Niizuma Satoshi, Tsukazaki Masao, Suda Hitomi, Murata Takeshi, Ohwada Jun, Ozawa Sawako, Fukuda Hiroshi, Murasaki Chikako, Kohchi Masami, Morikami Kenji, Yoshinari Kiyoshi, Endo Mika, Ura Masako, Tanimura Hiromi, Miyazaki Yoko, Takasuka Tsuyoshi, Kawashima Akira, Nanba Eitaro, Nakano Kounosuke, Ogawa Kotaro, Kobayashi Kazuko, Okabe Hisafumi, Umeda Isao, Shimma Nobuo
Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd, 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
Bioorg Med Chem Lett. 2009 Apr 1;19(7):2018-21. doi: 10.1016/j.bmcl.2009.02.031. Epub 2009 Feb 12.
Novel hexacyclic camptothecin analogs containing cyclic amidine, urea, or thiourea moiety were designed and synthesized based on the proposed 3D-structure of the topoisomerase I (Topo I)/DNA/camptothecin ternary complex. The analogs were prepared from 9-nitrocamptothecin via 7,9-diaminocamptothecin derivatives as a key intermediate. Among them, 7c exhibited in vivo antitumor activities superior to CPT-11 in human cancer xenograft models in mice at their maximum tolerated doses though its in vitro antiproliferative activity was comparable to SN-38 against corresponding cell lines.
基于拓扑异构酶I（Topo I）/DNA/喜树碱三元复合物的三维结构，设计并合成了含有环状脒、尿素或硫脲部分的新型六环喜树碱类似物。这些类似物以9-硝基喜树碱为原料，通过7,9-二氨基喜树碱衍生物作为关键中间体制备而成。其中，7c在小鼠人癌异种移植模型中，以最大耐受剂量给药时，体内抗肿瘤活性优于伊立替康，尽管其体外抗增殖活性与SN-38对相应细胞系的活性相当。
