Discovery of Tryptanthrin Derivatives as Potent Inhibitors of Indoleamine 2,3-Dioxygenase with Therapeutic Activity in Lewis Lung Cancer (LLC) Tumor-Bearing Mice

Citations Over TimeTop 12% of 2013 papers

Abstract

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.

Related Papers

• → Induction of Indoleamine 2,3-Dioxygenase In Vivo by IFN-con1(2001)9 cited
• → Pharmacological Inhibition of the Immunomodulatory Enzyme Indoleamine 2,3-Dioxygenase (IDO) Cooperatively Leverages Cytotoxic Chemotherapy(2005)
• → ATP promotes immunosuppressive MSCs inhibiting lymphocyte proliferation and expressing indoleamine dioxygenase(2017)
• Screening of the inhibitory activity of Korea local plant extracts against indoleamine 2,3-dioxygenase (IDO) = 한국 자생식물 추출물의 Indoleamine 2,3-dioxygenase (IDO) 저해활성(2011)
• 教15-2 妊娠免疫とIDO (Indoleamine 2, 3-dioxygenase)(アレルギー疾患の発症における免疫・神経・内分泌系のクロストーク,ミニシンポジウム,教育コース15(基礎・その他),第22回日本アレルギー学会春季臨床大会)(2010)