3570
B. Smith et al. / Bioorg. Med. Chem. Lett. 22 (2012) 3567–3570
3
N
R1
4
2
NH
5
R3
R2
S
1
5a-l
Figure 3. Structure of 2-aminothiazoles analogs 5.
Table 2
Biological activity of 2-aminothiazoles analogs 5a–la,b,c,d,e,f,g,h
R1
R2
R3
PGE2 (%)
COX-2e (%)
COX-2f (IC50
,
lM)
PGE2 (EC50
,
l
M)
d
g
Compd
5a
5b
5c
5d
5e
5f
5g
5h
5i
Ph
Ph
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Me
3-OCH2O-4-Ph
4-CN-Ph
4-OMe-Ph
4-OPh-Ph
Ph
4-OPh-Ph
3-OCH2O-4-Ph
4-CN-Ph
4-OMe-Ph
4-OMe-Ph
4-OPh-Ph
4-OPh-Ph
C(O)Ph
C(O)Ph
C(O)Ph
C(O)Ph
C(O)Me
C(O)Me
C(O)Me
C(O)Me
C(O)Me
Et
NR
NR
NR
—
—
—
—
—
—
—
—
—
>5
—
—
—
—
—
—
—
42.0
29.9
87.9
25.3
22.4
58.5
94.4
87.1
80.4
6
1
1
3
4
4
1
3
3
—
—
28.9 15
0.39 0.07
—
—
—
—
—
49.3
41.3
—
5j
5k
5l
4
5
>5
>5
>5
0.32 0.14
0.37 0.07
0.09 0.04
Et
h
CH(OH)Me
À16.9 10
a
b
c
Celecoxib was used as a positive control (PGE2, 5.70 3.28% and EC50 = 1.15 0.06 nM; COX-2, 85.6 4.4% inhibition and IC50 = 0.03 0.01).12
NR, no observed reduction.
Not determined.
d
e
f
% of inhibition of PGE2 levels in HCA-7 cells at 1
% of inhibition of COX-2 levels in vitro at 5 M concentration SD (n = 3).
In vitro IC50 for COX-2 inhibition SD (n = 3).
lM concentration SD (n = 3).
l
g
h
EC50 for PGE2 level reduction in HCA-7 cells SD (n = 3).
To be considered as no inhibition of activity rather than induction of activity.
9. Giroux, A.; Boulet, L.; Brideau, C.; Chau, A.; Claveau, D.; Cote, B.; Ethier, D.;
Frenette, R.; Gagnon, M.; Guay, J.; Gurial, S.; Mancini, J. A.; Martins, E.; Masse,
F.; Methot, N.; Riendeau, D.; Rubin, J.; Xu, D.; Yu, H.; Ducharme, Y.; Friesen, R.
W. Bioorg. Med. Chem. Lett. 2009, 19, 5837.
10. Moon, J. T.; Jeon, J. Y.; Park, H. A.; Noh, Y.-S.; Lee, K.-T.; Kim, J.; Choo, D. J.; Lee, J.
Y. Bioorg. Med. Chem. 2010, 20, 734.
reduced PGE2 levels. Future synthetic efforts will be focused on
further development of aminothiazoles with diverse substitution
patterns that will continue to reveal important structure activity
relationship features and aid in the identification of more potent
compounds with anticancer activity in vivo.
11. Hamza, A.; Zhao, X.; Tong, M.; Tai, H. H.; Zhan, C. G. Bioorg. Med. Chem. 2011, 19,
6077.
12. Kabalka, G. W.; Mereddy, A. R. Tetrahedron Lett. 2006, 47, 5171.
13. Masquelin, T.; Obrecht, D. A. Tetrahedron 2001, 57, 153.
Acknowledgments
14. Isakson, P. C.; Zhang, Y. Y.; Veenhuizen, A. W.; Seibert, K.; Perkins, W. E.;
Koboldt, C. M.; Gregory, S. A.; Cogburn, J. N.; Burton, E. G.; Anderson, G. D.; Yu,
S. S.; Rogier, D. J.; Rogers, R. S.; Miyashiro, J. M.; Malecha, J. W.; Lee, J. F.;
Graneto, M. J.; Docter, S.; Collins, P. W.; Carter, J. S.; Bertenshaw, S. R.; Talley, J.
J.; Penning, T. D. J. Med. Chem. 1997, 40, 1347.
15. Chang, H. H.; Song, Z.; Wisner, L.; Tripp, T.; Gokhale, V.; Meuillet, E. J. Invest.
16. General procedure for the preparation of 2e: 2-Bromo-1-(4-methoxyphenyl)
The authors would like to thank financial support provided by
an NIH training Grant research fellowship (BCP Fellowship, Grant
#
5T32GM008804-09), the University of Arizona College of
Pharmacy for start-up funds and SR01CA138702. Finally, the
authors graciously acknowledge Kristen Keck for selected com-
pound purification, Alex Laetsch for compound management and
Nicole Schechter for group coordination.
ethanone
7 (0.437 mmol, 100 mg) and N-(4-phenoxyphenyl)thiourea 8
(0.437 mmol, 107 mg) were suspended in ethanol (2 mL) and subjected to
microwave irradiation at 110 °C for 10 min. The resulting solution was diluted
with CH2Cl2 (10 mL) and washed with a saturated aqueous solution of Na2CO3
(20 mL). The organic layer was dried (MgSO4) and evaporated under reduced
pressure. The resulting crude residue was purified by silica gel column
chromatography (EtOAc–hexanes, gradient) using a ISCO™ system to give
aminothiazole 2e as a light orange solid (0.246 mmol, 92 mg, 56%). mp: 125.5–
127 °C; 1H NMR (300 MHz, DMSO-d6) d 10.25 (br s, 1H), 7.85 (d, J = 8.7 Hz, 2H),
7.77 (d, J = 8.9 Hz, 2H), 7.37 (t, J = 7.8 Hz, 2H), 7.14 (s, 1H), 7.13–7.02 (m, 3H),
7.02–6.94 (m, 4H), 3.79 (s, 3H). 13C NMR (75 MHz, DMSO-d6) d 163.9, 159.7,
158.6, 150.9, 150.8, 138.4, 130.8, 128.3, 127.9, 123.5, 120.9, 119.2, 118.4, 114.8,
101.4, 56.0. LC–MS [MH]+ 375.1.
References and notes
1. Iyer, J. P.; Srivastava, P. K.; Dev, R.; Dastidar, S. G.; Ray, A. Expert Opin. Ther.
Targets 2009, 13, 849.
2. Friesen, R. W.; Mancini, J. A. J. Med. Chem. 2008, 51, 4059.
3. Tawab, M. A.; Zettl, H.; Zsilavecz, M. S. Curr. Med. Chem. 2009, 16, 2042.
4. Wang, D.; DuBois, R. Nat. Rev. Cancer 2010, 10, 181.
5. (a) Hanahan, D.; Weinberg, R. A. Cell 2000, 100, 57; (b) Hanahan, D.; Weinberg,
R. A. Cell 2011, 144, 646.
6. Greenhough, A.; Smartt, H. J. M.; Moore, A. E.; Roberts, H. R.; Williams, A. C.;
Paraskeva, C.; Kaidi, A. Carcinogenesis 2009, 30, 377.
7. Riendeau, D.; Aspiotis, R.; Ethier, D.; Gareau, Y.; Grimm, E. L.; Guay, J.; Guiral, S.;
Juteau, H.; Mancini, J. A.; Methot, N.; Rubin, J.; Friesen, W. Bioorg. Med. Chem.
Lett. 2005, 15, 3352.
8. Cote, B.; Boulet, L.; Brideau, C.; Claveau, D.; Ethier, D.; Frenette, R.; Gagnon, M.;
Giroux, A.; Guay, J.; Guiral, S.; Mancini, J.; Martins, E.; Masse, F.; Methot, N.;
Riendeau, D.; Rubin, J.; Xu, D.; Yu, H.; Ducharme, Y.; Friesen, R. W. Bioorg. Med.
Chem. Lett. 2007, 17, 6816.
17. PGE2 production assay: Cells were seeded in 6-well plates and incubated
overnight in DMEM/10% FBS. They were serum starved for the next 18 h. Cells
were then treated with 10 ng/ml IL-1b and increasing concentration of
compounds (dissolved in DMSO) in 1 mL serum-free medium. After 72 h of
incubation, the supernatants were collected for PGE2 level detection using the
PGE2 EIA kit (R&D Systems).
18. COX-2 cell-free assay: COX-2 activity was measured by a COX Fluorescent
inhibitor screen assay kit following the manufacturer’s instructions (Cayman