Mechanistic insights into the activation of ester prodrugs of 666-15

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:30

Article

Xie, Fuchun¹  Martin-Acosta, Pedro¹  Li, Bingbing X.¹  Xiao, Xiangshu^1,2 

[1] Dept Chem Physiol & Biochem, Program Chem Biol, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97239 USA

[2] Oregon Hlth & Sci Univ, Knight Canc Inst, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97239 USA

关键词: CREB;    Cancer;    Inhibitor;    Prodrug;    Transcription;   

DOI  :  10.1016/j.bmcl.2020.127455

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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