Biological evaluation, chelation, and molecular modeling studies of novel metal-chelating inhibitors of NF-kappaB-DNA binding: structure activity relationships.
Previously, we have reported that aurintricarboxylic acid (ATA) is one of the most potent inhibitors of the DNA binding of transcription factor NF-kappaB. We now report the NF-kappaB-DNA binding inhibitory activity of ATA analogues. An electrophoretic mobility shift assay has shown that bromopyrogallol red (BPR) is the most effective inhibitor of NF-kappaB-DNA binding among the studied analogues. The molecular modeling studies showed that BPR makes a strong network of hydrogen bonds with the DNA-binding region of the p50 subunit of NF-kappaB and has electronegative potential on its peripheral surface. Because zinc has been reported to influence the DNA binding of NF-kappaB, the interaction of these analogues with zinc was studied. Chemical speciation and formation-constant studies showed that BPR forms the most stable 1:1 complex with zinc. BPR has also been found to be the most potent antioxidant among the studied analogues.
Sharma
Rakesh K
RK
Department of Chemistry, University of Delhi, Delhi-7, India. rksharma@vsnl.com
Chopra
Shilpa
S
Sharma
Som D
SD
Pande
Vineet
V
Ramos
Maria J
MJ
Meguro
Kazuyuki
K
Inoue
Jun-ichiro
J
Otsuka
Masami
M
D000998:Antiviral Agents / Q000737:chemistry*; D001312:Aurintricarboxylic Acid / Q000031:analogs & derivatives* / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004560:Electricity; D024202:Electrophoretic Mobility Shift Assay; D006860:Hydrogen Bonding; D008958:Models, Molecular; D016328:NF-kappa B / Q000737:chemistry / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D011485:Protein Binding; D011748:Pyrogallol / Q000737:chemistry; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
D000998:Antiviral Agents; D002614:Chelating Agents; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D009942:Organometallic Compounds; D011748:Pyrogallol; D001312:Aurintricarboxylic Acid; D004247:DNA; D015032:Zinc