Synthesis and biological activities of a pH-dependently activated water-soluble prodrug of a novel hexacyclic camptothecin analog

被引：16

作者：

Ohwada, Jun ^{[1
]}

Ozawa, Sawako ^{[1
]}

Kohchi, Masami ^{[1
]}

Fukuda, Hiroshi ^{[1
]}

Murasaki, Chikako ^{[1
]}

Suda, Hitomi ^{[1
]}

Murata, Takeshi ^{[1
]}

Niizuma, Satoshi ^{[1
]}

Tsukazaki, Masao ^{[1
]}

Ori, Kazutomo ^{[1
]}

Yoshinari, Kiyoshi ^{[1
]}

Itezono, Yoshiko ^{[1
]}

Endo, Mika ^{[1
]}

Ura, Masako ^{[1
]}

Tanimura, Hiromi ^{[1
]}

Miyazaki, Yoko ^{[1
]}

Kawashima, Akira ^{[1
]}

Nagao, Shunsuke ^{[1
]}

Namba, Eitarou ^{[1
]}

Ogawa, Koutarou ^{[1
]}

Kobayashi, Kazuko ^{[1
]}

Okabe, Hisafumi ^{[1
]}

Umeda, Isao ^{[1
]}

Shimma, Nobuo ^{[1
]}

机构：

[1] Chugai Pharmaceut Co Ltd, Div Res, Kanagawa 2478530, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 10期

关键词：

Camptothecin analog; Topoisomerase I inhibitor; TP300; Antitumor agent; Water-soluble; Prodrug; Drug resistance; BCRP; ANTITUMOR-ACTIVITY; IRINOTECAN CPT-11; TOPOISOMERASE-I; METABOLITE; SN-38; GLUCURONIDATION; INHIBITION;

D O I：

10.1016/j.bmcl.2009.03.123

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (> 10 mg/ml), stable below pH 4 and rapidly generates 1 at physiological pH in vitro. The rapid (ca. < 1 min) 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. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：2772 / 2776

页数：5

共 47 条

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