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.
journal_name
ACS Med Chem Lettjournal_title
ACS medicinal chemistry lettersauthors
Li BX,Xie F,Fan Q,Barnhart KM,Moore CE,Rheingold AL,Xiao Xdoi
10.1021/ml500330nsubject
Has Abstractpub_date
2014-08-22 00:00:00pages
1104-9issue
10issn
1948-5875journal_volume
5pub_type
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