title: Computer design, synthesis, and bioactivity analyses of drugs like fingolimod used in the treatment of multiple sclerosis.
abstract: Multiple sclerosis (MS) is a very common disease of vital importance. In the MS treatment, some drugs such as fingolimod which help to protect nerves from damage are used. The main goal of the drug therapy in MS is to take control of the inflammation which leads to the destruction of myelin and axons in nerve cell and thus prevent and stop the progression of the disease. Fingolimod (FTY720) is an orally active immunomodulatory drug that has been used for the treatment of relapsing-remitting multiple sclerosis. It is a sphingosine-1-phosphate receptor modulator which prevents lymphocytes from contributing to an autoimmune reaction by inhibiting egress of lymphocytes them from lymph nodes. In this study, we have computer designed, synthesized and characterized two novel derivatives of FTY720, F1-12h and F2-9, and have determined their underlying mechanism of their beneficial effect in SH-SY5Y, SK-N-SH, and U-118 MG cell lines. For this purpose, we first determined the regulation of the cAMP response element (CRE) activity and cAMP concentration by F1-12h and F2-9 together with FTY720 using pGL4.29 luciferase reporter assay and cAMP immunoassay, respectively. Then, we have determined their effect on MS- and GPCR-related gene expression profiles using custom arrays along with FTY720 treatment at non-toxic doses (EC10). It was found that both derivatives significantly activate CRE and increase cAMP concentration in all three cell lines, indicating that they activate cAMP pathway through cell surface receptors as FTY720 does. Furthermore, F1-12h and F2-9 modulate the expression of the pathway related genes that are important in inflammatory signaling, cAMP signaling pathway, cell migration as well as diverse receptor and transcription factors. Expression of the genes involved in myelination was also increased by the treatment with F1-12h and F2-9. In summary, our data demonstrate that the two novel FTY720 derivatives act as anti-inflammatory ultimately by influencing the gene expression via the cAMP and downstream transcription factor CRE pathway. In conclusion, F1-12h and F2-9 might contribute future therapies for autoimmune diseases such as multiple sclerosis.
authors.affiliation: Department of Biology, Faculty of Arts & Sciences, Pamukkale University, 20070 Kınıklı, Denizli, Turkey.
authors.forename: Gurbet Çelik
authors.initials: GÇ
authors.lastname: Turgut
authors.affiliation: Department of Chemistry, Faculty of Science, Gazi University, 06500 Ankara, Turkey.
authors.forename: Doğukan
authors.initials: D
authors.lastname: Doyduk
authors.affiliation: Department of Chemistry, Faculty of Science, Gazi University, 06500 Ankara, Turkey. Electronic address: yildirir@gazi.edu.tr.
authors.forename: Yılmaz
authors.initials: Y
authors.lastname: Yıldırır
authors.affiliation: Department of Chemistry, Faculty of Science, Gazi University, 06500 Ankara, Turkey.
authors.forename: Serkan
authors.initials: S
authors.lastname: Yavuz
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Bezmialem Vakıf University, 34093 İstanbul, Turkey.
authors.forename: Atilla
authors.initials: A
authors.lastname: Akdemir
authors.affiliation: Department of Chemistry, Faculty of Science, Gazi University, 06500 Ankara, Turkey.
authors.forename: Ali
authors.initials: A
authors.lastname: Dişli
authors.affiliation: Department of Biology, Faculty of Arts & Sciences, Pamukkale University, 20070 Kınıklı, Denizli, Turkey.
authors.forename: Alaattin
authors.initials: A
authors.lastname: Şen
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D000068876:Fingolimod Hydrochloride / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D009103:Multiple Sclerosis / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000068876:Fingolimod Hydrochloride
keywords: Fingolimod; Glioblastoma; Molecular modeling studies; Multiple sclerosis (MS); Neuroblastoma; S1P1 agonists