Cancer selective metallocenedicarboxylates of the fungal cytotoxin illudin M.

Abstract

The diester 2a obtained from 1,1'-ferrocenedicarboxylic acid and the highly and indiscriminately cytotoxic fungal metabolite illudin M (1) displayed antiproliferative activity at submicromolar IC(50) (72 h) values against a panel of eight cancer cell lines. Compound 2a was about 40 times less toxic than 1 to nonmalignant human foreskin fibroblasts (HF). The analogous bis(illudinyl M) 1,1'-ruthenocenedicarboxylate (2b) exhibited submicromolar IC(50) (72 h) values only against MDA-MB-231 and MCF-7/Topo breast carcinoma and HL-60 leukemia cells. Cytotoxicity studies in the presence of inhibitors of c-Jun N-terminal kinase (JNK) or extracellular signal-regulated kinase (ERK) revealed that the high efficacy of 2a, but not that of 2b, against HCT-116 colon cancer cells depends on active JNK/ERK signaling. A new illudin M lactone 5 was of low anticancer activity, but its ruthenocene diester 6b also reached single-digit micromolar IC(50) (72 h) values in HCT-116, MCF-7, and HL-60 leukemia cells while not affecting HF. Compounds 2a and 6b were tolerated by mice symptom-free at single doses as high as 25 mg/kg body weight, which is evidence for them being chemically stable under physiological conditions. Compound 2a displayed a manageable in vivo toxicity profile when given repeatedly in high doses.

• Authors: Rainer Schobert, Sebastian Seibt, Katharina Mahal, Aamir Ahmad, Bernhard Biersack, Katharina Effenberger-Neidnicht, Subhash Padhye, Fazlul H Sarkar, Thomas Mueller
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 54 Issue 18 Pg. 6177-82 (Sep 22 2011) ISSN: 1520-4804 [Electronic] United States
• PMID: 21848340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Coordination Complexes
• Esters
• Lactones
• Polycyclic Sesquiterpenes
• Sesquiterpenes
• illudin M
• Ruthenium
• Iron
• Extracellular Signal-Regulated MAP Kinases
• JNK Mitogen-Activated Protein Kinases

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Coordination Complexes (chemical synthesis, chemistry, pharmacology)
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Esters
• Extracellular Signal-Regulated MAP Kinases (physiology)
• Fungi
• Humans
• Iron
• JNK Mitogen-Activated Protein Kinases (physiology)
• Lactones (chemical synthesis, chemistry, pharmacology)
• Mice
• Mice, Nude
• Polycyclic Sesquiterpenes
• Ruthenium
• Sesquiterpenes (chemical synthesis, chemistry, pharmacology)
• Signal Transduction
• Structure-Activity Relationship