Li Bingbing X, Xie Fuchun, Fan Qiuhua, Barnhart Kerry M, Moore Curtis E, Rheingold Arnold L, Xiao Xiangshu
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.
Transmed Oncology , Cave Creek, Arizona 85327, United States.
ACS Med Chem Lett. 2014 Aug 22;5(10):1104-9. doi: 10.1021/ml500330n. eCollection 2014 Oct 9.
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.
CREB（环磷酸腺苷反应元件结合蛋白）已被证明在肿瘤起始、进展和转移中发挥重要作用。我们发现萘酚AS-E，一种可穿透细胞的CREB抑制剂，在体外多种癌细胞系中呈现出抗增殖活性。然而，它的水溶性有限。在本报告中，我们描述了一种具有体内抗癌活性的CREB介导基因转录的水溶性抑制剂（化合物6）。出乎意料的是，化合物6被发现是化合物12的前药，这需要前所未有的远程O，N-酰基转移。这种转移的速率取决于pH值和温度。据我们所知，这是首次表明远程O，N-酰基转移可被用作前药活化策略来提高水溶性。这种类型的前药可能适用于其他具有空间排列的羟基酰胺的结构，以改善它们的水溶性。
