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

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

  • ACS Med Chem Lett. 2014 Aug 22;5(10):1104-9. doi: 10.1021/ml500330n.
Bingbing X Li 1,  Fuchun Xie 1,  Qiuhua Fan 1,  Kerry M Barnhart 2,  Curtis E Moore 3,  Arnold L Rheingold 3,  Xiangshu Xiao 4
Affiliations

Affiliations

  • 1 Program in Chemical Biology, Department of Physiology and Pharmacology, and Knight Cancer Institute, Oregon Health & Science University , 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States ; Program in Chemical Biology, Department of Physiology and Pharmacology, and Knight Cancer Institute, Oregon Health & Science University , 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
  • 2 Transmed Oncology , Cave Creek, Arizona 85327, United States.
  • 3 Department of Chemistry and Biochemistry, University of California San Diego , La Jolla, California 92093, United States.
  • 4 Program in Chemical Biology, Department of Physiology and Pharmacology, and Knight Cancer Institute, Oregon Health & Science University , 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States ; Program in Chemical Biology, Department of Physiology and Pharmacology, and Knight Cancer Institute, Oregon Health & Science University , 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States ; Program in Chemical Biology, Department of Physiology and Pharmacology, and Knight Cancer Institute, Oregon Health & Science University , 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, United States.
PMID: 25313320 DOI: 10.1021/ml500330n
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.

Keywords

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

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