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

• Published in: Bioorganic & medicinal chemistry 2011-07, Vol.19 (13), p.3965-3972
• Main Authors: Luo, Weiming, Yu, Qian-sheng, Salcedo, Isidro, Holloway, Harold W., Lahiri, Debomoy K., Brossi, Arnold, Tweedie, David, Greig, Nigel H.
• Format: Article
• Language: English
• Subjects: 3-Substituted 2,6-dioxopiperidines; Alzheimer disease; Animals; Biological and medical sciences; biological assessment; Bones, joints and connective tissue. Antiinflammatory agents; Cell Line, Tumor; condensation; Dithiocarbamates; Drug Design; Iminium rearrangement; Lenalidomide; lipopolysaccharides; Medical sciences; Mice; N-substituted EM-12; necrosis; Neurodegenerative diseases; Parkinson disease; Pharmacology. Drug treatments; Phthalimides - chemistry; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - toxicity; Revlimid; Thalidomide; Thalidomide - analogs & derivatives; Thalidomide - chemical synthesis; Thalidomide - chemistry; Thalidomide - toxicity; TNF-α inhibition; toxicity; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2011.05.029

Eleven N-substituted 3-(phthalimidin-2-yl)-2,6-dioxopiperidines and 3-substituted 2,6-dioxopiperidines were designed, synthesized and assessed for TNF-α lowering activity. 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 16and 18were 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, 17and 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.