K. Tanabe et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2633–2635
2635
14. Zhou, L.; Ino, A.; Dai, W.-M.; Nishimoto, S. Bioorg.
Med. Chem. 1999, 7, 2591.
enhancement ratios in vitro (SERin vitro) at 0.5 mM for 1a
and 1c were 2.4 and 2.6, respectively (see Fig. 2).
15. Nicolaou, K. C.; Skokotas, G.; Maligres, P.; Zuccarello,
G.; Schweiger, E. J.; Toshima, K.; Wendeborn, S. Angew.
Chem., Int. Ed. Engl. 1989, 28, 1272.
16. Haruna, K.; Tanabe, K.; Ishii, A.; Dai, W.-M.; Hatta, H.;
Nishimoto, S. Bioorg. Med. Chem. 2003, 11, 5311.
17. Dai, W.-M.; Lai, K. W.; Wu, A.; Hamaguchi, W.; Lee,
Y. H. M.; Zhou, L.; Ishii, A.; Nishimoto, S. J. Med. Chem.
2002, 45, 758.
It is also seen from Figure 2 that carboxylic acid
derivative 1c showed higher hypoxic-cell radiosensitiz-
ing activity than acetate 1a, although the GSH-depletion
reactivity of 1c as measured by the second-order rate
constant k2 for nucleophilic addition (Table 1) was
about half that of 1a. By reference to the partition
coefficient (Po=w) between 1-octanol and water listed in
Table 1, 1a is of much higher lipophilicity (Po=w ¼ 15:0)
than carboxylic acid derivative 1c (Po=w ¼ 2:2). It seems
that 1c may readily permeate the cell membrane because
of its appropriately low lipophilicity, while highly lipo-
philic 1a is subject to trapping by the cell membrane.
Thus, appropriate lipophilicity and GSH-depletion
reactivity are important factors in the molecular design
of a family of propargylic sulfones containing a 2-
nitroimidazole function for hypoxic-cell radiosensitizers
with cellular NPSH-depletion ability.
18. Dai, W.-M.; Li, Q.; Fong, K. C.; Chow, C. W.; Zhou, L.;
Hamaguchi, W.; Nishimoto, S. Bioorg. Med. Chem. Lett.
1999, 9, 2789.
19. Compound 1a: Mp 148–150 °C. 1H NMR (CDCl3,
300 MHz) d 8.43 (d, 2H, J ¼ 9:0 Hz), 8.17 (d, 2H,
J ¼ 9:0 Hz), 7.13 (s, 1H), 7.13 (s, 1H), 5.22–5.19 (1H),
4.88 (dd, 1H, J ¼ 14:8, 3.0 Hz), 4.49 (dd, 1H, J ¼ 14:8,
7.5 Hz), 4.02 (s, 2H), 2.63–2.45 (2H), 1.96 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 169.5, 151.2, 143.3, 130.1,
128.4, 126.6, 124.5, 82.8, 76.6, 70.7, 69.2, 51.1, 48.7, 22.0,
20.6, 14.2; FABMS (NBA) m=z 437 [(M+H)þ]; HRMS
calcd for C17H17O8N4S [(M+H)þ] 437.0767, found
437.0773.
1
20. Compound 1b: H NMR (DMSO-d6 400 MHz) d 7.93 (d,
In summary, we synthesized propargylic sulfones con-
taining a 2-nitroimidazole function to investigate their
GSH-depletion reactivity and hypoxic-cell radiosensi-
tizing activity. These compounds were confirmed to
reduce the intracellular NPSH level and exhibited a very
high value of SERin vitro, thus, they are promising can-
didates as novel radiosensitizers for the treatment of
hypoxic tumor cells.
2H, J ¼ 7:2 Hz), 7.75 (t, 1H, J ¼ 7:2 Hz), 7.65 (t, 2H,
J ¼ 7:2 Hz), 7.49 (s, 1H), 7.15 (s, 1H), 5.19 (m, 1H), 4.67
(dd, 1H, J ¼ 14:0, 3.2 Hz), 4.49 (s, 2H), 4.37 (dd, 1H,
J ¼ 14:0, 8.8 Hz), 2.66–2.55 (2H), 1.86 (s, 3H); 13C NMR
(DMSO-d6 100 MHz) d 169.1, 144.6, 138.0, 134.1, 129.1,
128.2, 128.1, 127.7, 82.0, 71.5, 68.9, 51.1, 47.3, 21.4, 20.3;
FABMS (NBA) m=z 392 [(M+H)þ]; HRMS calcd for
C17H18O6N3S [(M+H)þ] 392.0916, found 392.0923.
21. Compound 1c: Mp 64–66 °C. 1H NMR (DMSO-d6
300 MHz) d 8.45 (d, 2H, J ¼ 9:0 Hz), 8.20 (d, 2H,
J ¼ 9:0 Hz), 7.51 (s, 1H), 7.11 (s, 1H), 5.17 (m, 1H), 4.54
(dd, 1H, J ¼ 12:8, 3.0 Hz), 4.37 (dd, 1H, J ¼ 12:8, 7.5 Hz),
3.42 (s, 2H), 2.61 (m, 6H), 2.40–2.31 (4H); 13C NMR
(DMSO-d6 75 MHz) d 173.0, 171.2, 150.7, 143.2, 130.0,
128.3, 127.8, 124.4, 82.5, 71.0, 69.1, 56.0, 51.0, 47.1, 28.4,
21.4, 18.5; FABMS (NBA) m=z 495 [(M+H)þ]; HRMS
calcd for C19H19O10N4S [(M+H)þ] 495.0822, found
495.0802.
Acknowledgements
We are grateful to Dr. Wei-Min Dai (Department of
Chemistry, The Hong Kong University of Science and
Technology) for his valuable discussions.
22. The reactivity of GSH toward propargylic sulfones were
measured by the Ellmanꢀs method. See: Tietze, F. Anal.
Biochem. 1969, 27, 502. To an aqueous solution of 10 mM
GSH and 20 mM aqueous EDTAÆ2Na was added a
solution of propargylic sulfones in 1:9 v/v mixture of
acetonitrile and phosphate buffer. The resulting mixture
was incubated at 37 °C for the given periods of reaction.
Aliquot (0.1 mL) was withdrawn from the mixture and
was poured immediately into phosphate buffer (0.9 mL)
containing 0.2 mM of the Ellmanꢀs reagent (5,50-dithio-
bis(2-nitrobenzoic acid), DTNB). The concentration of
unreacted GSH was determined by UV absorption spec-
troscopy at the maximum absorption wavelength at
412 nm.
References and notes
1. Liphard, M.; Bothe, E.; Schulte-frohlinde, D. Int. J.
Radiat Biol. 1990, 58, 603.
2. Alper, T. Cellular Radiobiology; Cambridge University:
Cambridge, 1979.
3. Astor, M. B.; Anderson, V.; Mester, A. Pharmacol. Ther.
1998, 39, 115.
4. Held, K. D. Pharmacol. Ther. 1988, 39, 123.
5. Howard-Glanders, P. Nature 1960, 186, 485.
6. Chapman, J. D.; Greenstock, C. L.; Reuvers, A. P.; Dugle,
D. L. Radiat. Res. 1975, 64, 365.
7. Biaglow, J. E.; Varnes, M. E.; Clark, E. P.; Epp, E. R.
Radiat. Res. 1983, 95, 473.
8. Bump, E. A.; Yu, N. Y.; Brown, J. M. Science 1982, 217,
544.
9. Bump, E. A.; Yu, N. Y.; Brown, J. M. Int. J. Oncol. Biol.
Phys. 1982, 84, 39.
23. Dai, W.-M.; Fong, K. C.; Danjo, H.; Nishimoto, S.;
Solow, M.; Mak, W. L.; Yeung, M. L. Bioorg. Med. Chem.
Lett. 1996, 6, 1093.
24. EMT6/KU cells were grown as monolayer in Eagleꢀs
minimum essential medium (MEM) supplemented with
12.5% fetal bovine serum (FBS) and L-glutamine. MEM
10. Harris, J. W.; Power, J. A. Radiat. Res. 1973, 56, 97.
11. Han, A.; Sinclair, W. K.; Kimler, B. F. Radiat. Res. 1976,
65, 337.
12. Nishimoto, S.; Zhou, L. Bioorg. Med. Chem. Lett. 1994, 4,
439.
13. Zhou, L.; Nishimoto, S. Int. J. Radiat Biol. 1995, 67, 335.
was adjusted to pH 7.5 by 10% aqueous NaHCO3 solu-
tion. All propargylic sulfones for evaluation were dis-
solved in FBS free MEM containing small amount of
DMSO. Cells were seeded into glass cultural dishes, 24 h
prior to experiment, to establish an exponential growth
condition.