Synthesis and Functional Investigations of Computer Designed Novel Cladribine-Like Compounds for the Treatment of Multiple Sclerosis
| Autor: | Yavuz, S., Çetin, A., Akdemir, A., Doyduk, D., Dişli, A., Çelik Turgut, G., Şen, Alaattin |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
synthesis
protein p53 T-Lymphocytes Apoptosis multiple sclerosis Raji cell line T lymphocyte 4 fluoro n [9 (4 hydroxy 5 (hydroxymethyl)tetrahydrofuran 2 yl) 9h purin 6 yl)benzamide antineoplastic agent comparative study DNA strand breakage B-Lymphocytes computer aided design drug effect Cell Cycle cell line unclassified drug Molecular Docking Simulation priority journal fluorescence antiinflammatory agent signal transduction Immunosuppressive Agents DNA repair cladribine derivative Antineoplastic Agents cladribine chemistry Article Multiple Sclerosis Relapsing-Remitting DNA fragmentation assay drug mechanism gene expression profiling computer simulation double stranded DNA break Humans human structure activity relation B lymphocyte human cell DNA Breaks 2 amino 2 [4 (6 amino 9h purin 9 yl)butyl]propane 1 3 diol molecular docking immunosuppressive agent CCRF-CEM cell line CCRF-CEM cells RAJI cells DNA damage drug synthesis Molecular modeling studies immunomodulating agent metabolism ATR protein |
| DOI: | 10.1002/ardp.201700185 |
| Popis: | Cladribine (2-CdA) is used as an anti-cancer drug but is currently studied as a potential treatment for use in relapsing-remitting multiple sclerosis (MS). In this study, we computer designed, synthesized, and characterized two novel derivatives of 2-CdA, K1–5d and K2–4c, and investigated their underlying mechanism of beneficial effect using the CCRF-CEM and RAJI cell lines. For this purpose, we first determined their effect on MS and DNA damage and repair-related gene expression profiles using custom arrays along with 2-CdA treatment at non-toxic doses. Then, we determined whether cells underwent apoptosis after treatment with 2-CdA, K1–5d, and K2–4c in CCRF-CEM and RAJI cells, using the DNA fragmentation assay. It was found that both derivatives modulated the expression of the pathway-related genes that are important in inflammatory signaling, apoptosis, ATM/ATR, double-strand break repair, and the cell cycle. Furthermore, 2-CdA, K1–5d, and K2–4c significantly activated apoptosis in both cell lines. In summary, our data demonstrate that although both derivatives act as anti-inflammatory and apoptotic agents, inducing the accumulation of DNA strand breaks and activating the ultimate tumor suppressor p53 in T and B lymphocytes, the K1–5d derivative has shown more promising activities for further studies. © 2017 Deutsche Pharmazeutische Gesellschaft |
| Databáze: | OpenAIRE |
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