| Literature DB >> 19362835 |
Jun Ohwada1, Sawako Ozawa, Masami Kohchi, Hiroshi Fukuda, Chikako Murasaki, Hitomi Suda, Takeshi Murata, Satoshi Niizuma, Masao Tsukazaki, Kazutomo Ori, Kiyoshi Yoshinari, Yoshiko Itezono, Mika Endo, Masako Ura, Hiromi Tanimura, Yoko Miyazaki, Akira Kawashima, Shunsuke Nagao, Eitarou Namba, Koutarou Ogawa, Kazuko Kobayashi, Hisafumi Okabe, Isao Umeda, Nobuo Shimma.
Abstract
CH0793076 (1) is a novel hexacyclic camptothecin analog showing potent antitumor activity in various human caner xenograft models. To improve the water solubility of 1, water-soluble prodrugs were designed to generate an active drug 1 nonenzymatically, thus expected to show less interpatient PK variability than CPT-11. Among the prodrugs synthesized, 4c (TP300, hydrochloride) having a glycylsarcosyl ester at the C-20 position of 1 is highly water-soluble (>10mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. <1min) generation of 1 after incubation of TP300 with plasma (mouse, rat, dog and monkey) was also demonstrated. TP300 showed a broader antitumor spectrum and more potent antitumor activity than CPT-11 in various human cancer xenograft models.Entities:
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Year: 2009 PMID： 19362835 DOI： 10.1016/j.bmcl.2009.03.123
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823