Isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxylon.
Isolation and biochemical characterization of a new topoisomerase I inhibitor from Ocotea leucoxylon.
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DOI：
10.1021/np990442s
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发表时间：
2000-01
影响因子：
5.1
通讯作者：
Bing-Nan Zhou;Randall K. Johnson;Michael R. Mattern;Xiangyang Wang;Sidney M. Hecht;Hans T. Beck;A. Ortiz;David G. I. Kingston
中科院分区：
文献类型：
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作者：
Bing-Nan Zhou;Randall K. Johnson;Michael R. Mattern;Xiangyang Wang;Sidney M. Hecht;Hans T. Beck;A. Ortiz;David G. I. Kingston
在我们继续从植物中寻找潜在的肿瘤抑制物的过程中，我们发现Ocoteeleucoxylan的粗提物在酵母试验中显示出典型的拓扑异构酶I抑制剂的选择性活性，以检测DNA损伤剂。采用生物测定定向分离的方法，分离得到主要的生物活性成分，鉴定为阿朴吗啡生物碱双中心酮(4)，也分离出非活性生物碱双中心碱(3)。化合物4对RAD52修复缺陷酵母菌RS322(IC(12)和TOPO1缺陷菌株Rs321(IC(12)和GT；2000微克/毫升)和修复熟练菌株RJ03(IC(12)和TOPO1缺陷菌Rs321(IC(12)和GT；2000微克/毫升)没有活性。重组人拓扑异构酶I的生化研究表明，双中心酮(4)是人酶的抑制物。克隆形成研究表明，它具有微弱的细胞毒性，但其毒性机制与喜树碱及其衍生物不同。
In a continuation of our search for potential tumor inhibitors from plants, we found that a crude extract from Ocotea leucoxylon showed selective activity typical of inhibitors of the enzyme topoisomerase I in a yeast assay for DNA-damaging agents. Using a bioassay-directed fractionation approach, the major bioactive compound was isolated and identified as the known aporphine alkaloid dicentrinone (4); the inactive alkaloid dicentrine (3) was also isolated. Compound 4 showed selective bioactivity against the rad52 repair-deficient yeast strain RS322 (IC(12) 49 microg/mL) and was inactive against the rad52- and topo1-deficient strain RS321 (IC(12) > 2000 microg/mL) and against the repair-proficient strain RJ03 (IC(12) > 2000 microg/mL). Biochemical studies with recombinant human topoisomerase I indicated that dicentrinone (4) is an inhibitor of the human enzyme. Colony formation studies suggest that it is weakly cytotoxic, but that its mechanism of toxicity differs from that of camptothecin and its derivatives.