title: 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.
abstract: Eight 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.
authors.affiliation: Drug Design & Development Section, Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Weiming
authors.initials: W
authors.lastname: Luo
authors.forename: Qian-sheng
authors.initials: QS
authors.lastname: Yu
authors.forename: Isidro
authors.initials: I
authors.lastname: Salcedo
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: Arnold
authors.initials: A
authors.lastname: Brossi
authors.forename: David
authors.initials: D
authors.lastname: Tweedie
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015195:Drug Design; D000077269:Lenalidomide; D051379:Mice; D010797:Phthalimides / Q000737:chemistry*; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D010797:Phthalimides; D010880:Piperidines; D014409:Tumor Necrosis Factor-alpha; C037432:phthalimidine; D013792:Thalidomide; D000077269:Lenalidomide