2- and 3-Substituted 1,4-Naphthoquinone Derivatives as Subversive Substrates of Trypanothione Reductase and Lipoamide Dehydrogenase from Trypanosoma cruzi:  Synthesis and Correlation between Redox Cycling Activities and in Vitro Cytotoxicity

Abstract

Trypanothione reductase (TR) is both a valid and an attractive target for the design of new trypanocidal drugs. Starting from menadione, plumbagin, and juglone, three distinct series of 1,4-naphthoquinones (NQ) were synthesized as potential inhibitors of TR from Trypanosoma cruzi (TcTR). The three parent molecules were functionalized at carbons 2 and/or 3 by various polyamine chains. Optimization of TcTR inhibition and TcTR specificity versus human disulfide reductases was achieved with the 3,3'-[polyaminobis(carbonylalkyl)]bis(1,4-NQ) series 19-20, in which an optimum chain length was determined for inhibition of the trypanothione disulfide reduction. The most active derivatives against trypanosomes in cultures were also studied as subversive substrates of TcTR and lipoamide dehydrogenase (TcLipDH). The activities were measured by following NAD(P)H oxidation as well as coupling the reactions to the reduction of cytochrome c which permits the detection of one-electron transfer. For TcTR, 20(4-c) proved to be a potent subversive substrate and an effective uncompetitive inhibitor versus trypanothione disulfide and NADPH. Molecular modeling studies based on the known X-ray structures of TcTR and hGR were conducted in order to compare the structural features, dimensions, and accessibility of the cavity at the dimer interface of TcTR with that of hGR, as one of the putative NQ binding sites. TcLipDH reduced the plumbagin derivatives by an order of magnitude faster than the corresponding menadione derivatives. Such differences were not observed with the pig heart enzyme. The most efficient and specific subversive substrates of TcTR and TcLipDH exhibited potent antitrypanosomal activity in in vitro T. brucei and T. cruzi cultures. The results obtained here confirm that reduction of NQs by parasitic flavoenzymes is a promising strategy for the development of new trypanocidal drugs.

Activity of 7-methyljuglone derivatives against Mycobacterium tuberculosis and as subversive substrates for mycothiol disulfide reductase

“…[5] and [26] The native functions of these enzymes involve the NAD(P)Hdependent reduction of disulfide bonds in proteins or oxidised versions of low molecular weight thiols such as glutathione. The enzyme-mediated toxicity of quinones/naphthoquinones is a consequence of their enzymatic reduction to semiquinone radicals (Fig.…”

“…Naphthoquinones are widely distributed in plants, fungi and some animals 1 and many are found to exhibit an interesting range of pharmacological properties including antibacterial, [2] and [3] antiviral, 4 trypanocidal, 5 anticancer, 6 antimalarial, [7] and [8] and antifungal 9 activity. Other quinone-related scaffolds such as 2-H-pyran-3(6H)-one derivatives 10 natalensis 12 and that of diospyrin 22, isolated from this plant, was observed against drugresistant strains of M. tuberculosis.…”

Natural Products Active Against African Trypanosomes: A Step Towards New Drugs

“…It has been reported that quinones, especially 1,4-naphthoquinones such as plumbagin 78, can induce oxidative stress in trypanosomes (T. congolense 61 and T. cruzi 62 ). This may be explained by their reduction to semi-quinone radicals by enzymes such as those present in the mitochondrial electron transport chain and the trypanothione reductase, a key enzyme of the trypanosomal antioxidant thiol metabolism.…”

Interactions of Quinones with Thioredoxin Reductase

“…glutathione reductase, lipoamide dehydrogenase, and trypanothione reductase, has been studied in significant detail (26 -28). The interactions with quinones may also concomitantly inhibit the normal reactions of these enzymes (29). Previously, studies of mammalian TrxR regarding interactions with quinones include the demonstrated reduction of ubiquinone-10, 2-methyl-1,4-naphthoquinone, and alloxan (14,30).…”