Novel type of prodrug activation through a long-range O,N-acyl transfer: A case of water-soluble CREB inhibitor

Bingbing X. Li, Fuchun Xie, Qiuhua Fan, Kerry M. Barnhart, Curtis E. Moore, Arnold L. Rheingold, Xiangshu Xiao

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)1104-1109
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume5
Issue number10
DOIs
StatePublished - Oct 9 2014

Fingerprint

Cyclic AMP Response Element-Binding Protein
Prodrugs
Solubility
Chemical activation
Water
Transcription
Amides
Hydroxyl Radical
Tumors
Neoplasms
Genes
Cells
Neoplasm Metastasis
Cell Line
Temperature

Keywords

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

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

Novel type of prodrug activation through a long-range O,N-acyl transfer : A case of water-soluble CREB inhibitor. / Li, Bingbing X.; Xie, Fuchun; Fan, Qiuhua; Barnhart, Kerry M.; Moore, Curtis E.; Rheingold, Arnold L.; Xiao, Xiangshu.

In: ACS Medicinal Chemistry Letters, Vol. 5, No. 10, 09.10.2014, p. 1104-1109.

Research output: Contribution to journalArticle

Li, Bingbing X. ; Xie, Fuchun ; Fan, Qiuhua ; Barnhart, Kerry M. ; Moore, Curtis E. ; Rheingold, Arnold L. ; Xiao, Xiangshu. / Novel type of prodrug activation through a long-range O,N-acyl transfer : A case of water-soluble CREB inhibitor. In: ACS Medicinal Chemistry Letters. 2014 ; Vol. 5, No. 10. pp. 1104-1109.
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