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The immunosuppressive activities of newly synthesized azaphenothiazines in human and mouse models

Abstract

In this study, we evaluated the activities of new types of azaphenothiazines in the following immunological assays: the proliferative response of human peripheral blood mononuclear cells induced by phytohemagglutin A or anti-CD3 antibodies; lipopolysaccharide-induced cytokine production by human PBMC; the secondary, humoral immune response in mice to sheep erythrocytes (in vitro); and delayed-type hypersensitivity in mice to ovalbumin (in vivo). In some tests, chlorpromazine served as a reference drug. The compounds exhibited differential inhibitory activities in the proliferation tests, with 10H-2,7-diazaphenothiazine (compound 1) and 6-(3-dimethylaminopropyl)diquinothiazine (compound 8) being most suppressive. Compound 1 was selected for further studies, and was found to be strongly suppressive in the humoral immune response even at low concentrations (1 μg/ml). Compound 1 also inhibited the delayed-type hypersensitivity lipopolysaccharide-induced production of tumor necrosis factor and interleukin-6 in cultures of human blood cells. As there were only two subjects in this study, the effects of these compounds on human blood cells need to be confirmed. In this paper, we also discuss the structure-activity relationships of selected compounds.

Abbreviations

AFC:

antibody-forming cells

CNS:

central nervous system

DMF:

dimethylformamide

DMSO:

dimethyl sulfoxide

DTH:

delayed-type hypersensitivity

FCS:

fetal calf serum

GI50 :

inhibition of cell growth (the concentration needed to reduce the growth of treated cells to half that of untreated cells)

IFN-γ:

interferon gamma

IL:

interleukin

i.p.:

intraperitoneally

LPS:

lipopolysaccharide

MDR:

multidrug resistance

MTT:

(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NS:

not significant

OVA:

ovalbumin

PBMC:

peripheral blood mononuclear cells

PHA:

phytohemagglutinin

RPMI-1640:

Rosewell Park Memorial Institute Medium

s.c.:

subcutenaously

SRBC:

heep red blood cells

TNF-α:

tumor necrosis factor alpha

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Correspondence to Krystian Pluta.

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Zimecki, M., Artym, J., Kocięba, M. et al. The immunosuppressive activities of newly synthesized azaphenothiazines in human and mouse models. Cell Mol Biol Lett 14, 622–635 (2009). https://doi.org/10.2478/s11658-009-0025-1

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  • DOI: https://doi.org/10.2478/s11658-009-0025-1

Key words

  • Azaphenothiazines
  • Immune response
  • PBMC
  • Proliferation
  • Cytokines