4,5-Disubstituted 1,2,3-triazoles: Effective Inhibition of Indoleamine 2,3-Dioxygenase 1 Enzyme Regulates T cell Activity and Mitigates Tumor Growth

Abstract

The improvement of body’s own immune system is considered one of the safest approaches to fight against cancer and several other diseases. Excessive catabolism of the essential amino acid, L-tryptophan (L-Trp) assists the cancer cells to escape normal immune obliteration. The formation of disproportionate kynurenine and other downstream metabolites suppress the T cell functions. Blocking of this immunosuppressive mechanism is considered as a promising approach against cancer, neurological disorders, autoimmunity, and other immune-mediated diseases. Overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme is directly related to the induction of immunosuppressive mechanisms and represents an important therapeutic target. Several classes of small molecule-based IDO1 inhibitors have been already reported, but only few compounds are currently being evaluated in various stages of clinical trials as adjuvants or in combination with chemo- and radiotherapies. In the quest for novel structural class(s) of IDO1 inhibitors, we developed a series of 4,5-disubstituted 1,2,3-triazole derivatives. The optimization of 4,5-disubstituted 1,2,3-triazole scaffold and comprehensive biochemical and biophysical studies led to the identification of compounds, 3i, 4i, and 4k as potent and selective inhibitors of IDO1 enzyme with IC50 values at a low nanomolar level. These potent compounds also showed strong IDO1 inhibitory activities in MDA-MB-231 cells with no/negligible level of cytotoxicity. The T cell activity studies revealed that controlled regulation of IDO1 enzyme activity in the presence of these potent compounds could induce immune response against breast cancer cells. The compounds also showed excellent in vivo antitumor efficacy (of tumor growth inhibition = 79–96%) in the female Swiss albino mice. As a consequence, this study describes the first example of 4,5-disubstituted 1,2,3-triazole based IDO1 inhibitors with potential applications for immunotherapeutic studies.

Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

“…We synthesised three of the compounds described in this work (original compound numbers: 1d, 64 ; 2 g, 65 ; and 3 g, 66 ) but could not reproduce the published IC 50 values. In our hands, compounds 64 and 65 showed no inhibition of IDO1, although their published IC 50 values were 2.51 µ M and 0.39 µ M, respectively 59 . Compound 66 , which has a published IC 50 value of 0.62 µ M, showed a weak activity in our tests, with an IC 50 value of 800 µ M. The lower activities might be due to higher purities of our compounds and are in line with weak activities measured for other compounds of this type ( Table 2 ).…”

“…Compound 9 forms a direct bond to the haem iron, a hydrogen bond with Ser167 through its hydroxy function, and hydrophobic interactions through its chloro substituent, leading to a LE of 0.76 kcal/mol/HA. A few 4,5-disubstituted 1,2,3-triazoles with nanomolar activities have been reported 59 , but as we detail below, we failed to reproduce these results. Interestingly, the N-phenyl-1,2,3-triazol-4-amine ( 10 ) developed by Vertex 60 demonstrates an IDO1 inhibition mechanism distinct from the 4-phenyl1,2,3-triazoles despite a similar binding mode 22 .…”

“…Here, we show that an electron-withdrawing 5-nitrile substitution yielded a slightly active compound ( 62 , 630 µ M), while combination of the 5-methyl substituent with the 5-Cl substituent on the phenyl ring yielded an inactive compound ( 63 , NI). Compounds with this substitution pattern have recently been further explored by Panda and co-workers 59 , who described 11 compounds with nanomolar IC 50 values. We synthesised three of the compounds described in this work (original compound numbers: 1d, 64 ; 2 g, 65 ; and 3 g, 66 ) but could not reproduce the published IC 50 values.…”

“…Ethyl 4–(3-chlorophenyl)-1 H -1,2,3-triazole-5-carboxylate ( 65 ) 59 : To a stirred solution of ethyl-3–(4-chlorophenyl)propiolate ( 59 ) (209 mg, 1.0 mmol) in DMSO (2 mL), NaN 3 (182 mg, 2.8 mmol) was added, and the solution was stirred under reflux at 70 °C for 6 h. After completion of the reaction, the mixture was cooled to rt and quenched with water. After extraction with EtOAc, the organic layer was collected, washed with brine, dried (anh.…”

Silver Mediated Banert Cascade with Carbon Nucleophiles

“…The triazole heterocycle has been widely adopted as a key molecular building block for a variety of synthetic applications including in drug discovery, − medicinal chemistry, − bioconjugation, , and material science. − Triazoles are small, polar, and stable N -heterocycles that can be used as a peptidomimetic, ,, amide isostere, , N -acetyl lysine mimic, , or glycosyl surrogate. − N H-triazoles contain a hydrogen bond donor, more closely resembling sugars and native amides, relative to N -substituted triazoles. N H-triazoles can adopt three N–H tautomeric structures, providing additional flexibility, and they have demonstrated utility in multiple contexts. − …”