). In contrast, cytotoxicity within a series of 11 alpha, 13-dihydrohelenalin esters (9-12) was shown to be directly related to the size and lipophilicity of the ester side chain, dihydrohelenalin (9) being 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 pharmacological data have been reported so far, revealed further interesting influences of the substitution pattern on cytotoxicity. The results may be interpreted in terms of lipophilicity and steric effects on the accessibility of the reactive sites considered responsible for biological activity.
Beekman
A C
AC
Department of Pharmaceutical Biology, University Centre for Pharmacy, Groningen Institute for Drug Studies, University of Groningen, The Netherlands.
Woerdenbag
H J
HJ
van Uden
W
W
Pras
N
N
Konings
A W
AW
Wikström
H V
HV
Schmidt
T J
TJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000302:isolation & purification* / Q000494:pharmacology; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004354:Drug Screening Assays, Antitumor; D007783:Lactones / Q000302:isolation & purification* / Q000494:pharmacology; D051379:Mice; D008961:Models, Structural; D008968:Molecular Conformation; D012717:Sesquiterpenes / Q000302:isolation & purification* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D007783:Lactones; D012717:Sesquiterpenes; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue