title: Selective inhibitors of glutathione transferase P1 with trioxane structure as anticancer agents.
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.
authors.affiliation: Department of Pharmacology, Medical Faculty, University of Cologne, Gleuler Str. 24, 50931 Cologne (Germany); Institute of Organic Chemistry, Department of Chemistry, University of Cologne, Greinstr. 4, 50939 Cologne (Germany).
authors.forename: Maria
authors.initials: M
authors.lastname: Bräutigam
authors.forename: Nicole
authors.initials: N
authors.lastname: Teusch
authors.forename: Tobias
authors.initials: T
authors.lastname: Schenk
authors.forename: Miriam
authors.initials: M
authors.lastname: Sheikh
authors.forename: Rocky Z
authors.initials: RZ
authors.lastname: Aricioglu
authors.forename: Swantje H
authors.initials: SH
authors.lastname: Borowski
authors.forename: Jörg-Martin
authors.initials: JM
authors.lastname: Neudörfl
authors.forename: Ulrich
authors.initials: U
authors.lastname: Baumann
authors.forename: Axel G
authors.initials: AG
authors.lastname: Griesbeck
authors.forename: Markus
authors.initials: M
authors.lastname: Pietsch
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051549:Glutathione S-Transferase pi / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology
chemical_list: C503429:1,2,4-trioxane; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; C484555:GSTA1 protein, human; D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase
keywords: enzyme kinetics; inhibitors; peroxides; photooxygenation; transferases