Novel Type of Prodrug Activation through a Long-Range O,N-Acyl Transfer: A Case of Water-Soluble CREB Inhibitor

作者：Li Bingbing X; Xie Fuchun; Fan Qiuhua; Barnhart Kerry M; Moore Curtis E; Rheingold Arnold L; Xiao Xiangshu^*

来源：ACS Medicinal Chemistry Letters, 2014, 5(10): 1104-1109.

DOI：10.1021/ml500330n

• CREB
• prodrug
• water-soluble inhibitor
• anticancer
• O,N-acyl transfer

CREB (cANIP 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,Nacyl 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.

• 出版日期2014-10