H. O. Kim et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2091–2093
2093
Table 1. SAH inhibitory activity of the target nucleosides
Moon, H. R.; Lee, K. M.; Kim, H. O.; Kim, H.-D.; Chun,
M. W.; Park, H.-Y.; Kim, K.; Sheen, Y. Y. Nucleosides,
Nucleotides, Nucleic Acids 2003, 22, 919.
NH2
2. (a) Cantoni, G. L. Biological methylation and drug design.
In The Centrality of S-Adenosylhomocysteinase in the
Regulation of the Biological Utilization of S-Adenosyl-
methionine; Borchardt, R. T., Creveling, C. R., Ueland,
P. M., Eds.; Humana: Clifton, NJ, 1986; pp 227–238; (b)
Turner, M. A.; Yang, X. D.; Kuczera, K.; Borchardt,
R. T.; Howell, P. L. Cell. Biochem. Biophys. 2000, 33, 101.
3. De Clercq, E. Biochem. Pharmacol. 1987, 36, 2567.
4. Borchardt, R. T.; Wolfe, M. S. J. Med. Chem. 1991, 34,
1521.
5. Yaginuma, S.; Muto, N.; Tsujino, M.; Sudate, Y.;
Hayashi, M.; Otani, M. J. Antibiot. 1981, 34, 359.
6. Keller, B. T.; Borchardt, R. T. Biological methylation and
drug design. In Metabolism and Mechanism of Action of
Neplanocin A–A Potent Inhibitor of S-Adenosylhomocys-
teine Hydrolase; Borchardt, R. T., Creveling, C. R.,
Ueland, P. M., Eds.; Humana: Clifton, NJ, 1986; pp 385–
396.
N
N
X
N
N
Y
HO
OH
Compound
IC50 (lM)a
1 (X ¼ H, Y ¼ CH2OH)
2 (X ¼ F, Y ¼ CH2OH)
3 (X ¼ H, Y ¼ H)
0.89
0.47
8.7
4 (X ¼ F, Y ¼ H)
8.9
a Determined using pure recombinant enzyme obtained from human
placenta.
cofactorNAD þ to investigate whetherits mechanism of
action is irreversible as fluoro-neplanocin A (2). As
expected, fluoro-DHCeA (4) exhibited the same irre-
versible inhibition of SAH as fluoro-neplanocin A (2),
while DHCeA (3) exhibited the same reversible inhibi-
tion as neplanocin A (1).
7. Matuszewska, B.; Borchardt, R. T. J. Biol. Chem. 1987,
262, 265.
8. Jeong, L. S.; Yoo, S. J.; Lee, K. M.; Koo, M. J.; Choi,
W. J.; Kim, H. O.; Moon, H. R.; Lee, M. Y.; Park, J. G.;
Lee, S. K.; Chun, M. W. J. Med. Chem. 2003, 46, 201.
9. Wolfe, M. S.; Lee, Y.; Bartlett, W. J.; Borcherding, D. R.;
Borchardt, R. T. J. Med. Chem. 1992, 35, 1782.
10. Borcherding, D. R.; Scholtz, S. A.; Borchardt, R. T.
J. Org. Chem. 1987, 52, 5457.
11. Turner, M. A.; Yuan, C. S.; Borchardt, R. T.; Hershfield,
M. S.; Smith, G. D.; Howell, P. L. Nat. Struct. Biol. 1998,
369.
12. Choi, W. J.; Park, J. G.; Yoo, S. J.; Kim, H. O.; Moon,
H. R.; Chun, M. W.; Jung, Y. H.; Jeong, L. S. J. Org.
Chem. 2001, 66, 6490.
13. Moon, H. R.; Choi, W. J.; Kim, H. O.; Jeong, L. S.
Tetrahedron: Asymmetry 2002, 13, 1189.
14. To a stirred solution of 8 (1.50 g, 2.88 mmol) and
N-fluorobenzenesulfonimide (1.09 g, 3.46 mmol) in dry
tetrahydrofuran (30 mL) was added slowly n-butyl lithium
(1.6 M solution in hexanes, 5.40 mL, 8.64 mmol) at )78 °C
under nitrogen atmosphere and the reaction mixture was
stirred at the same temperature for 1 h. After usual work-
up, the residue was purified by silica gel column chroma-
tography (hexanes/ethyl acetate ¼ 30:1) to give an insep-
arable mixture (1.16 g) of 9 and its hydrogen substituted
3. Summary
We have synthesized fluoro-DHCeA (4) using electro-
philic fluorination reaction as a key step. Fluoro-
DHCeA (4) was almost as potent as DHCeA (3), but
exhibited irreversible inhibition of enzyme unlike
DHCeA (3) showing reversible inhibition. From this
study, we have discovered the important role of the 40-
hydroxymethyl group in binding to the active site of the
enzyme. This result will contribute greatly to the design
of the potent nucleoside analogues inhibiting SAH.
Acknowledgement
derivative in 7/1 ratio.
This work was supported by Korea Research Founda-
tion Grant (KRF-2003-E-00003).
25
15. ½aꢀ
¼
)172.39 (c 0.77, MeOH); UV (MeOH) kmax
D
260.0 nm; 19F NMR (376 MHz, MeOH-d4) d )121.59; H
NMR (400 MHz, MeOH-d4) d 8.19 (s, 1H, 8-H), 8.18 (s,
1H), 5.63 (m, 1H), 5.60 (m, 1H), 4.75 (m, 1H), 4.68 (td,
J ¼ 1:2, 6.0 Hz, 1H); 13C NMR (100 MHz, MeOH-d4)
d 163.67, 163.33, 162.12, 159.26, 157.42, 153.82, 151.15,
142.07, 120.65, 110.11 (d, J ¼ 4:9 Hz), 76.56 (d,
J ¼ 4:2 Hz), 70.71 (d, J ¼ 10:4 Hz), 62.93 (d, J ¼ 18:2 Hz).
Anal. Calcd forC 10H10FN5O2: C, 47.81; H, 4.01; N, 27.88.
Found: C, 47.88; H, 4.11; N, 27.54.
1
References and notes
1. The part of this work was published in the Proceeding of
XV International Roundtable, 10–14 September 2002,
Leuven, Belgium; Jeong, L. S.; Park, J. G.; Choi, W. J.;