L. Zhang et al. / Bioorg. Med. Chem. Lett. 17 (2007) 2118–2122
2121
Figure 4. (A) View of allosteric site in presence of compound A4. (B) View of allosteric site in presence of compound A17.
Table 2. Activities of quinoxalinylurea derivatives
Acknowledgment
This work was financially supported by the National
Natural Science Foundation of China (Grants
30230400 and 30572255).
H
N
R1
R1
N
O
N
N
O
N
R2
R3
References and notes
Compound R1
NR2R3
JSP-1 IC50 (lM)a
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Cannon, J. P.; Cabriera-Hansen, M.; Meyer, C. F.;
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A15
A16
A17
A18
A19
A20
A21
A22
A23
2-Furyl Dimethylamine >40
2-Furyl N-Methyl-butylamine 5.55 0.56
2-Furyl N-Ethyl-butylamine
2-Furyl Dipropylamine
2-Furyl Ethylamine
2.35 0.65
2.50 0.06
>40
2-Furyl Isopropylamine
2-Furyl tert-Butylamine
2-Furyl Isobutylamine
2-Furyl n-Butylamine
>40
8.05 0.97
8.36 0.18
2.79 0.25
a Data are means of three independent experiments.
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Replacing with long chain or sterically hindered alkyl
groups, the compounds A16–A18 and A21–A23 showed
significant activity comparable with A2–A4. Further-
more, enzymatic kinetics studies on compound A17 also
indicated that it is a reversible and noncompetitive
inhibitor of JSP-1 (Figs. 2 and 3).
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In summary, we have synthesized and investigated preli-
minary SAR for a novel series of quinoxalinylurea
derivatives with JSP-1 inhibitory activity based on the
compound A1 obtained through high-throughput
screening. The result of in vitro biological experiment
showed that these compounds were noncompetitive
and reversible inhibitors of JSP-1. Through computa-
tional modeling, an allosteric site in JSP-1 was found,
and based on the docking study we provided a hypoth-
esis that a hydrophobic subpocket is close-by and can be
utilized to improve the binding affinity. The biological
assay performed on the second round compounds con-
firmed that bulky alkyl groups appended to the piperi-
dine-3-carboxamide would benefit the affinity to JSP-1.
The further study is going on.
15. Takano, Y.; Shiga, F.; Asano, J.; Ando, N.; Uchiki, H.;
Anraku, T. Bioorg. Med. Chem. Lett. 2003, 13, 3521.