ascorbic-acid and tryptanthrine

Indoleamine 2,3-dioxygenase (IDO-1) is emerging as an important new therapeutic target for the treatment of cancer, neurological disorders, and other diseases that are characterized by pathological tryptophan metabolism. However, only a few structural classes are known to be IDO-1 inhibitors. In this study, a natural compound tryptanthrin was discovered to be a novel potent IDO-1 inhibitor by screening of indole-based structures. Three series of 13 tryptanthrin derivatives were synthesized, and the structure-activity analysis was undertaken. The optimization led to the identification of 5c, which exhibited the inhibitory activity at a nanomolar level. In vitro 5c dramatically augmented the proliferation of T cells. When administered to Lewis lung cancer (LLC) tumor-bearing mice, 5c significantly inhibited IDO-1 activity and suppressed tumor growth. In addition, 5c reduced the numbers of Foxp3(+) regulatory T cells (Tregs), which are known to prevent the development of efficient antitumor immune responses.

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Dose-Response Relationship, Drug; Drug Discovery; Enzyme Inhibitors; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Lung Neoplasms; Mice; Molecular Structure; Quinazolines; Structure-Activity Relationship; Xenograft Model Antitumor Assays