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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MDPI AG
2017-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/22/11/1936 |
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doaj-4e44d84ce9064c2e81331c77846a7c572020-11-24T21:00:26ZengMDPI AGMolecules1420-30492017-11-012211193610.3390/molecules22111936molecules22111936Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) InhibitorsDong-Ho Lee0Joo-Youn Lee1Jieun Jeong2Miok Kim3Kyung Won Lee4Eunseo Jang5Sunjoo Ahn6Chang Hoon Lee7Jong Yeon Hwang8Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaKorea Chemical Bank, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaBio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, KoreaIndoleamine 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.https://www.mdpi.com/1420-3049/22/11/1936indoleamine 2,3-dioxygenase 1N’-hydroxyindazolecarboximidamidecancer immunotherapytryptophan depletionkynurenine production |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Dong-Ho Lee Joo-Youn Lee Jieun Jeong Miok Kim Kyung Won Lee Eunseo Jang Sunjoo Ahn Chang Hoon Lee Jong Yeon Hwang |
| spellingShingle |
Dong-Ho Lee Joo-Youn Lee Jieun Jeong Miok Kim Kyung Won Lee Eunseo Jang Sunjoo Ahn Chang Hoon Lee Jong Yeon Hwang Synthesis and Molecular Modeling Studies of N′-Hydroxyindazolecarboximidamides as Novel Indoleamine 2,3-Dioxygenase 1 (IDO1) Inhibitors Molecules indoleamine 2,3-dioxygenase 1 N’-hydroxyindazolecarboximidamide cancer immunotherapy tryptophan depletion kynurenine production |
| author_facet |
Dong-Ho Lee Joo-Youn Lee Jieun Jeong Miok Kim Kyung Won Lee Eunseo Jang Sunjoo Ahn Chang Hoon Lee Jong Yeon Hwang |
| author_sort |
Dong-Ho Lee |
| title |
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_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_sort |
synthesis and molecular modeling studies of n′-hydroxyindazolecarboximidamides as novel indoleamine 2,3-dioxygenase 1 (ido1) inhibitors |
| publisher |
MDPI AG |
| series |
Molecules |
| issn |
1420-3049 |
| publishDate |
2017-11-01 |
| 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. |
| topic |
indoleamine 2,3-dioxygenase 1 N’-hydroxyindazolecarboximidamide cancer immunotherapy tryptophan depletion kynurenine production |
| url |
https://www.mdpi.com/1420-3049/22/11/1936 |
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