In summary we have developed an efficient synthetic route to

In summary, we have developed an efficient synthetic route to the required urea-isostere containing hydroxamic acid-based inhibitor . The target molecule, , was found to retain the inhibitory potency of the corresponding carbo-analog against glyoxalase-I while possessing resistance to cleavage by γ-glutamyl transpeptidase. The design of metabolically stable glyoxalase-I inhibitors based on may be useful in potentiating the antitumor activity of α-ketoaldehydes. We are currently designing and synthesizing ester prodrugs of that would potentially possess the ability to penetrate cell membranes and thus render suitable for testing against tumor cells. Acknowledgments The authors thank Dr. Diana S. Hamilton (Late Prof. Donald Creighton’s laboratory) at the University of Maryland for generously providing us a sample of compound 3.
Introduction The glyoxalase pathway is the main cellular system responsible for the elimination of methylglyoxal, a toxic compound due to its high reactivity toward proteins and nucleic LY294002 sale amino groups (Thornalley, 1990). In eukaryotic cells, this 2-oxoaldehyde is mainly formed during glycolysis from the phosphate group β-elimination of the triose phosphates (Lohman and Meyerhof, 1934). Through the sequential action of glyoxalase I (GLO1, lactoylglutathione methylglyoxal-lyase, EC 4.4.1.5) and glyoxalase II (GLO2, hydroxyacylglutathione hydrolase, EC 3.1.2.6), methylglyoxal is converted into d-lactate using glutathione as the cofactor (Thornalley, 1990). Being ubiquitous and relevant in the cell detoxification of methylglyoxal, the glyoxalase pathway has been studied in some human protozoan parasites as a potential drug target, namely in Plasmodium falciparum, Leishmania spp. and Trypanosoma spp. Hence, differences in glyoxalase I and II enzymes between humans and parasites have been identified (Fig. 1, Table 1). The first enzyme of the glyoxalase pathway, glyoxalase I, is typically a homodimer with the active site located at the interface of the two subunits (Ariza et al., 2006, Barata et al., 2010, Cameron et al., 1997, He et al., 2000, Sukdeo et al., 2004). However, exceptions are found in P. falciparum (Iozef et al., 2003), where glyoxalase I is a monomeric enzyme with two active sites. It is allosterically regulated and, as in mammalian cells, depends on glutathione. A difference concerning thiol specificity occurs in trypanosomatids, where reduced trypanothione is used instead of glutathione to convert methylglyoxal into the corresponding thioester (Ariza et al., 2006, Irsch and Krauth-Siegel, 2004, Silva et al., 2008, Sousa Silva et al., 2005). Interestingly, the trypanosomatid Trypanosoma brucei does not have a glyoxalase I enzyme but has two glyoxalase II coding genes, raising several questions about the function of the glyoxalase pathway in this parasite (Wendler et al., 2009). Glyoxalase II is the second enzyme of the pathway and hydrolyzes the thioester into d-lactate, regenerating the thiol. In T. brucei, only one of these GLO2 enzymes displays a functional glyoxalase II activity (Wendler et al., 2009). P. falciparum also has two glyoxalase II enzymes, one located in the cytosol and the other containing a target sequence to the apicoplast (Urscher et al., 2011). However, the existence of a glyoxalase I-like protein (GILP) probably located to the apicoplast, unique in malarial parasites, but inactive with the typical GLO1 substrates is intriguing (Akoachere et al., 2005, Urscher et al., 2011). Despite some basic features shared between protozoan parasites, several differences are found in their metabolism, and the glyoxalase pathway is no exception (Fig. 1). In this review, we present the landscape of knowledge on this thiol-dependent system in protozoan parasites responsible for human diseases: the apicomplexan P. falciparum and Toxoplasma gondii, the enteric parasites Entamoeba histolytica and Giardia lamblia, and the trypanosomatids Leishmania spp., T. brucei and T. cruzi.