title: 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.affiliation: Organic Chemistry Laboratory, University Bayreuth, 95447 Bayreuth, Germany. Rainer.Schobert@uni-bayreuth.de
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
authors.forename: Sebastian
authors.initials: S
authors.lastname: Seibt
authors.forename: Katharina
authors.initials: K
authors.lastname: Mahal
authors.forename: Aamir
authors.initials: A
authors.lastname: Ahmad
authors.forename: Bernhard
authors.initials: B
authors.lastname: Biersack
authors.forename: Katharina
authors.initials: K
authors.lastname: Effenberger-Neidnicht
authors.forename: Subhash
authors.initials: S
authors.lastname: Padhye
authors.forename: Fazlul H
authors.initials: FH
authors.lastname: Sarkar
authors.forename: Thomas
authors.initials: T
authors.lastname: Mueller
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004952:Esters; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005658:Fungi; D006801:Humans; D007501:Iron; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D000081223:Polycyclic Sesquiterpenes; D012428:Ruthenium; D012717:Sesquiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D056831:Coordination Complexes; D004952:Esters; D007783:Lactones; D000081223:Polycyclic Sesquiterpenes; D012717:Sesquiterpenes; C052673:illudin M; D012428:Ruthenium; D007501:Iron; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases