Synthesis and biological evaluation of novel tryptoline derivatives as indoleamine 2,3-dioxygenase (IDO) inhibitors

• Published in: Bioorganic & medicinal chemistry Vol. 21; no. 5; pp. 1159 - 1165
• Main Authors: Tanaka, Minoru, Li, Xin, Hikawa, Hidemasa, Suzuki, Takafumi, Tsutsumi, Katsuhiko, Sato, Masashi, Takikawa, Osamu, Suzuki, Hideharu, Yokoyama, Yuusaku
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.03.2013; Elsevier
• Subjects: Age; Alzheimer disease; Biochemistry & Molecular Biology; Biomimetic synthesis; Carbolines - chemical synthesis; Carbolines - chemistry; Carbolines - metabolism; cataract; Cataracts; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Evaluation, Preclinical; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - metabolism; Humans; IDO; Indole; Indoleamine 2,3-dioxygenase; Indoleamine-Pyrrole 2,3,-Dioxygenase - antagonists & inhibitors; Indoleamine-Pyrrole 2,3,-Dioxygenase - metabolism; Life Sciences & Biomedicine; neoplasms; Pharmacology & Pharmacy; Physical Sciences; Protein Binding; Science & Technology; Stereoisomerism; tryptoline; Tryptoline derivatives; Tryptophan; Tryptophan - chemistry; Tryptophan 2,3-dioxygenase; Tumors; Tryptophan; Indoleamine 2,3-dioxygenase; Tryptoline derivatives; IDO; Biomimetic synthesis; CELLS; CATABOLISM; MECHANISM; SUPPRESSION; CANCER; ENZYME; TRYPTOPHAN DEGRADATION; EXPRESSION; BINDING; ALKALOIDS
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.12.028

Indoleamine 2,3-dioxygenase (IDO) plays a significant role in several disorders such as Alzheimer’s disease, age-related cataracts and tumors. A series of novel tryptoline derivatives were synthesized and evaluated for their inhibitory activity against IDO. Substituted tryptoline derivatives (11a, 11c, 11e, 12b and 12c) were demonstrated to be more potent than known inhibitor MTH-Trp. Suzuki–Miyaura cross-coupling reaction of 11a–d with phenylboronic acid proceeded in high yields. In most cases, C5 and C6 substitutions on the corresponding indole ring were well tolerated. The tryptoline derivative 11c is a promising chemical lead for the discovery of novel IDO inhibitors.