Cancer selective metallocenedicarboxylates of the fungal cytotoxin illudin M.
Cancer selective metallocenedicarboxylates of the fungal cytotoxin illudin M.
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真菌细胞毒素隐球菌素 M 的癌症选择性茂金属二羧酸盐。
DOI：
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发表时间：
2011
影响因子：
7.3
通讯作者：
T. Mueller
中科院分区：
文献类型：
--
作者：
R. Schobert;Sebastian Seibt;K. Mahal;Aamir Ahmad;B. Biersack;K. Effenberger;S. Padhye;F. Sarkar;T. Mueller
从1，1 '-二茂铁二羧酸和高度和无差别细胞毒性真菌代谢物伊鲁菌素M（1）获得的二酯2a对一组8种癌细胞系显示出亚微摩尔IC（50）（72 h）值的抗增殖活性。化合物2a对非恶性人类包皮成纤维细胞（HF）的毒性比1小约40倍。类似物1，1 '-二茂烯二羧酸双（隐花烯基M）酯（2b）仅对MDA-MB-231和MCF-7/Topo乳腺癌和HL-60白血病细胞显示亚微摩尔IC（50）（72 h）值。在c-Jun N-末端激酶（JNK）或细胞外信号调节激酶（ERK）的抑制剂存在下的细胞毒性研究揭示，2a而不是2b针对HCT-116结肠癌细胞的高功效取决于活性JNK/ERK信号传导。一种新的伊鲁菌素M内酯5的抗癌活性较低，但其茂烯二酯6 b在HCT-116、MCF-7和HL-60白血病细胞中也达到了个位数微摩尔IC（50）（72 h）值，而不影响HF。化合物2a和6 b在高达25 mg/kg体重的单次剂量下被小鼠耐受，这是它们在生理条件下化学稳定的证据。当以高剂量重复给药时，化合物2a显示出可管理的体内毒性特征。
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.
有机金属抗癌化合物。
影响因子：
7.3
作者：
Gasser G;Ott I;Metzler-Nolte N
通讯作者：
Metzler-Nolte N
隐伞素作为抗癌药物的临床前评价。
影响因子：
11.2
作者：
Kelner,MJ;McMorris,TC;Beck,WT;Zamora,JM;Taetle,R
通讯作者：
Taetle,R