5
834
S. M. Park et al. / Bioorg. Med. Chem. Lett. 20 (2010) 5831–5834
the mode of action of 6d, among the several metabolic effects
of fluoropyrimidines, the efficacy of compound 6d might be re-
lated to its inhibition of the key enzyme thymidylate synthase
Supplementary data
(
TS).
To determine the selective toxicity of the perfluoroalkyltriazole
nucleoside analogues toward cancer cells, we performed a prolifer-
ation assay using CCD-33Lu (lung fibroblast normal) cells (Fig. 3).
Interestingly, none of the perfluoroalkyltriazole nucleoside ana-
logues exhibited any toxicity toward normal lung fibroblast cells,
References and notes
1.
(a) Damaraju, V. L.; Damaraju, S.; Young, J. D.; Baldwin, S. A.; Mackey, J.;
Sawyer, M. B.; Cass, C. E. Oncogene 2003, 22, 7524; (b) Ewald, B.; Sampath, D.;
Plunkett, W. Oncogene 2008, 27, 6522.
even at 10
lM. In contrast, the reference drugs floxuridine and
2. (a) Duschinsky, R.; Pleven, E.; Heidelberger, C. J. Am. Chem. Soc. 1957, 79, 4559;
b) Smith, I. C.; Hutcheon, A. W.; Heys, S. D. Curr. Pharm. Des. 2000, 6, 327; (c)
Kamm, Y. J.; Wagener, D. J.; Rietjens, I. M.; Punt, C. J. Anticancer Drugs 1998, 9,
71; (d) Clayman, G. L.; Lippman, S. M.; Laramore, G. E.; Hong, W. K. In Cancer
(
doxorubicin displayed serious toxicities toward normal cells, with
values of GI50 greater than 100-fold of those of the perfluoroalkyl-
triazole nucleoside analogues.
3
Medicine; Bast, R. C., Kufe, D. W., Pollock, R. E., Weichselbaum, R. R., Holland, J.
F., Frei, E., Eds., 5th ed.; BC Decker Inc.: Ontario, 2000; pp 407–505.
In summary, we have investigated perfluoroalkyltriazole-pre-
0
3. (a) Studer, A.; Hadida, S.; Ferritto, R.; Kim, S.-Y.; Jeger, P.; Wipf, P.; Curran, D. P.
Science 1997, 275, 823; (b) Pongdee, R.; Liu, H.-W. Bioorg. Chem. 2004, 32, 393;
senting nucleosides as anticancer drug candidates. A 2 -deoxyuri-
dine derivative (6d) featuring an appended perfluorodecyl-
substituted triazole unit displayed significant anticancer effects
against selected cancer cell lines (PC-3, MDA-MB-231, ACHN) and
superior cancer cell-selective antiproliferation effects relative to
reference drugs (floxuridine and doxorubicin). Although we lack
evidence regarding the cancer cell inhibitory mechanism of 6d,
we suspect that it involves interactions with the enzyme TS. To
date, most perfluorocarbons have been applied in materials science
because of their interesting physical properties. Our findings are
meaningful because these perfluoroalkyltriazole-substituted
nucleosides are the first to have found potential medicinal applica-
tions. We are continuing our search for more effective anticancer
drugs based on perfluoroalkyltriazole nucleosides and their mech-
anisms of action.
(
c) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881; (d) Curran, D. P.
Science 2008, 321, 1645.
4
.
.
Olsen, J. A.; Banner, D. W.; Seiler, P.; Wagner, B.; Tschopp, T.; Obst-Sander, U.;
Kansy, M.; Müller, K.; Diederich, F. ChemBioChem 2004, 5, 666.
Lee, Y. S.; Park, S. M.; Kim, B. H. Bioorg. Med. Chem. Lett. 2009, 19, 1126.
5
6. (a) Park, S. M.; Lee, Y. S.; Kim, B. H. Chem. Commun. 2003, 2912; (b) Park, S. M.;
Shen, Y.; Kim, B. H. Org. Biomol. Chem. 2007, 5, 610; (c) Lee, Y. S.; Park, S. M.;
Kim, H. M.; Park, S. K.; Lee, K.; Lee, C. W.; Kim, B. H. Bioorg. Med. Chem. Lett.
2
009, 19, 4688.
7. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467; (b)
McGuigan, C.; Yarnold, C. J.; Jones, G.; Velazquez, S.; Barucki, H.; Brancale, A.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem. 1991, 34, 2275; (c)
Cristofoli, W. A.; Wiebe, L. I.; De Clercq, E.; Andrei, G.; Snoeck, R.; Balzarini, J.;
Knaus, E. E. J. Med. Chem. 2007, 50, 2851; (d) Terrence, P. E.; Spencer, J. W.;
Bobst, A. M.; Descamps, J.; De Clercq, E. J. Med. Chem. 1978, 21, 228; (e) Robins,
M. J.; Manfredini, S.; Wood, S. G.; Wanklin, R. J.; Rennie, B. A.; Sacks, S. L. J. Med.
Chem. 1991, 34, 2275.
8. (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004;
(
b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int.
Ed. 2002, 41, 2596.
Acknowledgments
9
.
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.;
Warren, J. T.; Bokesch, H.; Kenney, S.; Boyd, M. R. J. Natl. Cancer Inst. 1990, 82,
1107.
This work was supported by the NRF Grant (No. 20090065415)
and EPB center funded by the Korean government (MEST) and par-
tially by a Grant from KRIBB Research Initiative Program.
1
0. (a) Rooseboom, M.; Commandeur, J. N.; Vermeulen, N. P. Pharmacol. Rev. 2004,
6, 53; (b) Miwa, M.; Ura, M.; Nishida, M.; Sawada, N.; Ishikawa, T.; Mori, K.;
Shimma, N.; Umeda, I.; Ishitsuka, H. Eur. J. Cancer 1988, 34, 1274.
5