PMID- 17321745
OWN - NLM
STAT- MEDLINE
DCOM- 20070518
LR  - 20141120
IS  - 0968-0896 (Print)
IS  - 0968-0896 (Linking)
VI  - 15
IP  - 8
DP  - 2007 Apr 15
TI  - A chromone analog inhibits TNF-alpha induced expression of cell adhesion 
      molecules on human endothelial cells via blocking NF-kappaB activation.
PG  - 2952-62
AB  - The interaction between leukocytes and the vascular endothelial cells (EC) via 
      cellular adhesion molecules plays an important role in various inflammatory and 
      immune diseases. The molecules that block these interactions have been targeted 
      as potential therapeutic targets for acute and chronic inflammatory diseases. In 
      an effort to develop potent cell adhesion molecule inhibitors, a series of 
      chromone derivatives bearing alkoxycarbonylvinyl unit at the C-3 position, that 
      is, the chromones 8a-d and 9a-d, were designed and synthesized, and evaluated for 
      their ICAM-1 inhibitory activity on human endothelial cells as well as their 
      effect on NADPH-catalyzed rat microsomal lipid peroxidation. A structure-activity 
      relationship was established and we found that length of the alkyl moiety of the 
      chromone-3-yl-acrylate is important for this activity. Further, we found that 
      incorporation of unsaturation in the alcohol moiety increases the potential of 
      the compound for the inhibition of TNF-alpha induced expression of ICAM-1 and 
      also for the inhibition of lipid peroxidation. Out of the screened compounds, the 
      most potent compound ethyl trans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylate (8a) was 
      taken for further study. We have found that compound 8a also significantly 
      inhibited the TNF-alpha induced expression of VCAM-1 and E-selectin, which play 
      key roles in various inflammatory diseases. This inhibition was found to be 
      concentration dependent. The functional consequences of inhibiting cell adhesion 
      molecules were studied by performing cell-adhesion assay. We found that compound 
      8a significantly blocks the adhesion of neutrophils to endothelial monolayer. To 
      elucidate the molecular mechanism of inhibition of cell adhesion molecules, we 
      investigated the status of nuclear transcription factor-kappaB (NF-kappaB) and 
      were able to establish that compound 8a significantly blocked the TNF-alpha 
      induced activation of NF-kappaB.
FAU - Kumar, Sarvesh
AU  - Kumar S
AD  - Molecular Immunogenetics Laboratory, Institute of Genomics and Integrative 
      Biology, University of Delhi Campus (North), Mall Road, Delhi 110 007, India.
FAU - Singh, Brajendra K
AU  - Singh BK
FAU - Pandey, Anil K
AU  - Pandey AK
FAU - Kumar, Ajit
AU  - Kumar A
FAU - Sharma, Sunil K
AU  - Sharma SK
FAU - Raj, Hanumantharao G
AU  - Raj HG
FAU - Prasad, Ashok K
AU  - Prasad AK
FAU - Van der Eycken, Erik
AU  - Van der Eycken E
FAU - Parmar, Virinder S
AU  - Parmar VS
FAU - Ghosh, Balaram
AU  - Ghosh B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070212
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Cell Adhesion Molecules)
RN  - 0 (Chromones)
RN  - 0 (E-Selectin)
RN  - 0 (Indicators and Reagents)
RN  - 0 (NF-kappa B)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Tubulin)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - 53-59-8 (NADP)
SB  - IM
MH  - Animals
MH  - Biotransformation/drug effects
MH  - Blotting, Western
MH  - Cell Adhesion/drug effects
MH  - Cell Adhesion Molecules/*biosynthesis
MH  - Cell Line
MH  - Cell Survival/drug effects
MH  - Cells, Cultured
MH  - Chromones/*chemical synthesis/*pharmacology
MH  - Drug Design
MH  - E-Selectin/biosynthesis
MH  - Endothelial Cells/drug effects/*metabolism
MH  - Flow Cytometry
MH  - Humans
MH  - In Vitro Techniques
MH  - Indicators and Reagents
MH  - Intercellular Adhesion Molecule-1/biosynthesis
MH  - Lipid Peroxidation/drug effects
MH  - Microsomes, Liver/drug effects/metabolism
MH  - NADP/metabolism
MH  - NF-kappa B/*metabolism
MH  - Neutrophils/drug effects
MH  - Rats
MH  - Spectrometry, Mass, Electrospray Ionization
MH  - Spectrophotometry, Infrared
MH  - Spectrophotometry, Ultraviolet
MH  - Structure-Activity Relationship
MH  - Transcription Factor RelA/biosynthesis
MH  - Tubulin/biosynthesis
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/*pharmacology
MH  - Vascular Cell Adhesion Molecule-1/biosynthesis
EDAT- 2007/02/27 09:00
MHDA- 2007/05/19 09:00
CRDT- 2007/02/27 09:00
PHST- 2006/11/01 00:00 [received]
PHST- 2007/02/07 00:00 [revised]
PHST- 2007/02/08 00:00 [accepted]
PHST- 2007/02/27 09:00 [pubmed]
PHST- 2007/05/19 09:00 [medline]
PHST- 2007/02/27 09:00 [entrez]
AID - S0968-0896(07)00105-8 [pii]
AID - 10.1016/j.bmc.2007.02.004 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2007 Apr 15;15(8):2952-62. doi: 10.1016/j.bmc.2007.02.004. Epub 
      2007 Feb 12.