Rugulactone derivatives act as inhibitors of NF-κB activation and modulates the transcription of NF-κB dependent genes in MDA-MB-231cells.

Abstract

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.

• Authors: Debendra K Mohapatra, D Sai Reddy, M Janaki Ramaiah, Sowjanya Ghosh, Vikram Pothula, Swetha Lunavath, Shine Thomas, S N C V L Pushpa Valli, Manika Pal Bhadra, Jhillu S Yadav
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 24 Issue 5 Pg. 1389-96 (Mar 01 2014) ISSN: 1464-3405 [Electronic] England
• PMID: 24508135 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• CCNE1 protein, human
• Cyclin E
• Lactones
• NF-kappa B
• Oncogene Proteins
• bcl-X Protein
• rugulactone
• Cyclin-Dependent Kinase Inhibitor p27
• Poly(ADP-ribose) Polymerases
• Cyclin-Dependent Kinase 2

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Cyclin E (metabolism)
• Cyclin-Dependent Kinase 2 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (genetics, metabolism)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Humans
• Lactones (chemical synthesis, chemistry, pharmacology)
• MCF-7 Cells
• NF-kappa B (antagonists & inhibitors, metabolism)
• Oncogene Proteins (metabolism)
• Poly(ADP-ribose) Polymerases (metabolism)
• Structure-Activity Relationship
• Transcription, Genetic (drug effects)
• bcl-X Protein (metabolism)