3.1 The design and synthesis of NF-κB inhibitors
Bromophenol derivatives are unique compounds that exist in many marine
organisms, such as algae , ascidians and sponges
(Utkina et al. , 2001). The
structural specificity of bromophenols makes them exhibit a variety of
biological activities, including enzyme inhibition
(Lee et al. , 2007), anti-oxidation
(Fu et al. , 1995),
anti-inflammatory (Wiemer et al. ,
1991), anti-microbial (Xu et al. ,
2003) and cytotoxic activities (Xuet al. , 2004), etc., which shows a good prospect for the
development of new drugs. NF-κB is a significant target for development
anti-inflammation drugs, hence, we designed and synthesized various
NF-κB inhibitors (Figure 1), and we screened their transcriptional
inhibitory activity using NF-κB reporter assay. The activity studies of
compounds 238-242 found that the hydroxyl of R1 and the
bromine of R2 are important for inhibitory activity,
such as compounds 239 and 241. The activity studies of compounds 242-268
found that hydroxyl or methoxyl of R6 are important for
inhibitory activity, such as compounds 259, 265 and 268. The activity
studies of compounds 269-280 found that hydroxyl or methoxyl of
R5 give compounds 269 and 270 (Figure 2A) similar high
inhibitory activity at 10 μM (S Table2). We further evaluated in NF-κB
luciferase assay at different dosages. Our results showed that 269 and
270 exhibited inhibition with IC50 values 5.91 μM and
2.49 μM, and PTL as a positive control (Figure 2B), suggesting that
compound 270 with the methoxy group at the R5 position
and the hydroxyl group at the R6 position showed the
highest NF-κB transcriptional inhibitory activity, and 270 may be an
NF-κB inhibitor.