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Synthesis and Immunomodulation of Human Lymphocyte Proliferation and Cytokine (Interferon‐γ) Production of Four Novel Malonitrilamides
Author(s) -
Hadizadeh Farzin,
Moallem Seyed Adel,
Jaafari Mahmoud Reza,
Shahab Mahdi,
Alahyari Maryam,
Rameshrad Maryam,
Samiei Afshin
Publication year - 2009
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2009.00812.x
Subject(s) - leflunomide , cytokine , mixed lymphocyte reaction , metabolite , lymphocyte , immune system , in vitro , chemistry , pharmacology , interferon , active metabolite , biochemistry , biology , immunology , rheumatoid arthritis , t cell
Leflunomide is an immunomodulator drug with applications in the management of arthritis rheumatoid. In this study, four novel analogs ( 4a – d ) of A771726, the active metabolite of leflunomide were synthesized and examined in vitro for their immunomodulation activity by examining human lymphocyte proliferation and determination of the cytokine interferon‐γ concentrations in human lymphocyte cell culture. For this purpose, 5 × 10 4 human lymphocyte cells were incubated at 37 °C in 5% CO 2 with phytohemagglutinin and one of the analogs (concentrations 1–100 m m ), negative controls or cyclosporine (0.1 m m ). Effects of the compounds on lymphocyte proliferation and interferon‐γ production were determined by MTT assay and enzyme‐linked immunosorbent assay, respectively. Our results showed that all four compounds dose‐dependently suppressed lymphocyte proliferation. Moreover, these compounds at some concentrations reduced interferon‐γ production which is an indicator of the immune response. Generally, the most potent analog was 4b with an amide linkage (X=NH) and the weakest analog was 4a with an ester linkage (X=O). Compound 4a has little similarity with the leflunomide active metabolite which has an amide linkage. In this study, four novel compounds were synthesized that showed considerable immunosuppressive effects that deserve further investigations.