title: Novel Type of Prodrug Activation through a Long-Range O,N-Acyl Transfer: A Case of Water-Soluble CREB Inhibitor.
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.
authors.affiliation: 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.
authors.forename: Bingbing X
authors.initials: BX
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Fuchun
authors.initials: F
authors.lastname: Xie
authors.affiliation: 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.
authors.forename: Qiuhua
authors.initials: Q
authors.lastname: Fan
authors.affiliation: Transmed Oncology , Cave Creek, Arizona 85327, United States.
authors.forename: Kerry M
authors.initials: KM
authors.lastname: Barnhart
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego , La Jolla, California 92093, United States.
authors.forename: Curtis E
authors.initials: CE
authors.lastname: Moore
authors.affiliation: Department of Chemistry and Biochemistry, University of California San Diego , La Jolla, California 92093, United States.
authors.forename: Arnold L
authors.initials: AL
authors.lastname: Rheingold
authors.affiliation: 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.
authors.forename: Xiangshu
authors.initials: X
authors.lastname: Xiao
keywords: CREB; O,N-acyl transfer; anticancer; prodrug; water-soluble inhibitor