1024 Bull. Korean Chem. Soc. 2013, Vol. 34, No. 4
Communications to the Editor
Table 1. Inhibitory activity of 1a-e and 2a-m on PTP1B
a
IC50 (µM)
Compounds
Compounds
IC50 (µM)
1b
2a
2b
2c
2d
2e
2f
6.94 0.69
2g
2h
2i
11.03 0.71
35.31 4.50
NA
b
NA
2.90 0.12
10.65 0.56
21.40 3.47
8.45 1.23
18.99 1.53
3.40 0.21
2j
20.28 1.51
NA
2k
2l
26.41 0.80
2.49 0.23
2m
c
UA
a
The pNPP assay. IC50 values were determined by regression analyses
b
and expressed as means SD of three replications. Not active at 20 µg/
c
mL concentration. Positive control.
changed Vmax values when the inhibitor concentration was
increased. Meanwhile, the result of the Lineweaver-Burk
plot confirmed 2b as a competitive inhibitor of PTP1B for
intersecting at the y-axis of a nest of lines with increased
inhibitor concentration (Fig. 2(c)). The results indicate that
2b binds the catalytic pocket of PTP1B and behaves as a
competitor to the substrate. The Ki value calculated from
Figure 2(d) was 0.54 µM.
In conclusion, a series of furan-chalcone derivatives were
identified as reversible and competitive PTP1B inhibitors
with IC50 values in the micromolar range. These results
should provide a promising starting point for PTP1B and
other PTPs inhibitor design. This is an initial report and
optimization of these compounds is in progress.
Figure 2. Characterization of 2b to PTP1B. (a) Time-independent i
initial velocity was determined in the presence of various concen
Lineweaver-Burk plot. (d) Ki determination.
activity than the compounds containing electron-donating
groups (i.e., 2g-j) on the whole level. These results indicated
that electron-withdrawing groups facilitated PTP1B inhibi-
tion. Three hydroxy-substituted derivatives (i.e., 2k-m) were
also designed and prepared, containing 2-OH, 3-OH and 2,4-
OH. The pharmacology test revealed that monohydroxy-
chalcones (i.e., 2k-l) showed no activity at 20 µg/mL and
weaker PTP1B inhibitory activity, respectively. But interest-
ingly, introduction of two hydroxyl groups to compound 1b
at the 2- and 4-position of the A ring (2m) dramatically
improved PTP1B inhibitory activity with IC50 values of 2.49
0.23 µM. The above results suggest that increasing the
number of hydroxyl groups on the A ring in chalcones leads
to stronger binding and improves potential inhibitory effects
against PTP1B. This is consistent with results reported pre-
Acknowledgments. This work was supported by the
National Natural Science Foundation of China (Grants
20962021 and 81125023) and the National Program on Key
Basic Research Project of China (973 Program, 2012CB524906).
And the publication of this paper was supported by the Korean
Chemical Society.
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