Abstract
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.
Original language | English (US) |
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Pages (from-to) | 1104-1109 |
Number of pages | 6 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 5 |
Issue number | 10 |
DOIs | |
State | Published - Oct 9 2014 |
Keywords
- CREB
- O, N -acyl transfer
- anticancer
- prodrug
- water-soluble inhibitor
ASJC Scopus subject areas
- Biochemistry
- Drug Discovery
- Organic Chemistry