Program in Chemical Biology, Department of Chemical Physiology and Biochemistry, 3181 SW Sam Jackson Park Road, Portland, OR 97239, United States.
Program in Chemical Biology, Department of Chemical Physiology and Biochemistry, 3181 SW Sam Jackson Park Road, Portland, OR 97239, United States; Knight Cancer Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239, United States.
Bioorg Med Chem Lett. 2020 Oct 1;30(19):127455. doi: 10.1016/j.bmcl.2020.127455. Epub 2020 Jul 28.
cAMP-response element binding protein (CREB) is an oncogenic transcription factor implicated in many different types of cancer. We previously reported the discovery of 666-15 as a potent inhibitor of CREB-mediated gene transcription. In an effort to improve the aqueous solubility of 666-15, amino ester prodrugs 1 and 4 were designed and synthesized. Detailed chemical and biological studies of 1 and 4 revealed that a small portion of the prodrugs were converted into 666-15 through intermediate 3 instead of a long-range O,N-acyl transfer reaction that was initially proposed. These results provide unique insights into the activation of these ester prodrugs.
cAMP 反应元件结合蛋白（CREB）是一种致癌转录因子，与许多不同类型的癌症有关。我们之前报道了发现 666-15 是一种有效的 CREB 介导的基因转录抑制剂。为了提高 666-15 的水溶性，设计并合成了氨基酸酯前药 1 和 4。对 1 和 4 的详细化学和生物学研究表明，一小部分前药通过中间体 3转化为 666-15，而不是最初提出的长距离 O，N-酰基转移反应。这些结果为这些酯前药的激活提供了独特的见解。
