Molecules 2017, 22(11), 1936; https://doi.org/10.3390/molecules22111936
Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
Dong-Ho Lee 1,2,†
, Joo-Youn Lee 3,†, Jieun Jeong 1, Miok Kim 1,4, Kyung Won Lee 1,4, Eunseo Jang 1, Sunjoo Ahn 1,5, Chang Hoon Lee 1,4,*
and Jong Yeon Hwang 1,4,5,*
, Joo-Youn Lee 3,†, Jieun Jeong 1, Miok Kim 1,4, Kyung Won Lee 1,4, Eunseo Jang 1, Sunjoo Ahn 1,5, Chang Hoon Lee 1,4,*
and Jong Yeon Hwang 1,4,5,*
1
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea
2
Department of Chemistry, Sogang University, Seoul 121-742, Korea
3
Korea Chemical Bank, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Korea
4
Immunotherapy Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea
5
Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Korea
†
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 25 September 2017 / Revised: 8 November 2017 / Accepted: 8 November 2017 / Published: 9 November 2017
(This article belongs to the Section Medicinal Chemistry)
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive enzyme that is highly overexpressed in various cancer cells and antigen-presenting cells. It has emerged as an attractive therapeutic target for cancer immunotherapy, which has prompted high interest in the development of small-molecule inhibitors. To discover novel IDO1 inhibitors, we designed and synthesized a series of N′-hydroxyindazolecarboximidamides. Among the compounds synthesized, compound 8a inhibited both tryptophan depletion and kynurenine production through the IDO1 enzyme. Molecular docking studies revealed that 8a binds to IDO1 with the same binding mode as the analog, epacadostat (INCB24360). Here, we report the synthesis and biological evaluation of these hydroxyindazolecarboximidamides and present the molecular docking study of 8a with IDO1. View Full-TextKeywords:
indoleamine 2,3-dioxygenase 1; N’-hydroxyindazolecarboximidamide; cancer immunotherapy; tryptophan depletion; kynurenine production
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Lee, D.-H.; Lee, J.-Y.; Jeong, J.; Kim, M.; Lee, K.W.; Jang, E.; Ahn, S.; Lee, C.H.; Hwang, J.Y. Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors. Molecules 2017, 22, 1936.
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