Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Larraufie, Marie-Helene¹  Yang, Wan Seok¹  Jiang, Elise²  Thomas, Ajit G.³  Slusher, Barbara S.^3,4  Stockwell, Brent R.^1,2,5 

[1] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

[2] Columbia Univ, Dept Chem, New York, NY 10027 USA

[3] Johns Hopkins Med, Brain Sci Inst, Baltimore, MD USA

[4] Johns Hopkins Med, Dept Neurol, Baltimore, MD USA

[5] Columbia Univ, Howard Hughes Med Inst, New York, NY 10027 USA

关键词: Reactive carbonyl;    Ferroptosis;    Covalent;    Erastin;    Metabolic stability;   

DOI  :  10.1016/j.bmcl.2015.07.018

来源: Elsevier

【 摘 要 】

Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a potentially useful strategy for enhancing compound potency. However, aldehydes are metabolically unstable, which precludes the use of this strategy for compounds to be tested in animal models or in human clinical studies. To overcome this limitation, we designed ketone-based functionalities capable of forming reversible covalent adducts, while displaying high metabolic stability, and imparting improved water solubility to their pendant scaffold. We tested this strategy on the ferroptosis inducer and experimental therapeutic erastin, and observed substantial increases in compound potency. In particular, a new carbonyl erastin analog, termed IKE, displayed improved potency, solubility and metabolic stability, thus representing an ideal candidate for future in vivo cancer therapeutic applications. (C) 2015 Published by Elsevier Ltd.

【 授权许可】

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