title: 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: Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: mohapatra@iict.res.in.
authors: Debendra K
authors: DK
authors: Mohapatra
authors: Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: D Sai
authors: DS
authors: Reddy
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: M Janaki
authors: MJ
authors: Ramaiah
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: Sowjanya
authors: S
authors: Ghosh
authors: Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: Vikram
authors: V
authors: Pothula
authors: Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: Swetha
authors: S
authors: Lunavath
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: Shine
authors: S
authors: Thomas
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: S N C V L Pushpa
authors: SN
authors: Valli
authors: Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
authors: Manika Pal
authors: MP
authors: Bhadra
authors: Natural Products Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India. Electronic address: manika@iict.res.in.
authors: Jhillu S
authors: JS
authors: Yadav
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C475820:CCNE1 protein, human; D019927:Cyclin E; D007783:Lactones; D016328:NF-kappa B; D015513:Oncogene Proteins; D051020:bcl-X Protein; C548571:rugulactone; D050760:Cyclin-Dependent Kinase Inhibitor p27; D011065:Poly(ADP-ribose) Polymerases; D051357:Cyclin-Dependent Kinase 2
keywords: Chromatin immunoprecipitation (ChIP); Histone deacetylase (HDAC); Luciferase (Luc); Nuclear Factor-kappa B (NF-κB); Poly (ADP)-ribose polymerase (PARP); Polymerase chain reaction (PCR)