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Design, Synthesis, and Antitumor Activity of 4-Halocolchicines and Their Pro-drugs Activated by Cathepsin B

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journal contribution
posted on 12.05.2011, 00:00 by Naoko Yasobu, Mariko Kitajima, Noriyuki Kogure, Yoshiyuki Shishido, Takeshi Matsuzaki, Masato Nagaoka, Hiromitsu Takayama
Novel colchicine derivatives possessing various substituents at the C4 position were prepared. Among them, 4-halo derivatives 36 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.