组织蛋白酶B激活的4-卤代秋水仙碱及其前药的设计、合成与抗肿瘤活性
Design, Synthesis, and Antitumor Activity of 4-Halocolchicines and Their Pro-drugs Activated by Cathepsin B.
作者信息
Yasobu Naoko, Kitajima Mariko, Kogure Noriyuki, Shishido Yoshiyuki, Matsuzaki Takeshi, Nagaoka Masato, Takayama Hiromitsu
机构信息
Graduate School of Pharmaceutical Sciences, Chiba University.
Yakult Central Institute for Microbiological Research.
出版信息
ACS Med Chem Lett. 2011 Mar 4;2(5):348-52. doi: 10.1021/ml100287y. eCollection 2011 May 12.
Abstract
Novel colchicine derivatives possessing various substituents at the C4 position were prepared. Among them, 4-halo derivatives 3-6 were found to exhibit higher activity against cancer cell lines (A549, HT29, HCT116) as well as on mice transplanted with the HCT116 human colorectal carcinoma cell line than colchicine (1). Further, utilizing the 4-substituted colchicines, we prepared pro-drugs having a dipeptide side chain and demonstrated that these pro-drugs were activated by cathepsin B, an enzyme overexpressed in tumor cells, and exhibited selective toxicity to the tumor cells.
摘要
制备了在C4位具有各种取代基的新型秋水仙碱衍生物。其中，发现4-卤代衍生物3-6对癌细胞系（A549、HT29、HCT116）以及对移植了HCT116人结肠癌细胞系的小鼠表现出比秋水仙碱（1）更高的活性。此外，利用4-取代秋水仙碱，我们制备了具有二肽侧链的前药，并证明这些前药被肿瘤细胞中过表达的组织蛋白酶B激活，对肿瘤细胞表现出选择性毒性。
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