A. Khalaj et al. / Bioorg. Med. Chem. Lett. 16 (2006) 6034–6038
6037
3. Palmer, B. D.; Wilson, W. R.; Cliff, S.; Denny, W. A.
J. Med. Chem. 1992, 35, 3214.
4. Lewis, D. F. V. Xenobiotica 1989, 19, 243.
5. Gill, P. G.; Denham, J. W.; Jamieson, P. G.; Yeoh, D. E.;
Olweny, C. J. Clin. Oncol. 1992, 10, 1037.
6. Sinclair, W. Int. J. Radiat. Oncol. Biol. Phys. 1981, 7, 631.
7. Adams, G. E. Br. Med. Bull. 1973, 29, 48.
8. Sheldon, P. W.; Smith, A. M. Br. J. Can. 1975, 31, 81.
9. Papadopoulou, M. V.; Bloomer, W. D. Drugs Future 2004,
29, 807.
10. Gardiner, J. M.; Loyns, C. R.; Schwalbe, C. H.; Barrett,
G. C.; Lowe, P. L. Tetrahedron 1995, 51, 4101.
11. For the preparation of the compound 7, a solution of
hydroxyurea 6 (76 mg, 1 mmol) and sodium ethoxide
(78 mg, 1 mmol) in 20 ml of EtOH was treated with
1 mmol of 1-(3-bromopropyl)-2,4-dinitrophenylamine 9
(305 mg, 1 mmol) and refluxed for 12 h. After evapo-
ration of the solvent under reduced pressure, com-
pound 7 was isolated from the residue by preparative
TLC (EtOAc–CHCl3 1:1) and purified by crystalliza-
tion from a CHCl3–Hexan mixture to give 135 mg
(36%) of 7 as a yellow solid, mp 183–185 °C. IR
(KBr) (mmax, cmÀ1): 3421, 1700, 1600, 1410. 1H NMR
(DMSO-d6 400 MHz) : 9.16 (d, 2H, J = 2.8 Hz), 8.88
(d, 1H, J = 2.8 Hz), 8.23 (dd, 1H, J = 2.8, 9.6 Hz), 7.46
(d, 1H, J = 6.4 Hz), 7.22 (d, 1H, J = 9.6 Hz), 3.60 (t,
2H, J = 6.4 Hz), 3.44–3.46 (m, 2H), 1.84 (m, 2H). MS
(Finingan, TSQ-70): m/z 353 (M+). Anal. Calcd for
C13H12FN5O6: C, 44.2; H, 3.42; N, 19.82. Found: C,
44.12; H, 3.41; N, 19.85.
Figure 3. Clonogenic survival of HT29 cells without (h) and upon (m)
Gamma-irradiation (4 Gy) at different times after incubation with
10 lM of the compounds 7 and 8. Data points were obtained from
three independent experiments, and the standard deviations are given
for each point (*p < 0.05, ***p < 0.001).
The radiosensitizing activity of both compounds 7 and 8
was high and did not increase significantly with increase
in the dose of radiation as it was found from the values
which were obtained by dividing the radiation dose
without over the radiation dose with the tested com-
pounds for the same survival levels.21 These values for
compound 7 at doses of 4, 8, and 12 G were equal to
1.64, 1.66, and 1.67, where it reduced the viability of
cells to 60.8%, 59.22%, and 59.56% of controls, respec-
tively. For compound 8 the corresponding values were
1.77, 1.68, and 1.95 for reduction of cell survival to
56.63%, 59.41%, and 51.07% of controls, respectively,
which statistically were not significantly different.
12. A solution of 5-fluorouracil 5 (1 g, 7.5 mmol) in 40 ml of
DMSO, was treated with K2CO3 (1.04 g, 2.5 mmol), KI
(5.4 g, 2.5 mmol), and (780 mg, 2.5 mmol) of the com-
pound 9 and the mixture was heated at 70–80 °C for 4 h.
The mixture was then treated with water, acidified with
HCl, and extracted with CHCl3. The residue after evap-
oration of the solvent was subjected to preparative TLC
(CHCl3–EtOH, 9:1) to isolate compound 8 which was
crystallized from a CH3OH–ether mixture to give 210 mg
(24%) of the pure product as yellow solid, mp 107–110 °C.
1
IR (KBr) (mmax, cmÀ1): 3356, 2919, 1613, 1511, 1332. H
NMR (DMSO-d6, 400 MHz) 9.02 (br, 1H, NH), 8.92 (br,
1H, NH), 8.86 (d, 1H, J = 2.8 Hz), 8.26 (dd, 1H, J = 2.8,
9.6 Hz), 7.26 (d, 1H, J = 9.6 Hz), 6.42 (br, 2H, NH), 3.77
(t, 2H, J = 5.6 Hz), 3.56–360 (m,2H), 1.90–1.95 (m, 2 H).
MS (Finingan, TSQ-70) m/z 299.1 (M+). Anal. Calcd for
C10H13N5O6: C, 44.30; H, 4.73; N, 18.79. Found: C, 44.41;
H, 4.72; N, 18.81.
From results of this investigation it seems that further
exploration of compounds 7 and 8 may be appropriate
since these compounds were not cytotoxic but increased
the sensitivity of the normal oxygenated cells to radia-
tion. The use of these compounds in conjunction with
tumor radiotherapy might result in much greater toxic-
ity to tumor than normal tissues.
13. The key intermediate 9 was prepared by ultrasound
promoted reaction of 2,4-dinitrophenylamine (1.86 g,
0.01 mol) with 1,3-dibromopropane (606 mg, 0.01 mol)
in the presence of sodium hydride (240 mg, 0.01 mol) in
10 ml of CH3CN at 40 °C for 10 min and isolated by the
flash chromatography (CHCl3) of the residue after evap-
oration of the solvent and recrystallized from a CHCl3–
Hexan mixture to give 2.088 g (68.7%) of the pure 9 as a
yellow solid; mp 63–67 °C. IR (KBr) (mmax, cmÀ1): 3365,
Acknowledgment
The authors thank the Pharmaceutical Research Centre
of the Faculty of Pharmacy, Tehran University of
Medical Sciences, for the financial support of this
investigation.
1
2919, 1613, 1511, 133. H NMR (CDCl3 400 MHz): 9.17
(d, 1H, J = 2.8 Hz), 8.62 (br, 1H, NH), 8.31 (dd, 1H,
J = 2.8, 9.6 Hz), 7.01 (d, 1H, J = 9.6 Hz), 3.64–3.66 (m,
2H), 3.54 (t, 2H, J = 6 Hz), 2.3 (m, 2H); MS (Finingan
TSQ-70) m/z 305 (M+). Anal. Calcd for C9H10BrN3O4: C,
35.55; H, 3.31; N, 13.82. Found: C, 35.61; H, 3.30; N,
13.77.
References and notes
14. Lambin, P.; Malaise, E. P.; Joiner, M. C. Int. J. Rad. Biol.
1996, 69, 279.
15. Calsson, J.; Hakansson, E.; Eriksson, V.; Graw, J.; Westr,
K.; Grawe, J.; Grussel, E.; Montelius, A.; Lundqvist, H.
Cancer. Biother. Radiopharm. 2003, 18, 663.
1. Ayuko, W.O. Int. Pat. Appl. WO 9427584, 1995; Chem.
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2. Palmer, B. D.; Wilson, W. R.; Pullen, S. M.; Denny, W. A.
J. Med. Chem. 1990, 33, 112.