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

ABSTRACT: 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.

SUBMITTER: Tang KW 

PROVIDER: S-EPMC6212999 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature