Melanoma-specific ferrocene esters of the fungal cytotoxin illudin M.
The unfavorable therapeutic index of the fungal cytotoxin illudin M was to be improved by covalent attachment of the redox modulator and phenyl isobiostere ferrocene. Esters of illudin M with ferrocenoic and 1,1'-ferrocenedioic acid were prepared, structurally characterised (X-ray), and tested for cytotoxicity [MTT assay, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide], induction of apoptosis (TUNEL assay; western blotting for caspase-9), and tumor specificity in cells of human HL-60 leukemia, human 518A2 melanoma, and in nonmalignant human foreskin fibroblasts. The diester of illudin M with 1,1'-ferrocenedioic acid was distinctly more antiproliferative and apoptosis inducing in the melanoma cells [half maximal inhibitory concentration, IC50(48 h) = 0.4+/-0.1 micromol/l] than in the HL-60 cells [IC50(48 h) = 3.0+/-1.6 micromol/l] and in the nonmalignant fibroblasts [IC50(48 h) = 3.7+/-1.9 micromol/l]. This corresponds to a doubling of the therapeutic index with respect to illudin M. The monoester of illudin M with ferrocenoic acid was nine times less efficacious in the cancer cells, when compared with the diester. In conclusion, the ferrocene diminishes the general toxicity of the illudin M moiety and increases its cell line specificity. The bis(illudinyl M) 1,1'-ferrocenedioate presumably operates by a synergistic, two-pronged attack on its molecular targets.
Knauer
Sebastian
S
Chemisches Laboratorium der Universität Bayreuth, Bayreuth D-95447, Germany.
Biersack
Bernhard
B
Zoldakova
Miroslava
M
Effenberger
Katharina
K
Milius
Wolfgang
W
Schobert
Rainer
R
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004952:Esters / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D000075163:Metallocenes; D008968:Molecular Conformation; D015394:Molecular Structure; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology; D013056:Spectrophotometry, Ultraviolet; D013379:Substrate Specificity
D000903:Antibiotics, Antineoplastic; D004952:Esters; D005296:Ferrous Compounds; D000075163:Metallocenes; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; C052673:illudin M; D053453:Caspase 9; D005978:Glutathione; C004998:ferrocene