Brief Articles
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 7 2359
(50 mL) at 0 °C was added MCPBA (0.364 g, 2.11 mmol) in
portions. The resulting mixture was stirred at room temperature
for 6 h and then diluted with water and made slightly basic with
Na2CO3 solution. The DCM layer was separated, and the aqueous
layer was extracted with DCM. The combined organic layers were
dried and evaporated to give a residue that was purified by silica
gel flash column chromatography (ethyl acetate-methanol 5:1) to
give 8g, yield 48%. 1H NMR (400 MHz, DMSO-d6): δ 11.32 (br,
s, 1H), 10.38 (br, s, 1H), 9.15 (s, 2H), 8.20 (m, 1H), 7.88 (m, 1H),
7.72-7.80 (m, 6H); EI-MS m/z 489 [M]+, 491 [M + 2]+; HRMS
calculated for C18H12BrN5O5SNa [M + Na]+: 511.9634, found:
511.9632. Anal. (C18H12BrN5O5S) C, H, N.
paca2, 14-fold for Panc203, 100-fold for CWR22R, and 20-
fold for the LnCap cell line was obtained for compound 6n
over 6m. Similarly, when compared to 7c, the activity of 7d
was increased by >117-fold for Panc203, 9-fold for Miapaca2,
>50-fold for Panc430, 39-fold for Panc1, and 7-fold for the
LAPC-4 cell line. A large decrease in the activity of 8g and 8h
(when compared to that of 6n) was also seen with the
modification of sulfide to sulfoxide and sulfone. Even though
6m and 6n were effective in inhibiting tubulin assembly, their
poor binding affinity for colchicine binding site indicates the
existence of an alternate binding site mechanism.
1-[4-(5-Bromopyrimidine-2-sulfonyl)phenyl]-3-(2-nitrobenzoyl)-
urea (8h). The title compound was synthesized from 6n according
to above procedure using 3 equiv of MCPBA, yield 56%. 1H NMR
(400 MHz, DMSO-d6): δ 11.42 (br, s, 1H), 10.55 (br, s, 1H), 9.23
(s, 2H), 8.21 (m, 1H), 7.76-7.97 (m, 7H); EI-MS m/z 505 [M]+,
507 [M + 2]+; HRMS calculated for C18H12BrN5O6SNa [M +
Na]+: 527.9583, found: 527.9592. Anal. (C18H12BrN5O6S) C, H,
N.
In conclusion, we have synthesized a series of sulfur
analogues of BPU. Some of these had excellent growth
inhibition activity against both pancreatic and prostate cancer
cell lines. 6n and 7d were both found to be more potent than 1.
These compounds are currently being evaluated for their in vivo
efficacy in animal models.20 These findings have encouraged
us to continue the development and testing of novel sulfur
analogues of BPU and to conduct further studies to investigate
SAR and their mechanisms of action.
Acknowledgment. We gratefully acknowledge the financial
support of grants from FAMRI and NIH. We thank the
Medicinal Chemistry Core of the SKCCC at Johns Hopkins for
conducting the NMR and LC-MS studies. This work was
partially supported by National Cancer Institute Contract #NO1-
CO-12400.
Experimental Section
General Procedure for the Synthesis of Compounds 6a-n.
1-[4-(5-Bromopyrimidin-2-ylsulfanyl)phenyl]-3-(2-nitrobenzoyl)-
urea (6n). A solution of 5-bromo-2-chloropyrimidine (5 g, 0.026
mol), 4-aminothiophenol (3.24 g, 0.026 mol), and K2CO3 (7.14 g,
0.052 mol) in dry DMSO (50 mL) was stirred at 120 °C for 2.5 h
under N2. After cooling, the reaction mixture was poured into water
and extracted with ethyl acetate. The organic layer was washed
with water and saturated brine and then dried. The solvent was
evaporated to give a residue that was purified by silica gel flash
column chromatography (ethyl acetate-hexane 1:3) to give 4-(5-
bromopyrimidin-2-ylsulfanyl)phenylamine (4n), yield 74%. 1H
NMR (400 MHz, CDCl3): δ 8.51 (s, 2H), 7.37 (d, J ) 8.0 Hz,
2H), 6.72 (d, J ) 8.0 Hz, 2H), 2.63 (s, 2H); EI-MS m/z 281 [M]+,
283 [M + 2]+.
Note Added after ASAP Publication. Changes were made
to author addresses and affiliations, to the Acknowledment, and
to a compound number in the Figure 1 caption in the version
of this manuscript posted March 11, 2006. The revised version
was posted March 22, 2006.
Supporting Information Available: Spectral data for 6a-8h
and experimental procedures for biological evaluation. This material
A solution of 2-nitrobenzoyl isocyanate (3 g, 0.016 mol) in dry
1,4-dioxane (15 mL) was added dropwise to a solution of 4n (2.93
g, 0.01 mol) in dry 1,4-dioxane (15 mL) with stirring at room
temperature. The reaction mixture was stirred for 18 h and then
diluted with water. The precipitated solid was collected by filtration
and washed with water. The solid was dissolved in ethyl acetate,
and the organic layer was washed with water 2-3 times, dried,
and concentrated to give 1-[4-(5-bromopyrimidin-2-ylsulfanyl)-
phenyl]-3-(2-nitrobenzoyl)urea (6n), yield 92%. 1H NMR (400
MHz, DMSO-d6): δ 11.32 (br, s, 1H), 10.35 (br, s, 1H), 8.78 (s,
2H), 8.22 (m, 1H), 7.91 (m, 1H), 7.77 (m, 2H), 7.67 (m, 2H), 7.57
(m 2H); EI-MS m/z 473 [M]+, 475 [M+2]+; HRMS calculated for
C18H12BrN5O4SNa [M+Na]+: 495.9685, found: 495.9701. Anal.
(C18H12BrN5O4S) C, H, N.
References
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General Procedure for the Synthesis of Compounds 7a-d.
1-(2-Aminobenzoyl)-3-[4-(5-bromopyrimidin-2-ylsulfanyl)phen-
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1
yield 62%. H NMR (400 MHz, DMSO-d6): δ 11.92 (br, s, 1H),
10.73 (br, s, 1H), 8.75 (s, 2H), 7.68 (m, 2H), 7.57 (m, 2H), 7.25
(m, 1H), 6.79 (m, 1H), 6.59 (m 2H); EI-MS m/z 443 [M]+, 445
[M + 2]+; HRMS calculated for C18H14BrN5O2SNa [M + Na]+:
465.9943, found: 465.9938. Anal. (C18H14BrN5O2S) C, H, N.
General Procedure for the Synthesis of Compounds 8a-h.
1-[4-(5-Bromopyrimidine-2-sulfinyl)phenyl]-3-(2-nitrobenzoyl)-
urea (8g). To a stirred solution of 6n (1.0 g, 2.11 mmol) in DCM
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antitumor activities of water-soluble benzoylphenylureas. Chem.
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