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-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.
Highlights
Psoriasis is a chronic inflammatory skin disorder that affects 2% of the world population [1]
Chemistry The synthesis of compounds 2a–6e is depicted in Scheme 1
Our design is aimed at retaining the anti-tumor necrosis factor (TNF)-α and anti-ILs pharmacological profiles from thalidomide and to enhance the efficacy against specific cytokines related to psoriasis
Summary
Psoriasis is a chronic inflammatory skin disorder that affects 2% of the world population [1]. Thalidomide has been found to inhibit basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6) production, and tumor necrosis factor-induced nuclear factor-κB activation in Jurkat cells [14,17,18,19] These cytokines, which result in suppression of inflammation, angiogenesis, and the immune response, play a crucial role in psoriasis [20,21,22]. It possesses multiple pharmacological applications and is widely used in clinical settings, it still possesses several induced side effects such as sedation, rash, constipation, peripheral neuropathy, dizziness, thromboembolism, and severe teratogenicity [23]. Figure 1F.igTuhre ch1e.miTchael strcuhcetmuirceasl ofsctruurcctuumresin, CofC-1c0u0rc0u4m, 2in-[,4-(CmCe-t1h0y0l0-4t,hio2)-p[4h-e(mnyelt]hyislo-tihniod)oplhineney-1l],3-dione, and LAiSsSoBinidoo-l1in4e2-51.,3-dione, and LASSBio-1425
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