Luo, WeimingYu, Qian-shengSalcedo, IsidroHolloway, Harold W.Lahiri, Debomoy K.Brossi, ArnoldTweedie, DavidGreig, Nigel H.2017-06-122017-06-122011-07-01Luo, W., Yu, Q., Salcedo, I., Holloway, H. W., Lahiri, D. K., Brossi, A., … Greig, N. H. (2011). Design, synthesis and biological assessment of novel N-substituted 3-(phthalimidin-2-yl)-2, 6-dioxopiperidines and 3-substituted 2, 6-dioxopiperidines for TNF-α inhibitory activity. Bioorganic & Medicinal Chemistry, 19(13), 3965–3972. http://doi.org/10.1016/j.bmc.2011.05.029https://hdl.handle.net/1805/12971Eight novel 2-(2,6-dioxopiperidin-3-yl)phthalimidine EM-12 dithiocarbamates 9 and 10, N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines 11-14 and 3-substituted 2,6-dioxopiperidines 16 and 18 were synthesized as tumor necrosis factor-α (TNF-α) synthesis inhibitors. Synthesis involved utilization of a novel condensation approach, a one-pot reaction involving addition, iminium rearrangement and elimination, to generate the phthalimidine ring required for the creation of compounds 9-14. Agents were, thereafter, quantitatively assessed for their ability to suppress the synthesis on TNF-α in a lipopolysaccharide (LPS)-challenged mouse macrophage-like cellular screen, utilizing cultured RAW 264.7 cells. Whereas compounds 9, 14 and 16 exhibited potent TNF-α lowering activity, reducing TNF-α by up to 48% at 30 μM, compounds 12, 17 and 18 presented moderate TNF-α inhibitory action. The TNF-α lowering properties of these analogs proved more potent than that of revlimid (3) and thalidomide (1). In particular, N-dithiophthalimidomethyl-3-(phthalimidin-2-yl)-2,6-dioxopiperidine 14 not only possessed the greatest potency of the analogs to reduce TNF-α synthesis, but achieved this with minor cellular toxicity at 30 μM. The pharmacological focus of the presented compounds is towards the development of well-tolerated agents to ameliorate the neuroinflammation, that is, commonly associated with neurodegenerative disorders, epitomized by Alzheimer's disease and Parkinson's disease.en-USPublisher PolicyThalidomideRevlimidN-substituted EM-12Dithiocarbamates3-substituted 26-dioxopiperidinesIminium rearrangementNeurodegenerative diseasesTNF-α inhibitionArticle