5724
J. Lee et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5722–5725
H
H
N
O2N
NH2
O2N
N
R
H2N
R
i
ii
O
O
7
8
9
Scheme 2. Reagents and conditions: (i) R-CO2H, HOBt, EDCI, Et3N, DMF, 90 °C, 20 h, 28–86%; (ii) Pd/C, H2, MeOH, rt, 1 h, 24–89% (except 9l); SnCl2, EtOH, reflux, 2 h, 46% (for
9l).
aminoquinazolines could be served as a scaffold for treatment of
melanoma.
Table 2
Cell line selectivity and enzymatic activity of the selected compounds 1o and 1q
Compd
IC50
(lM)
Acknowledgment
A375
HS27
V600E-b-Raf
c-Raf
1o
1q
Sorafenib
0.137
0.006
5.58
1.20
0.230
—
—
—
This research was supported by a grant (K00060-282) from the
Fundamental R&D Program for Core Technology of Materials
funded by the Ministry of Knowledge Economy, Republic of Korea.
19.5
0.765
0.038a
0.006a
a
Enzymatic assay data were cited from the literature (Wilhelm, S. M. et al. Cancer
Res. 2004, 64, 7099).
References and notes
acetate in formamide22 followed by bromination with N-bromo-
succinimide in the presence of AIBN gave the bromomethylquinaz-
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The synthesis of 9, which were served for the synthesis of 1a–r,
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nitrobenzamides 8 with Pd/C in MeOH or SnCl2 in EtOH afforded
the aminobenzenes 9, respectively, in 24–89 yields.
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25. A375P cells were purchased from American Type Culture Collection (ATCC,
Rockville, MD, US) and maintained in DMEM medium (Welgene, Daegu, Korea)
supplemented with 10% FBS (Welgene) and 1% penicillin/streptomycin
(Welgene) in a humidified atmosphere with 5% CO2 at 37 °C. A375P cells
were taken from culture substrate with 0.05% trypsin–0.02% EDTA and plated
at a density of 5 Â 103 cells/well in 96 well plates and then incubated at 37 °C
for 24 h in a humidified atmosphere with 5% CO2 prior to treatment of various
concentration (threefold serial dilution, 12 points) of test compounds. The
All the synthesized compounds were evaluated by MTT assays
using CellTiter 96Ò (Promega). Six compounds showed better anti-
proliferative activity against A375 human melanoma cell line than
Sorafenib. Among these compounds, 1a, 1b, 1o, and 1q possessed
the nanomolar antiproliferative activities. Especially, compound
1q bearing chromen-4-one moiety exhibited excellent antiprolifer-
ative activity with IC50 value of 0.006 lM.
In conclusion, a novel series of aminoquinazoline derivatives
was designed and synthesized. In our series, the representative
compound 1q exhibited not only excellent antiproliferative activ-
ity against A375 human melanoma cell line but also good selectiv-
ity over HS27 fibroblast cell line. These results suggest that