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

Lenz Lenz,Schmidt Schmidt,Krauth-Siegel Krauth-Siegel

doi:10.3390/molecules24203737

Lenz Lenz, Schmidt Schmidt + Show 1 more

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https://doi.org/10.3390/molecules24203737

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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.

Highlights

Sesquiterpene lactones (STLs) have, in many cases, been found to possess antiprotozoal activity.African trypanosomes (Trypanosoma brucei spp.), responsible for human African trypanosomiasis (HAT)appear to be sensitive to some sesquiterpene lactones (STL) [1,2,3]
The inhibitory activity of the 4,15-iso-atriplicolide esters on trypanothione reductase (TR) appears to be unique among the tested STLs, and cannot be a mere consequence of the presence of reactive Michael acceptor structures
The inactivity of two other furanoheliangolides, goyazensolide and budlein A, which are structurally very similar to the iso-atriplicolides, leads to the conclusion that the iso-atriplicolide scaffold with an exocyclic double bond between C-4 and C-15 enables these compounds to bind to the active center of TR in a specific manner

Summary

Introduction

Sesquiterpene lactones (STLs) have, in many cases, been found to possess antiprotozoal activity.African trypanosomes (Trypanosoma brucei spp.), responsible for human African trypanosomiasis (HAT)appear to be sensitive to some STLs [1,2,3]. T. brucei rhodesiense (Tbr, causing East African HAT) [4] and still ranges among the most active STLs against this parasites. We discovered several STLs of the furanoheliangolide type as potent trypanocides, namely, budlein A, goyazensolide and, most importantly, 4,15-iso-Atriplicolide tiglate [2] with IC50 values in a similar range or even lower than that of helenalin. The latter compound displayed an IC50 value of only 15 nM, and is currently the STL with the strongest anti-Tbr activity. Sesquiterpene lactones exert many of their biological activities by means of Michael-type additions of their reactive structure elements (mostly enone systems such as α,β-unsaturated lactone and ketone structures) to nucleophilic groups of their biological targets

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