Acylideneoxoindoles: a new class of reversible inhibitors of human transglutaminase 2 - PubMed (original) (raw)

Acylideneoxoindoles: a new class of reversible inhibitors of human transglutaminase 2

Cornelius Klöck et al. Bioorg Med Chem Lett. 2011.

Abstract

Inhibitors of human transglutaminase 2 (TG2) are anticipated to be useful in the therapy of a variety of diseases including celiac sprue as well as certain CNS disorders and cancers. A class of 3-acylidene-2-oxoindoles was identified as potent reversible inhibitors of human TG2. Structure-activity relationship analysis of a lead compound led to the generation of several potent, competitive inhibitors. Analogs with significant non-competitive character were also identified, suggesting that the compounds bind at one or more allosteric regulatory sites on this multidomain enzyme. The most active compounds had K(i) values below 1.0 μM in two different kinetic assays for human TG2, and may therefore be suitable for investigations into the role of TG2 in physiology and disease in animals.

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Figures

Figure 1

Figure 1

Selected TG2 inhibitors – irreversible dipeptide inhibitors (A), irreversible DHI-based inhibitors (B), irreversible DON-based substrate mimics (C), reversible thienopyrimidinones (D), irreversible imidazolium salts (E),, reversible azachalcones (F) and aryl-β-aminoethyl ketones (G, H),

Figure 2

Figure 2

Figure 3

Figure 3

Lineweaver-Burk analysis of the 6-chloro substituted compound 46, confirming its non-competitive inhibitory character. Reversibility was assigned based on the observation that preincubation of TG2 with inhibitors in the presence of 4 mM Ca+2 for 40 min did not appreciably alter the outcome of inhibition experiments (data not shown).

Scheme 1

Scheme 1

Synthesis of 3-acylidene-2-oxoindoles. Top: Synthesis of N1-H or N1-substituted analogues via condensation-dehydration of N1-H or N1-substituted isatins. Bottom: Synthesis of N1-substituted analogues via N-arylation of N1-H compounds. a) R3X (alkyl bromide or iodide), K2CO3, DMF, 16–48 h. b) acetone, NHEt2, 60 °C, 16 h or aryl methyl ketone, NHEt2, EtOH, RT, 2–48 h. c) HCl, AcOH, reflux, 0.5 h or HCl, AcOH, RT, 16 h. d) PhB(OH)2, CuSO4·5H2O, pyridine, DCM, 16 h.

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