Novel Type of Prodrug Activation through a Long-Range O,N-Acyl Transfer: A Case of Water-Soluble CREB Inhibitor
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- 作者：Bingbing X. Li ; Fuchun Xie ; Qiuhua Fan ; Kerry M. Barnhart ; Curtis E. Moore ; Arnold L. Rheingold ; Xiangshu Xiao
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2014
- 出版时间：October 9, 2014
- 年：2014
- 卷：5
- 期：10
- 页码：1104-1109
- 全文大小：386K
- ISSN：1948-5875
文摘
CREB (cAMP response element binding protein) has been shown to play an important role in tumor initiation, progression, and metastasis. We discovered that naphthol AS-E, a cell-permeable CREB inhibitor, presented antiproliferative activity in a broad panel of cancer cell lines in vitro. However, it has limited aqueous solubility. In this report, we described a water-soluble inhibitor (compound 6) of CREB-mediated gene transcription with in vivo anticancer activity. Unexpectedly, compound 6 was found to be a prodrug of compound 12 necessitating an unprecedented long-range O,N-acyl transfer. The rate of this transfer was pH- and temperature-dependent. To the best of our knowledge, this is the first time to show that a long-range O,N-acyl transfer could be exploited as a prodrug activation strategy to improve aqueous solubility. This type of prodrug may be applicable to other structures with spatially arranged hydroxyl amide to improve their aqueous solubility.