Biological evaluation, chelation, and molecular modeling studies of novel metal-chelating inhibitors of NF-kappaB-DNA binding: structure activity relationships.

Rakesh K Sharma, Shilpa Chopra, Som D Sharma, Vineet Pande, Maria J Ramos, Kazuyuki Meguro, Jun-ichiro Inoue, Masami Otsuka

Index: J. Med. Chem. 49 , 3595-601, (2006)

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Abstract

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.