Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2

Doreen E. Szollosi, Ola A M Ghoneim, Mohammed K. Manzoor, Jyothi Dhuguru, Ivan O. Edafiogho

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Pro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced, it can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn’s disease and rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-aryl piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized that this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.

Original languageEnglish (US)
Pages (from-to)2053-2061
Number of pages9
JournalInflammation
Volume39
Issue number6
DOIs
StatePublished - Dec 1 2016

Fingerprint

Chemokine Receptors
Tumor Necrosis Factor-alpha
Cytokines
Interleukin-6
Asthma
Lipopolysaccharides
Anti-Inflammatory Agents
Immunosuppressive Agents
Dimethyl Sulfoxide
Autoimmunity
Crohn Disease
Dexamethasone
Autoimmune Diseases
Rheumatoid Arthritis
Sepsis
Nitric Oxide
Enzyme-Linked Immunosorbent Assay
Macrophages
Control Groups
Wounds and Injuries

Keywords

  • asthma
  • autoimmunity
  • chemokines
  • inflammation
  • macrophages
  • piperazino-enaminones
  • pro-inflammatory cytokines

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Szollosi, D. E., Ghoneim, O. A. M., Manzoor, M. K., Dhuguru, J., & Edafiogho, I. O. (2016). Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2. Inflammation, 39(6), 2053-2061. https://doi.org/10.1007/s10753-016-0443-y

Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2. / Szollosi, Doreen E.; Ghoneim, Ola A M; Manzoor, Mohammed K.; Dhuguru, Jyothi; Edafiogho, Ivan O.

In: Inflammation, Vol. 39, No. 6, 01.12.2016, p. 2053-2061.

Research output: Contribution to journalArticle

Szollosi, DE, Ghoneim, OAM, Manzoor, MK, Dhuguru, J & Edafiogho, IO 2016, 'Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2', Inflammation, vol. 39, no. 6, pp. 2053-2061. https://doi.org/10.1007/s10753-016-0443-y
Szollosi, Doreen E. ; Ghoneim, Ola A M ; Manzoor, Mohammed K. ; Dhuguru, Jyothi ; Edafiogho, Ivan O. / Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2. In: Inflammation. 2016 ; Vol. 39, No. 6. pp. 2053-2061.
@article{c4ab06956662490db1641fd9e7cc5ad4,
title = "Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2",
abstract = "Pro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced, it can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn’s disease and rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-aryl piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized that this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.",
keywords = "asthma, autoimmunity, chemokines, inflammation, macrophages, piperazino-enaminones, pro-inflammatory cytokines",
author = "Szollosi, {Doreen E.} and Ghoneim, {Ola A M} and Manzoor, {Mohammed K.} and Jyothi Dhuguru and Edafiogho, {Ivan O.}",
year = "2016",
month = "12",
day = "1",
doi = "10.1007/s10753-016-0443-y",
language = "English (US)",
volume = "39",
pages = "2053--2061",
journal = "Inflammation",
issn = "0360-3997",
publisher = "Springer New York",
number = "6",

}

TY - JOUR

T1 - Novel Piperazino-Enaminones Suppress Pro-Inflammatory Cytokines and Inhibit Chemokine Receptor CCR2

AU - Szollosi, Doreen E.

AU - Ghoneim, Ola A M

AU - Manzoor, Mohammed K.

AU - Dhuguru, Jyothi

AU - Edafiogho, Ivan O.

PY - 2016/12/1

Y1 - 2016/12/1

N2 - Pro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced, it can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn’s disease and rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-aryl piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized that this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.

AB - Pro-inflammatory mediators including TNF-alpha, IL-6, and nitric oxide are important for the regulation of the immune response when an infection is present, but when overproduced, it can be responsible for the development of tissue and organ injury seen in sepsis, as well as severe asthma, and autoimmune diseases such as Crohn’s disease and rheumatoid arthritis. Data from our lab to characterize the novel compound enaminone E121 have suggested that macrophages stimulated with lipopolysaccharide (LPS) release significantly decreased levels of TNF-alpha and IL-6 as measured by enzyme-linked immunosorbent assay as compared to the DMSO control group. Additionally, functional experiments in a mouse model of asthma have shown that E121 is efficacious in decreasing airway hyperresponsiveness. A new set of compounds synthesized in our lab (JODI) have an N-aryl piperazino motif incorporated on the aromatic side of the enaminone pharmacophore. It was hypothesized that this would enhance their immunosuppressive activity as anti-inflammatory agents by also acting as a chemokine receptor antagonist. Our studies suggest that JODI appears to suppress TNF-alpha and IL-6 in a dose-dependent manner. The JODI compounds were also more effective in reducing TNF-alpha after LPS stimulation when compared to dexamethasone. Lastly, studies using MCP-1 suggest that the JODI compounds, and not E121, are able to block CCR2 signaling as evidenced by decreased total ERK1/2. These studies indicate that E121 and its corresponding piperazino analogs could act as strong anti-inflammatory agents in asthma or other autoimmunities where efficacious therapeutic options are needed.

KW - asthma

KW - autoimmunity

KW - chemokines

KW - inflammation

KW - macrophages

KW - piperazino-enaminones

KW - pro-inflammatory cytokines

UR - http://www.scopus.com/inward/record.url?scp=84986278298&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84986278298&partnerID=8YFLogxK

U2 - 10.1007/s10753-016-0443-y

DO - 10.1007/s10753-016-0443-y

M3 - Article

VL - 39

SP - 2053

EP - 2061

JO - Inflammation

JF - Inflammation

SN - 0360-3997

IS - 6

ER -