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.

Model Studies on Peroxidic Glutathione Transferase (GST) Inhibitors: C5‐Methylated 1,2,4‐Trioxanes with C6‐Acrylate Side Chains

“…One of the first active compounds discovered from our set of antimalarial 1,2,4‐trioxanes was the acrylate derivative 11 ,20 which exhibited inhibition with an IC 50 value in the high micromolar range 12. In a detailed structure–activity study, we subsequently determined that modification at the ester terminus is crucial, and the introduction of a methyl p ‐hydroxybenzoate group in compound 12 increased the inhibition activity by two orders of magnitude 12. The question of the current study was of whether 1,2,4‐trioxane ring modification by alkylation at C‐5 would be relevant for GST inhibition.…”

“…GST Assay: Activity of hpGSTP1 was determined according to Bräutigam et al12 Briefly, the reaction between GSH (1 m M ) and CDNB (1 m M ) was followed at λ = 340 nm over a period of 5 min. Total rates obtained in the presence of hpGSTP1 (3 μg mL –1 , 8 , 9 ; 1 μg mL –1 , 11 , 12 ) were corrected by rates of the non‐enzymatic reaction between GSH and CDNB determined without the addition of enzyme.…”

“…All highly potent antimalarial 1,2,4‐trioxanes 1 from our previous synthetic approach are alkylated at position C‐5,11 whereas the first 1,2,4‐trioxanes showing GST inhibition – compounds 2 – are unalkylated at C‐5 and possess an acrylate group at C‐6 (Figure 1). 12 Thus, the aim of this project is to shed light upon the question of whether or not the combination of these two structural motifs might lead to an increase in the GST inhibitory efficacy.…”

Strong Asymmetry in the Perepoxide Bifurcation Mechanism: The Large‐Group Effect in the Singlet Oxygen Ene Reaction with Allylic Alcohols

“…Such an approach would open the route to 1,3‐hydroxy hydroperoxides whereas 1,2hydroxy hydroperoxides are routinely accessible by hydroxydirected 1 O 2 ene reactions . These compounds are versatile starting materials for the syntheses of biologically relevant 1,2,4‐trioxepanes and 1,2,4‐trioxanes …”

Spiroverknüpfte und ringanellierte 1,2,4‐Trioxepan‐, 1,2,4‐Trioxocan‐ und 1,2,4‐Trioxonan‐Cyclohexadienone: cyclische Peroxide mit ungewöhnlicher Ringkonformationsdynamik

“…B. [15] Die fürdiese Prozesse verwendete (homo)allylische Alkohol/ Singulett-Sauerstoff-Route über Allylhydroperoxide limitiert diese Reaktion jedoch auf 1,2,4-Trioxane [12] und siebengliedrige Analoga wie 3. [12] Außerdem wurden Dyaden (zusätzlich zu Hybriden oder dimeren Strukturen) [13] aus natürlichen Artemisininderivaten und synthetischen Trioxanen hergestellt.…”