Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Braeutigam, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Teusch, Nicole UNSPECIFIED orcid.org/0000-0002-9030-1493 UNSPECIFIED Schenk, Tobias UNSPECIFIED UNSPECIFIED UNSPECIFIED Sheikh, Miriam UNSPECIFIED UNSPECIFIED UNSPECIFIED Aricioglu, Rocky Z. UNSPECIFIED UNSPECIFIED UNSPECIFIED Borowski, Swantje H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Neudoerfl, Joerg-Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumann, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Griesbeck, Axel G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Pietsch, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-408452
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:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PI CLASS GLUTATHIONE; S-TRANSFERASE; ETHACRYNIC-ACID; ISOZYME SPECIFICITY; DRUG-SENSITIVITY; PHASE-I; CANCER; TLK286; PLATINUM; ENZYMES Multiple languages Chemistry, Medicinal; Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/40845