Braeutigam, Maria, Teusch, Nicole ORCID: 0000-0002-9030-1493, Schenk, Tobias, Sheikh, Miriam, Aricioglu, Rocky Z., Borowski, Swantje H., Neudoerfl, Joerg-Martin, Baumann, Ulrich, Griesbeck, Axel G. and Pietsch, Markus (2015). Selective Inhibitors of Glutathione Transferase P1 with Trioxane Structure as Anticancer Agents. ChemMedChem, 10 (4). S. 629 - 640. WEINHEIM: WILEY-V C H VERLAG GMBH. ISSN 1860-7187

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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 phaseII 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 transferaseP1 (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 typeII 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Braeutigam, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teusch, NicoleUNSPECIFIEDorcid.org/0000-0002-9030-1493UNSPECIFIED
Schenk, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sheikh, MiriamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aricioglu, Rocky Z.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borowski, Swantje H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neudoerfl, Joerg-MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumann, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Griesbeck, Axel G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pietsch, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-403567
DOI: 10.1002/cmdc.201402553
Journal or Publication Title: ChemMedChem
Volume: 10
Number: 4
Page Range: S. 629 - 640
Date: 2015
Publisher: WILEY-V C H VERLAG GMBH
Place of Publication: WEINHEIM
ISSN: 1860-7187
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PI CLASS GLUTATHIONE; S-TRANSFERASE; ETHACRYNIC-ACID; ISOZYME SPECIFICITY; DRUG-SENSITIVITY; PHASE-I; CANCER; TLK286; PLATINUM; ENZYMESMultiple languages
Chemistry, Medicinal; Pharmacology & PharmacyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40356

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