Organic Chemistry Laboratory, University Bayreuth, 95447 Bayreuth, Germany.
J Med Chem. 2011 Sep 22;54(18):6177-82. doi: 10.1021/jm200359n. Epub 2011 Aug 30.
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.
从 1,1'-二茂铁二羧酸和高毒性、无选择性的真菌代谢产物伊鲁毒素 M（1）获得的二酯 2a，对八种癌细胞系的亚微摩尔 IC50（72 小时）值表现出抗增殖活性。化合物 2a 对非恶性人包皮成纤维细胞（HF）的毒性比 1 低约 40 倍。类似的双（伊鲁毒素 M）1,1'-钌二茂铁二羧酸酯（2b）仅对 MDA-MB-231 和 MCF-7/Topo 乳腺癌和 HL-60 白血病细胞表现出亚微摩尔 IC50（72 小时）值。在 c-Jun N-末端激酶（JNK）或细胞外信号调节激酶（ERK）抑制剂存在的情况下进行的细胞毒性研究表明，2a 对 HCT-116 结肠癌细胞的高效性，而不是 2b 的高效性，取决于活跃的 JNK/ERK 信号。一种新的伊鲁毒素 M 内酯 5 具有低抗癌活性，但它的钌二茂铁二酯 6b 对 HCT-116、MCF-7 和 HL-60 白血病细胞的 IC50（72 小时）值也达到了个位数微摩尔，而对 HF 没有影响。化合物 2a 和 6b 在高达 25mg/kg 体重的单剂量下，对小鼠没有产生任何症状，这证明它们在生理条件下化学性质稳定。当以高剂量重复给予时，化合物 2a 表现出可管理的体内毒性特征。
