Melanoma-specific ferrocene esters of the fungal cytotoxin illudin M.

Abstract

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.

• Authors: Sebastian Knauer, Bernhard Biersack, Miroslava Zoldakova, Katharina Effenberger, Wolfgang Milius, Rainer Schobert
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 20 Issue 8 Pg. 676-81 (Sep 2009) ISSN: 1473-5741 [Electronic] England
• PMID: 19606019 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Esters
• Ferrous Compounds
• Metallocenes
• Polycyclic Sesquiterpenes
• Sesquiterpenes
• illudin M
• Caspase 9
• Glutathione
• ferrocene

Topics

• Antibiotics, Antineoplastic (chemistry, pharmacology)
• Apoptosis (drug effects)
• Caspase 9 (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Esters (chemistry)
• Ferrous Compounds (chemistry)
• Fibroblasts (cytology, drug effects)
• Glutathione (chemistry)
• Humans
• Melanoma (drug therapy)
• Metallocenes
• Molecular Conformation
• Molecular Structure
• Polycyclic Sesquiterpenes
• Sesquiterpenes (chemistry, pharmacology)
• Spectrophotometry, Ultraviolet
• Substrate Specificity