Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility
[Display omitted] 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 us...
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| Published in: | Bioorganic & medicinal chemistry letters Vol. 25; no. 21; pp. 4787 - 4792 |
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| Main Authors: | , , , , , |
| Format: | Journal Article |
| Language: | English |
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Elsevier Ltd
01-11-2015
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| Abstract | [Display omitted]
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. |
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| AbstractList | 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 future
in vivo
cancer therapeutic applications. 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. [Display omitted] 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. |
| Author | Slusher, Barbara S. Larraufie, Marie-Helene Stockwell, Brent R. Jiang, Elise Thomas, Ajit G. Yang, Wan Seok |
| AuthorAffiliation | d Department of Neurology, Johns Hopkins Medicine, Baltimore, United States b Department of Chemistry, Columbia University, New York, New York 10027, United States c Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States e Howard Hughes Medical Institute, Columbia University, New York, New York 10027, United States a Department of Biological Sciences, Columbia University, 550 West 120th Street, 1208 Northwest Corner Building, MC 4846 New York, New York 10027, United States |
| AuthorAffiliation_xml | – name: e Howard Hughes Medical Institute, Columbia University, New York, New York 10027, United States – name: c Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States – name: b Department of Chemistry, Columbia University, New York, New York 10027, United States – name: a Department of Biological Sciences, Columbia University, 550 West 120th Street, 1208 Northwest Corner Building, MC 4846 New York, New York 10027, United States – name: d Department of Neurology, Johns Hopkins Medicine, Baltimore, United States |
| Author_xml | – sequence: 1 givenname: Marie-Helene surname: Larraufie fullname: Larraufie, Marie-Helene organization: Department of Biological Sciences, Columbia University, 550 West 120th Street, 1208 Northwest Corner Building, MC 4846, New York, NY 10027, United States – sequence: 2 givenname: Wan Seok surname: Yang fullname: Yang, Wan Seok organization: Department of Biological Sciences, Columbia University, 550 West 120th Street, 1208 Northwest Corner Building, MC 4846, New York, NY 10027, United States – sequence: 3 givenname: Elise surname: Jiang fullname: Jiang, Elise organization: Department of Chemistry, Columbia University, New York, NY 10027, United States – sequence: 4 givenname: Ajit G. surname: Thomas fullname: Thomas, Ajit G. organization: Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States – sequence: 5 givenname: Barbara S. surname: Slusher fullname: Slusher, Barbara S. organization: Brain Science Institute, Johns Hopkins Medicine, Baltimore, United States – sequence: 6 givenname: Brent R. surname: Stockwell fullname: Stockwell, Brent R. email: bstockwell@columbia.edu organization: Department of Biological Sciences, Columbia University, 550 West 120th Street, 1208 Northwest Corner Building, MC 4846, New York, NY 10027, United States |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/26231156$$D View this record in MEDLINE/PubMed |
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| Keywords | Covalent Ferroptosis Erastin Metabolic stability Reactive carbonyl |
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Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent... Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a... |
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| SubjectTerms | Cell Line, Tumor Cell Proliferation - drug effects Covalent Dose-Response Relationship, Drug Erastin Ferroptosis Humans Ketones - chemistry Ketones - metabolism Metabolic stability Molecular Structure Piperazines - chemical synthesis Piperazines - chemistry Piperazines - pharmacology Reactive carbonyl Small Molecule Libraries - chemical synthesis Small Molecule Libraries - chemistry Small Molecule Libraries - pharmacology Solubility Structure-Activity Relationship Water - chemistry |
| Title | Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility |
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