Zhouyu Wang

IDO as a drug target for cancer immunotherapy: recent developments in IDO inhibitors discovery

The indoleamine 2,3-dioxygenase (IDO) mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in tumor cells to escape a potentially effective immune response. IDO affects the differentiation and proliferation of T cells, triggering downstream signaling through GCN2, mTOR and AhR. Therefore, IDO is an attractive target for cancer immunotherapy. IDO inhibitors exhibit potent anticancer activities and might be very useful in combination with chemotherapy, radiotherapy or immunotherapy to trigger the rapid regression of aggressive tumors. However, the development of IDO pharmacological inhibitors has been a challenging work. This review highlights recent advances (2010–2015) in research related to the role of IDO in immune escape and pathogenic inflammation in cancer, and novel small-molecule IDO inhibitors with an emphasis on their chemical structures and modes of action.

Discovery and preliminary structure-activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties.

Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5.3μM. The structure-activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.

Catalyst-free chemoselective reduction of the carbon–carbon double bond in conjugated alkenes with Hantzsch esters in water

A simple, efficient and green protocol for chemoselective reduction of carbon–carbon double bond in conjugated alkenes with Hantzsch esters is described. Without any additional catalysts, a series of conjugated alkenes with strong electron-withdrawing groups were reduced in water with excellent yield. Functional groups such as nitrile, ester, nitro, fluoro, chloro, bromo, furanyl and benzyl are all tolerated by the reaction conditions employed.

Thiourea catalysed reduction of α-keto substituted acrylate compounds using Hantzsch ester as a reducing agent in water

The first method for the reduction of α-keto substituted acrylate compounds by Hantzsch ester in water under the catalysis of thiourea has been developed. The products were isolated in moderate to high yields (38–95%). These products are important intermediates in the synthesis of a series of natural products and other biologically active molecules.

A base promoted one pot solvent free version of the Ramachary reductive coupling/alkylation reaction for the synthesis of 2,2-disubstituted ethyl cyanoacetates

An N,N-diisopropylethylamine promoted solvent-free Ramachary reductive coupling/alkylation (RRC/A) reaction for the synthesis of 2,2-disubstituted ethyl cyanoacetates has been developed. A series of 2,2-disubstituted ethyl cyanoacetates were synthesized in one pot by the RRC/A reaction of commercially available aldehydes, ethyl cyanacetates, alkyl halides and Hantzsch ester. A solvent free two step multicomponent reaction has also been developed for the preparation of 2,2-dialkylated malononitriles and 2,2-dialkylated 4-nitrophenyl acetonitriles. All the designed RRC/A products could be easily obtained with good yields by these methods.

Correction: IDO as a drug target for cancer immunotherapy: recent developments in IDO inhibitors discovery

Correction for ‘IDO as a drug target for cancer immunotherapy: recent developments in IDO inhibitors discovery’ by Shan Qian et al., RSC Adv., 2016, 6, 7575–7581.

One-pot protocol to synthesize N-(β-nitro)amides by tandem Henry/Ritter reaction

A novel, efficient and atom economical one pot protocol for the synthesis of N-(β-nitro)amides has been described by combining the Henry reaction with the Ritter reaction. The designed products could be obtained from easily available aldehydes, nitroalkanes and nitriles with 60–83% overall yields under mild reaction conditions. In addition, the product can easily be transformed into diamine or protective amine derivatives.