Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents
Several thalidomide derivatives were synthesized and evaluated for their anti-inflammatory activity. Introduction of the benzyl group to the parent thalidomide is unfavorable in which 2-(1-benzyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4a) was inactivated. However, the inhibitory activities o...
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doaj-f4f6e6f0eae54b24b15f6ae2d88c9fc62020-11-24T21:28:03ZengMDPI AGInternational Journal of Molecular Sciences1422-00672018-10-011910306110.3390/ijms19103061ijms19103061Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis AgentsKai-Wei Tang0Zih-Chan Lin1Yeh-Long Chen2Cherng-Chyi Tzeng3Jia-You Fang4Chih-Hua Tseng5School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of BioMedical Sciences, Chang Gung University, Taoyuan 333, TaiwanDepartment of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, TaiwanDepartment of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung 807, TaiwanGraduate Institute of BioMedical Sciences, Chang Gung University, Taoyuan 333, TaiwanSchool of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, TaiwanSeveral thalidomide derivatives were synthesized and evaluated for their anti-inflammatory activity. Introduction of the benzyl group to the parent thalidomide is unfavorable in which 2-(1-benzyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4a) was inactivated. However, the inhibitory activities on TNF-α and IL-6 expression in HaCaT cells were improved by the substitution of a chloro- or methoxy- group at the phenyl position of 4a. The IL-6 inhibitory activity decreased in an order of 5c (69.44%) > 4c (48.73%) > 6c (3.19%) indicating the 3-substituted derivative is more active than the 4-substituted counterpart, which in turn is more active than the 2-substituted counterpart. Among them, 2-[1-(3-chlorobenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione (5c) was found to inhibit TNF-α and IL-6 expression in HaCaT cells with a higher potency than thalidomide and no significant cell cytotoxicity was detected at 10 μM. In psoriasis, Compound 5c reduced IL-6, IL-8, IL-1β and IL-24 in imiquimod-stimulated models. Our results indicated that compound 5c is a potential lead of novel anti-psoriasis agents. Structural optimization of compound 5c and its in vivo assay are ongoing.http://www.mdpi.com/1422-0067/19/10/3061thalidomidepsoriasistumor necrosis factoranti-inflammatoryanti-proliferative |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kai-Wei Tang Zih-Chan Lin Yeh-Long Chen Cherng-Chyi Tzeng Jia-You Fang Chih-Hua Tseng |
spellingShingle |
Kai-Wei Tang Zih-Chan Lin Yeh-Long Chen Cherng-Chyi Tzeng Jia-You Fang Chih-Hua Tseng Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents International Journal of Molecular Sciences thalidomide psoriasis tumor necrosis factor anti-inflammatory anti-proliferative |
author_facet |
Kai-Wei Tang Zih-Chan Lin Yeh-Long Chen Cherng-Chyi Tzeng Jia-You Fang Chih-Hua Tseng |
author_sort |
Kai-Wei Tang |
title |
Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents |
title_short |
Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents |
title_full |
Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents |
title_fullStr |
Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents |
title_full_unstemmed |
Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents |
title_sort |
synthesis and biological evaluation of thalidomide derivatives as potential anti-psoriasis agents |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2018-10-01 |
description |
Several thalidomide derivatives were synthesized and evaluated for their anti-inflammatory activity. Introduction of the benzyl group to the parent thalidomide is unfavorable in which 2-(1-benzyl-2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (4a) was inactivated. However, the inhibitory activities on TNF-α and IL-6 expression in HaCaT cells were improved by the substitution of a chloro- or methoxy- group at the phenyl position of 4a. The IL-6 inhibitory activity decreased in an order of 5c (69.44%) > 4c (48.73%) > 6c (3.19%) indicating the 3-substituted derivative is more active than the 4-substituted counterpart, which in turn is more active than the 2-substituted counterpart. Among them, 2-[1-(3-chlorobenzyl)-2,6-dioxopiperidin-3-yl]isoindoline-1,3-dione (5c) was found to inhibit TNF-α and IL-6 expression in HaCaT cells with a higher potency than thalidomide and no significant cell cytotoxicity was detected at 10 μM. In psoriasis, Compound 5c reduced IL-6, IL-8, IL-1β and IL-24 in imiquimod-stimulated models. Our results indicated that compound 5c is a potential lead of novel anti-psoriasis agents. Structural optimization of compound 5c and its in vivo assay are ongoing. |
topic |
thalidomide psoriasis tumor necrosis factor anti-inflammatory anti-proliferative |
url |
http://www.mdpi.com/1422-0067/19/10/3061 |
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