Insights into the mechanism of inhibition of tryptophan 2,3-dioxygenase by isatin derivatives

Abstract

Tryptophan 2,3-dioxygenase (TDO) is a cytosolic protein with a proven immunomodulatory function that promotes tumoral immune resistance and proliferation. Despite the interest in TDO as a therapeutic target in cancer treatment, the number of biologically useful inhibitors is limited. Herein, we report isatin derivatives as a new class of TDO inhibitors. Through structureactivity relationships and molecular docking studies, we optimized the inhibition potency of isatin derivatives by 4130-fold and elucidated the mechanistic details that control their mode of action. Hydrogen bond interactions between the compound and key active site residues of TDO, freedom upon rotation of the C3 chemical moiety and the presence of chlorines in the benzene ring of the compound comprise the properties that an isatin-based inhibitor requires to effectively inhibit the enzymatic activity of TDO.

Synthesis and evaluation of oxindoles as promising inhibitors of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1

“…Several research groups had successfully taken advantage of these hydrophobic interactions in the optimization of the IDO1 inhibition efficacies. 4,12,13 21 This also endorses the importance of C3-substituted oxindole moieties in designing inhibitors for these enzymes. The inhibition efficacies of these oxindole derivatives were determined by a spectrophotometric method.…”

“…Brassinin, tryptamine, carboline, keto-indoles, indol-2-yl ethanones, 1-methyl-tryptophan-tirapazamine, isatin and other indole derivatives also showed poor to moderate IDO1 inhibitory activities. [16][17][18][19][20][21][22] Comprehensive mechanistic studies of IDO1 induced L-Trp catabolism revealed that the addition of ferrous heme-iron coordinated molecular oxygen to the C2-C3 double bond of the pyrrole ring is the prerequisite for the IDO1 supported oxidation of L-Trp. These studies also proposed the formation of an epoxide intermediate state during the transformation of L-Trp to N-formylkynurenine by the IDO1 enzyme.…”

A One-Pot Divergent Sequence to Pyrazole and Quinoline Derivatives

“…A library of 12 compounds was prepared in order to study the versatility of the method which appears to be applicable to a range of isatin starting materials in which the 3-oxo group is active for aldol reactions. Furthermore, we acquired different spectroscopic analyses such as 15 N-MASNMR, 15 N-NMR and SXRD to confirm the structure of the products. To the best our knowledge, no 15 N-MASNMR spectra on 3-hydroxypyrazole scaffolds had previously been performed.…”

“…The 3-hydroxy-2-oxindole moiety is another related and widely represented motif present in several natural products (9,10,12) [10][11][12][13][14]. This scaffold has recently been employed in several areas of pharmacology (examples in Figure 2), and it has been described in the context of anti-cancer (tryptophan 2,3-dioxygenase inhibitor, 6) [15], anticonvulsant (8) [16], cytotoxic (11) [17] and growth hormone releasing agents (i.e., SM-130686, 7) [18,19]. Several methodologies for the generation of oxindole systems have been reported with one of these employing isatin [20].…”

Inhibitors of the Kynurenine Pathway

“…In 2014, a screening of 2,800 compounds from the library of the National Cancer Institute (USA) identified seven compounds inhibiting TDO, among them six quinones such as β-lapachone, taxifolin, nanaomycin A, and mitomycin C [130]. Later, the same group described derivatives of the naturally ocurring quinone isatin for TDO and IDO1 inhibition [131]. In these works, only enzymatic assay results were reported, and no additional tests were carried out.…”