Synthesis and Biological Evaluation of Thalidomide Derivatives as Potential Anti-Psoriasis Agents

被引:14
作者
Tang, Kai-Wei [1 ]
Lin, Zih-Chan [2 ]
Chen, Yeh-Long [3 ]
Tzeng, Cherng-Chyi [3 ]
Fang, Jia-You [2 ,4 ,5 ,6 ,7 ]
Tseng, Chih-Hua [1 ,8 ,9 ,10 ]
机构
[1] Kaohsiung Med Univ, Sch Pharm, Coll Pharm, Kaohsiung 807, Taiwan
[2] Chang Gung Univ, Grad Inst BioMed Sci, Taoyuan 333, Taiwan
[3] Kaohsiung Med Univ, Dept Med & Appl Chem, Coll Life Sci, Kaohsiung 807, Taiwan
[4] Chang Gung Univ, Hlth Aging Res Ctr, Chinese Herbal Med Res Team, Taoyuan 333, Taiwan
[5] Chang Gung Univ Sci & Technol, Res Ctr Food & Cosmet Safety, Taoyuan 333, Taiwan
[6] Chang Gung Univ Sci & Technol, Res Ctr Chinese Herbal Med, Taoyuan 333, Taiwan
[7] Chang Gung Mem Hosp, Dept Anesthesiol, Taoyuan 333, Taiwan
[8] Kaohsiung Med Univ, Dept Fragrance & Cosmet Sci, Coll Pharm, Kaohsiung 807, Taiwan
[9] Kaohsiung Med Univ Hosp, Dept Med Res, Kaohsiung 807, Taiwan
[10] Kaohsiung Municipal Tatung Hosp, Dept Pharm, Kaohsiung 807, Taiwan
关键词
thalidomide; psoriasis; tumor necrosis factor; anti-inflammatory; anti-proliferative; ANTIINFLAMMATORY AGENTS; TNF-ALPHA; SKIN; INFLAMMATION; INHIBITION; MECHANISMS; THERAPY; ANALOG;
D O I
10.3390/ijms19103061
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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- 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- and IL-6 expression in HaCaT cells with a higher potency than thalidomide and no significant cell cytotoxicity was detected at 10 M. In psoriasis, Compound 5c reduced IL-6, IL-8, IL-1 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.
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页数:16
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