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Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors

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 in...

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Autores principales: Lee, Dong-Ho, Lee, Joo-Youn, Jeong, Jieun, Kim, Miok, Lee, Kyung Won, Jang, Eunseo, Ahn, Sunjoo, Lee, Chang Hoon, Hwang, Jong Yeon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150275/
https://www.ncbi.nlm.nih.gov/pubmed/29120388
http://dx.doi.org/10.3390/molecules22111936
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author Lee, Dong-Ho
Lee, Joo-Youn
Jeong, Jieun
Kim, Miok
Lee, Kyung Won
Jang, Eunseo
Ahn, Sunjoo
Lee, Chang Hoon
Hwang, Jong Yeon
author_facet Lee, Dong-Ho
Lee, Joo-Youn
Jeong, Jieun
Kim, Miok
Lee, Kyung Won
Jang, Eunseo
Ahn, Sunjoo
Lee, Chang Hoon
Hwang, Jong Yeon
author_sort Lee, Dong-Ho
collection PubMed
description 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.
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spelling pubmed-61502752018-11-13 Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Lee, Dong-Ho Lee, Joo-Youn Jeong, Jieun Kim, Miok Lee, Kyung Won Jang, Eunseo Ahn, Sunjoo Lee, Chang Hoon Hwang, Jong Yeon Molecules Article 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. MDPI 2017-11-09 /pmc/articles/PMC6150275/ /pubmed/29120388 http://dx.doi.org/10.3390/molecules22111936 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lee, Dong-Ho
Lee, Joo-Youn
Jeong, Jieun
Kim, Miok
Lee, Kyung Won
Jang, Eunseo
Ahn, Sunjoo
Lee, Chang Hoon
Hwang, Jong Yeon
Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
title Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
title_full Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
title_fullStr Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
title_full_unstemmed Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
title_short Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors
title_sort synthesis and molecular modeling studies of n′-hydroxyindazolecarboximidamides as novel indoleamine 2,3-dioxygenase 1 (ido1) inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150275/
https://www.ncbi.nlm.nih.gov/pubmed/29120388
http://dx.doi.org/10.3390/molecules22111936
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