Cargando…
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...
Autores principales: | , , , , , , , , |
---|---|
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 |
_version_ | 1783356956351660032 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6150275 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT leedongho synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors AT leejooyoun synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors AT jeongjieun synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors AT kimmiok synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors AT leekyungwon synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors AT jangeunseo synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors AT ahnsunjoo synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors AT leechanghoon synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors AT hwangjongyeon synthesisandmolecularmodelingstudiesofnhydroxyindazolecarboximidamidesasnovelindoleamine23dioxygenase1ido1inhibitors |