460
D. Sun et al. / Bioorg. Med. Chem. Lett. 20 (2010) 458–460
Table 1
Antiproliferative activity for compounds 3a–d, 5, 6a,b, and 8a on cancer and normal cell linesa,b
Compound
Cytotoxicity, IC50 (lM)
MiaPaCa
MDA-MB-231
Foreskin fibroblasts
3a
3b
3c
3d
5
6a
6b
8a
1.0 0.3
0.8 0.2
4.0 1.0
40 10
0.6 0.2
150 30
50 5.0
50 5.0
25 5.0
40 + 10
9.0 3.0
4.0 0.5
20 3.0
250 50
5.0 2.0
150 50
75 25
75 25
20 5.0
150 50
200 20
16.5 2.5
200 10
350 30
100 10
400 20
300 20
250 10
100 10
250 20
2:1 Complex of 3a with iron
9a
a
Both MDA-MB231 and MiaPaCa cells were treated with various concentrations of compounds for 96 h. Cell viability was measured by MTT assay. Results represent
mean S.D. of three experiments.
b
Cytotoxicity for Deferasirox (DFX) in the same experiments were 4 1.0 lM for MiaPaCa, 10 2.5 lM in MDA-MB-231 cells, and 100 10 in foreskin fibroblasts.
18. Valko, M.; Rhodes, C. J.; Moncol, J.; Izakovic, M.; Mazur, M. Chem. Biol. Interact.
2006, 160, 1.
19. Gun, J.; Ekeltchik, I.; Lev, O.; Shelkov, R.; Melman, A. Chem. Commun. 2005,
5319.
iron(III) complexes. Simplicity of the synthesis of BHT chelators,
easy modification of their physical and chemical properties, and
their high antiproliferating activity make BHT chelators promising
candidates for further study as cancer chemotherapeutics.
20. Ekeltchik, I.; Gun, J.; Lev, O.; Shelkov, R.; Melman, A. Dalton Trans. 2006, 1285.
21. Chelators 3a,c and their iron complexes have been reported in the Ref. 21.
22. General procedure for preparation of 3a–d: To a solution of 1 (18.4 g, 100 mmol)
a solution of a
corresponding amine R1R2NH
References and notes
in ethyl acetate (300 mL)
(200 mmol) in THF (100 mL) was added dropwise at À2 °C under vigorous
stirring. The reaction was continued 15 min after completing the addition and
filtered. The filtrate was evaporated to afford 2,6-dichloro-4-R1,R2-amino-
1,3,5-triazines of type 2 that are purified by recrystallization from isopropanol.
To a suspension 2 (30 mmol) in dioxane at 0 °C (90 mL) was added a solution of
R3NHOH hydrochloride (120 mmol) and NaOH (5.4 g, 108 mmol) in water
(20 mL). The reaction mixture was stirred for 14 h, diluted with water and the
precipitated 3a–d were collected by filtration and recrystallized from
isopropanol.
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23. A solution of 2,4,6-trichlorotriazine (50 mmol) in acetone (100 mL) at À2 °C
under vigorous stirring was added dropwise a solution of MeOH (50 mmol) and
2,6-lutidine (50 mmol) in acetone (50 mL). The reaction mixture was stirred for
30 min. after completing the addition and then allowed to warm to room
temperature and stirred overnight. The reaction mixture was filtered, the
filtrate is poured into crushed ice and filtered. The precipitate of 4 is dried and
recrystallized from isopropanol. To a suspension of 4 (30 mmol) in dioxane at
0 °C (90 mL) was added a solution of MeNHOH hydrochloride (120 mmol) and
NaOH (5.4 g, 108 mmol) in water (20 mL). The reaction mixture was stirred for
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(400 MHz).
24. All newly synthesized compounds has adequate spectral data, for example, 3d
(400 MHz, CDCl3) 3.70 (m, 4H), 3.83 (m, 4H); 5 (400 MHz, D2O) 3.24 (s, 6H),
3.95 (s, 3H); 6a (400 MHz, D2O) 3.21 (s, 3H), 3.64 (br s, 8H); 6b (400 MHz,
CDCl3) 0.96 (t, J = 7 Hz, 3H), 1.38 (m, 2H), 1.54 (m, 2H), 3.37 (br s, 5H); 8a
(400 MHz, CDCl3) 2.94 (t, J = 9.6 Hz, 2H), 3.36 (s, 3H), 3.6–3.8 (m, 8H), 3.93 (t,
J = 9.6 Hz, 2H); 9a (400 MHz, CDCl3) 3.31 (s, 3H), 3.34 (s, 3H), 3.70–3.78 (m, 8H)
3.76 (s, 3H).
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26. The 2:1 3a–iron complex was prepared according to the procedure described in
Ref. 20.