Selective Inhibitors of Glutathione Transferase P1 with Trioxane Structure as Anticancer Agents |
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Authors: | Maria Bräutigam Prof. Dr. Nicole Teusch Tobias Schenk Miriam Sheikh Rocky Z. Aricioglu Swantje H. Borowski Dr. Jörg‐Martin Neudörfl Prof. Dr. Ulrich Baumann Prof. Dr. Axel G. Griesbeck Dr. Markus Pietsch |
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Affiliation: | 1. Department of Pharmacology, Medical Faculty, University of Cologne, Gleuler Str. 24, 50931 Cologne (Germany);2. Institute of Organic Chemistry, Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Cologne (Germany);3. Bio‐Pharmaceutical Chemistry, Faculty of Applied Natural Sciences, Cologne University of Applied Sciences, CHEMPARK Leverkusen, E39, 51368 Leverkusen (Germany);4. Institute of Biochemistry, Department of Chemistry, University of Cologne, Otto‐Fischer‐Str. 12‐14, 50674 Cologne (Germany) |
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Abstract: | The response to chemotherapy in cancer patients is frequently compromised by drug resistance. Although chemoresistance is a multifactorial phenomenon, many studies have demonstrated that altered drug metabolism through the expression of phase II conjugating enzymes, including glutathione transferases (GSTs), in tumor cells can be directly correlated with resistance against a wide range of marketed anticancer drugs. In particular, overexpression of glutathione transferase P1 (GSTP1) appears to be a factor for poor prognosis during cancer therapy. Former and ongoing clinical trials have confirmed GSTP1 inhibition as a principle for antitumor therapy. A new series of 1,2,4‐trioxane GSTP1 inhibitors were designed via a type II photooxygenation route of allylic alcohols followed by acid‐catalyzed peroxyacetalization with aldehydes. A set of novel inhibitors exhibit low micromolar to high nanomolar inhibition of GSTP1, revealing preliminary SAR for further lead optimization. Importantly, high selectivity over another two human GST classes (GSTA1 and GSTM2) has been achieved. The trioxane GSTP1 inhibitors may therefore serve as a basis for the development of novel drug candidates in overcoming chemoresistance. |
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Keywords: | enzyme kinetics inhibitors peroxides photooxygenation transferases |
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