Natural Sesquiterpene Lactones of the 4,15-iso-Atriplicolide Type are Inhibitors of Trypanothione Reductase

Abstract

In the course of our investigations on the antitrypanosomal potential of sesquiterpene lactones (STL), we have recently reported on the exceptionally strong activity of 4,15-iso-Atriplicolide tiglate, which demonstrated an IC50 value of 15 nM against Trypanosoma brucei rhodesiense, the etiologic agent responsible for East African human trypanosomiasis (HAT). Since STLs are known to often interact with their biological targets (e.g., in anti-inflammatory and anti-tumor activity) by means of the covalent modification of biological nucleophiles—most prominently free cysteine thiol groups in proteins—it was a straightforward assumption that such compounds might interfere with the trypanothione-associated detoxification system of trypanosomes. This system heavily relies on thiol groups in the form of the dithiol trypanothione (T(SH)2) and in the active centers of enzymes involved in trypanothione metabolism and homeostasis. Indeed, we found in the present study that 4,15-iso-atriplicolide tiglate, as well as its structural homologues, the corresponding methacrylate and isobutyrate, are inhibitors of trypanothione reductase (TR), the enzyme serving the parasites to keep T(SH)2 in the dithiol state. The TR inhibitory activity was demonstrated to be time-dependent and irreversible. Quite interestingly, of the several further STLs with different core structures that were also tested, none inhibited TR at a significant level. Thus, the TR inhibitory effect by the 4,15-iso-atriplicolide esters appears to be specific for this particular type of furanoheliangolide-type STL. Some structure–activity relationships can already be deduced on the basis of the data reported here, which may serve as the starting point for searching further, possibly more potent, TR inhibitors.

F1012‐2 Induced ROS‐Mediated DNA Damage Response through Activation of MAPK Pathway in Triple‐Negative Breast Cancer

“…In order to further evaluate whether F1012-2 induces an increase in ROS levels, we pretreated with antioxidant N-acetyl-L-cysteine (NAC) for 2 hours and found that ROS was completely eliminated by NAC (Figure 3(b)). Recent studies have shown that sesquiterpene lactones can bind to nucleophilic thiol compounds, including L-cysteine [25], which may explain this phenomenon. 7 BioMed Research International to facilitate the repair of DNA or initiate the apoptosis mechanism when DNA damage cannot be repaired.…”

In Vitro, In Vivo, and In Silico Studies of Cumanin Diacetate as a Potential Drug against Trypanosoma cruzi Infection

“…In an attempt to explain other possible mechanisms of action of cumanin and its derivatives and taking into consideration that STLs have shown interaction with TcTR, ,− a molecular docking study of compounds 1 – 9 was carried out. The criteria of including all cumanin series were based on the wide range of IC 50 values obtained on T.…”

“…Other STLs such as deoxymikanolide and STLs of the 4,15-iso-atriplicolide type have affected or have shown inhibition of TcTR. 23,24 The most promising STLs, compounds 2 and 7, showed ΔG dock in the range of komaroviquinona, a terpenoid compound that was taken as a reference for the study. It was found that the residues Glu466B, Ser470B, and Arg472B were involved in H-bonding of the most active STLs.…”

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

“…Recently, furanoheliangolide-type STLs, characterized by the presence of Michael-acceptor structural motifs, were demonstrated to be endowed with high-level in vitro activity against Trypanosoma brucei rhodesiense [55]. In their work, Lenz and colleagues [56] studied the molecular basis of the activity of different furanoheliangolides. The STL 4,15-iso-atriplicolide tiglate and its homologues were demonstrated to inhibit trypanothione reductase (TR), an enzyme playing a critical role in the metabolism and survival of trypanosomatids.…”