Rugulactone derivatives act as inhibitors of NF-κB activation and modulates the transcription of NF-κB dependent genes in MDA-MB-231cells
| Autor: | Sowjanya Ghosh, D. Sai Reddy, Debendra K. Mohapatra, Swetha Lunavath, Shine Thomas, M. Janaki Ramaiah, Jhillu S. Yadav, Manika Pal Bhadra, S.N.C.V.L. Pushpa Valli, Vikram Pothula |
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| Rok vydání: | 2013 |
| Předmět: |
Cyclin E
Transcription Genetic DNA damage Cell Survival Poly ADP ribose polymerase Clinical Biochemistry bcl-X Protein Pharmaceutical Science Antineoplastic Agents Biochemistry chemistry.chemical_compound Lactones Structure-Activity Relationship Cyclin D1 Cell Line Tumor Drug Discovery Humans Molecular Biology Oncogene Proteins biology Organic Chemistry Cyclin-dependent kinase 2 Cyclin-Dependent Kinase 2 NF-kappa B NF-κB Cell cycle Molecular biology G1 Phase Cell Cycle Checkpoints chemistry biology.protein MCF-7 Cells Molecular Medicine Histone deacetylase Poly(ADP-ribose) Polymerases Cyclin-Dependent Kinase Inhibitor p27 |
| Zdroj: | Bioorganicmedicinal chemistry letters. 24(5) |
| ISSN: | 1464-3405 |
| Popis: | Rugulactone and its analogues were synthesized following Horners-Wadsworth-Emmons and ring-closing metathesis as the key reactions. A library of new rugulactone analogues were designed, synthesized and evaluated for their anticancer activity in breast cancer cells. All analogues have shown anti-proliferative activity, while some of them exhibited significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G1 cell-cycle arrest in MDA-MB-231 cells. The cell cycle arrest nature was further confirmed by examining the effect on Cyclin E and Cdk2 proteins that acts at G1-S phase transition. Immunocytochemistry assay revealed that these compounds inhibited nuclear translocation of NF-κB protein, thereby activation of NF-κB was inhibited. The expression of NF-κB target genes such as Cyclin D1 and Bcl-xL were severely affected. Apart from acting on NF-κB, these compounds also regulate class I Histone deacetylase proteins such as (HDAC-3 and 8) that have a crucial and regulatory role in cell-proliferation. Simultaneously, the apoptotic inducing nature of these compounds was confirmed by activation of PARP protein, a protein that plays a key role in DNA damage and repair pathways. Among all compounds of this series 3g is the most potent compound and can be used for further studies. |
| Databáze: | OpenAIRE |
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