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Discovery and biological evaluation of tanshinone derivatives as potent dual inhibitors of indoleamine 2, 3-dioxygenase 1 and tryptophan 2, 3-dioxygenase. 2022

Jiangxin Liu, and Jian Ren, and Kun Yang, and Shuang Chen, and Xinni Yang, and Qin-Shi Zhao
State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650201, China.

Indoleamine 2, 3-dioxygenase 1 (IDO1) and tryptophan 2, 3-dioxygenase (TDO), catalyzing the first and rate-limiting step of tryptophan-kynurenine (Trp-Kyn) metabolism pathway, are the appealing targets for cancer immunotherapy. A few dual IDO1/TDO inhibitors are reported in literature. However, small-molecule IDO1 and TDO inhibitors are not yet available for clinical use. Here, we report synthetic analogues of the naturally occurring terpenoids tanshinone IIA and crytotanshinone, and their IDO1/TDO inhibitory activities using enzymatic and cellular assays. The most potent compound 30 was further characterized with respect to the direct interaction, inhibition kinetics, and different binding modes against IDO1 and TDO through surface plasmon resonance (SPR), enzyme kinetics, and spectroscopic analysis approaches, respectively. Preliminary mechanistic studies showed that 30 significantly promoted cell apoptosis through the potential mitochondria-mediated Bcl-2/Bax pathway. IDO1-overexpressing HeLa cells, mimicking cancer cells, were sensitive to 30 treatments. These results provide further insights for new clinical application of tanshinones, the main component of traditional herbal medicine.

UI MeSH Term Description Entries
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D006367 HeLa Cells The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for, among other things, VIRUS CULTIVATION and PRECLINICAL DRUG EVALUATION assays. Cell, HeLa,Cells, HeLa,HeLa Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D014364 Tryptophan An essential amino acid that is necessary for normal growth in infants and for NITROGEN balance in adults. It is a precursor of INDOLE ALKALOIDS in plants. It is a precursor of SEROTONIN (hence its use as an antidepressant and sleep aid). It can be a precursor to NIACIN, albeit inefficiently, in mammals. Ardeydorm,Ardeytropin,L-Tryptophan,L-Tryptophan-ratiopharm,Levotryptophan,Lyphan,Naturruhe,Optimax,PMS-Tryptophan,Trofan,Tryptacin,Tryptan,Tryptophan Metabolism Alterations,ratio-Tryptophan,L Tryptophan,L Tryptophan ratiopharm,PMS Tryptophan,ratio Tryptophan
D014366 Tryptophan Oxygenase A dioxygenase with specificity for the oxidation of the indoleamine ring of TRYPTOPHAN. It is a LIVER-specific enzyme that is the first and rate limiting enzyme in the kynurenine pathway of TRYPTOPHAN catabolism. Tryptophan Pyrrolase,TDO Dioxygenase,Tryptophan 2,3-Dioxygenase,2,3-Dioxygenase, Tryptophan,Dioxygenase, TDO,Oxygenase, Tryptophan,Pyrrolase, Tryptophan,Tryptophan 2,3 Dioxygenase
D045784 Abietanes A subclass of cyclical DITERPENES that contain the abietane ring structure. Abietane Diterpene,Abietane Diterpenoid,Abietane Diterpenoids,Diterpenes, Abietane,Isopimarane,Isopimaranes,Totarane Diterpene,Totarane Diterpenes,Totaranes,Diterpenes, Pimarane,Pimaranes,Abietane Diterpenes,Diterpene, Abietane,Diterpene, Totarane,Diterpenoid, Abietane,Pimarane Diterpenes
D050503 Indoleamine-Pyrrole 2,3,-Dioxygenase A dioxygenase with specificity for the oxidation of the indoleamine ring of TRYPTOPHAN. It is an extrahepatic enzyme that plays a role in metabolism as the first and rate limiting enzyme in the kynurenine pathway of TRYPTOPHAN catabolism. IDO Dioxygenase,Indolamine-2,3-Dioxygenase,Indoleamine 2,3-Dioxygenase,Indoleamine-Oxygen 2,3-Oxidoreductase (Decyclizing),Dioxygenase, IDO,Indolamine 2,3 Dioxygenase,Indoleamine 2,3 Dioxygenase

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