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

Abstract

The diastereoselective porphyrin‐sensitized singlet oxygen ene reaction of allylic alcohol (I) gives the key precursor (II), which can be easily converted into the title trioxane derivatives.

Synthetic Approaches to Mono- and Bicyclic Perortho-Esters with a Central 1,2,4-Trioxane Ring as the Privileged Lead Structure in Antimalarial and Antitumor-Active Peroxides and Clarification of the Peroxide Relevance

“…In recent publications, we have also demonstrated the new potential of cyclic peroxides from the 1,2,4-trioxane family to inhibit certain glutathione transferases (GSTs), an important class of detoxification enzymes that are upregulated by tumor cells [ 44 , 45 ]. In order to demonstrate the relevance of the central peroxide ring system, we designed the synthesis of a 1,3-dioxane 15 ( Scheme 7 ) that is structurally related to the biologically active 1,2,4-trioxane 11 (pNP = 4-nitrophenyl) [ 44 ].…”

A General and Practical Approach for the Synthesis of 1,2,4‐Trioxanes Catalyzed by Silica‐Ferric Chloride

“…Among them, 1,2,4‐trioxanes have been attracting considerable interest of researchers in the fields of medicinal chemistry and pharmacology since the 1,2,4‐trioxane structural motif was found to be the core structure in artemisinin – the active pharmacophore against both chloroquinine‐sensitive and chloroquinine‐resistant malaria (Figure ) . Due to the fascinating biological activities of these structural compounds, some synthetic methods have been developed to construct 1,2,4‐trioxanes, for example, (i) rearrangements of ketodioxetanes, (ii) photochemical reaction of β‐ionone derivatives in the presence of oxygen, (iii) the reaction of endoperoxides with cyclohexanones, (iv) the photooxidation of enol ethers with oxygen followed by rearrangement of the resulting 1,2‐dioxetanes in the presence of trialkylsilyl triflates, (iv) the photo‐oxygenation of dihydropyrans, and (v) the condensation of β‐hydroxy hydroperoxides with carbonyl compounds in the presence of acid catalysts such as hydrochloric acid, p ‐toluenesulfonic acid ( p ‐TSA), 10‐camphorsulfonic acid (CSA), pyridinium p ‐toluenesulfonate (PPTS) and boron trifluoride . However, some of these synthetic methods suffer from certain constraints such as use of large amounts of strong acid, unsatisfactory yields, long reaction times, poorly accessible starting materials or narrow substrate scope, and this limits the application of these methods for large‐scale synthesis for 1,2,4‐trioxanes.…”

ADUC Prizes: A. Andrieu‐Brunsen, I. Siewert, and T. Magauer / Carl Duisberg Memorial Prize: F. R. Fischer / Honorary Membership of the Gesellschaft Deutscher Chemiker: D. Jahn / Windaus Medal and Herbert C. Brown Award: A. Fürstner / Gottfried Wilhelm Leibniz Prize: B. List / Rottendorf Prize: M. Pietsch / Seymour Schulich Lectureship Award: M. T. Reetz / Akademiepreis für Chemie: M. Schnell

“…Pietsch's research is focused on disease‐related enzymes and protein–protein interactions. His report on selective inhibitors of glutathione transferase P1 was featured on a cover of ChemMedChem , and he has also reported in the European Journal of Organic Chemistry on peroxidic glutathione transferase inhibitors …”