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

Weiming Luo, Qian Sheng Yu, Isidro Salcedo, Harold W. Holloway, Debomoy Lahiri, Arnold Brossi, David Tweedie, Nigel H. Greig

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)3965-3972
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number13
DOIs
StatePublished - Jul 1 2011

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Tumor Necrosis Factor-alpha
Addition reactions
Aptitude
Thalidomide
Macrophages
Neurodegenerative Diseases
Parkinson Disease
Toxicity
Lipopolysaccharides
Condensation
Cultured Cells
Alzheimer Disease
Pharmacology
2-(2,6-dioxopiperidin-3-yl)phthalimidine

Keywords

  • 3-Substituted 2,6-dioxopiperidines
  • Dithiocarbamates
  • Iminium rearrangement
  • N-substituted EM-12
  • Neurodegenerative diseases
  • Revlimid
  • Thalidomide
  • TNF-α inhibition

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

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. / Luo, Weiming; Yu, Qian Sheng; Salcedo, Isidro; Holloway, Harold W.; Lahiri, Debomoy; Brossi, Arnold; Tweedie, David; Greig, Nigel H.

In: Bioorganic and Medicinal Chemistry, Vol. 19, No. 13, 01.07.2011, p. 3965-3972.

Research output: Contribution to journalArticle

Luo, Weiming ; Yu, Qian Sheng ; Salcedo, Isidro ; Holloway, Harold W. ; Lahiri, Debomoy ; Brossi, Arnold ; Tweedie, David ; Greig, Nigel H. / 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. In: Bioorganic and Medicinal Chemistry. 2011 ; Vol. 19, No. 13. pp. 3965-3972.
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AU - Yu, Qian Sheng

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AU - Holloway, Harold W.

AU - Lahiri, Debomoy

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