Development of new scaffolds as reversible tissue transglutaminase inhibitors, with improved potency or resistance to glutathione addition

Abstract

Previous studies within our group have yielded a class of cinnamoyl-based competitive reversible inhibitors for tissue transglutaminase (TG2), with values as low as 1.0 μM (compound). However, due to the electrophilic nature of their alkene moiety, this class of inhibitors is susceptible to nucleophilic attack by glutathione, a key element in cellular metabolism and toxicity response. To address this issue, we made several modifications to the inhibitor scaffold, ultimately showing that a bis(triazole) scaffold increased resistance to nucleophilic attack, with compound being the most potent ( = 10 μM). In the process of reducing reactivity, we also prepared a new class of inhibitors, replacing the alkene of with an alkyne, leading to a significant increase in potency for compound ( = 420 nM).

Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase

“…On the basis of the kinetic data shown in Table 4, aromaticity is not necessary to achieve modest inhibition efficiency; the cyclohexyl (34), isopropyl (35), ethyl (36), and methyl (37) sulfonamides all gave comparable inhibition values to those of the aromatic derivatives. Interestingly, the electronrich thiophene sulfonamide derivative (38) showed poor inhibition, while the methyl sulfonamide (37) had the best inhibition kinetics of the series. Furthermore, inhibitor 37 has a significantly lower calculated log P value, fewer rotatable bonds, and a molecular weight of only 480.6 g/mol, all of which may slightly favor its cellular permeability.…”

“…Several academic and industrial research groups have contributed to the design and evaluation of peptidomimetic and small molecule reversible and covalent hTG2 inhibitors, as summarized in several recent reviews. − While some studies have focused on reversible inhibitors of hTG2, the majority have focused on the development of potent and selective covalent inhibitors that target the nucleophilic active-site Cys277 residue. Some representative examples of peptidic and peptidomimetic irreversible inhibitors of hTG2 are shown in Figure .…”

The diamond anniversary of tissue transglutaminase: a protein of many talents

“…Other novel scaffold inhibitors are dominated by reversible inhibitors of tTG. One of the better studied classes of compounds are a series of nitrocinnamoyl inhibitors identified by the Keillor laboratory [100]. Although lead molecule CP4d (Figure 7) had comparable potency to many of the peptidomimetic scaffolds ( K i of 1 µM), it also contains a Michael-acceptor functionality rendering it vulnerable to nucleophilic attack by common biomolecules like glutathione (GSH).…”

Coumarin–triazole Hybrids and Their Biological Activities

“…Some coumarin–triazole hybrids also exhibited potential as Cathepsin S , glycogen phosphorylase and glucose‐6‐phosphatase , transglutaminases , nonpeptidic protease inhibitors, as well as anticoagulant agents , warrant further investigations.…”