Chemistry Letters Vol.32, No.10 (2003)
909
R
References and Notes
N3
HO
N3
#
1
2
Present address: Ribapharm, 3300 Hyland, Costa Mesa, CA 92626.
M. L. Zapp, S. Stern, and M. R. Green, Cell, 74, 969 (1993).
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K. B. Sanders, H. N. Troung, and A. W. Crarnik, Bioorg. Med.
Chem. Lett., 5, 2755 (1995).
a
O
O
H2
N
O
NH2
HO
OH
2
10 R = H
16 R = 3-NH2
17 R = 3-Pyridyl
18 R = 3-F
19 R = 4-OMe
20 R = Pentafluoro
11 R = 2-Br
12 R = 3-Br
13 R = 4-Br
14 R = 3-I
3
W. A. Greenberg, E. S. Priestley, P. S. Sears, P. B. Alper, C.
Rosenbohm, M. Hendrix, S. C. Hung, and C. H. Wong, J. Am.
Chem. Soc., 121, 6527 (1999).
15 R = 3-NO2
Scheme 2. Reagents and conditions: (a) i: RCH2Br, DMF,
NaH; ii: CH3CO2H/H2O, 60 ꢁC, 3 h; iii: Me3P/THF/H2O,
35–55% overall yields.
4
5
6
7
Y. L. Ding, S. A. Hofstadler, E. E. Swayze, and R. H. Griffey, Org.
Lett., 3, 1621 (2001).
G. S. Gadaginamath, A. S. Shyadlingeri, and R. R. Kavali, Indian
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Farmaco, 51, 793 (1996).
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Wilson, in ‘‘Structure, Motion, Interaction and Expression of
Biological Macromolecules,’’ ed. by R. H. Sarma and M. H. Sarma,
Adenine Press (1998), p 137.
P. B. Alper, S. C. Hung, and C. H. Wong, Tetrahedron Lett., 37,
6029 (1996).
R. N. Butler, in ‘‘Advances in Heterocyclic Chemistry,’’ ed. by
A. R. Katritzky and A. J. Boulton, Academic Press, New York,
NY (1977), Vol. 21, p 323.
As heterocyclic neamine mimetics, these final heterocyclic
neamine mimetics may not show good activities in the biolog-
ical screening assay. However, by using ESI-MS RNA binding
assay, we still can measure their RNA binding affinities,12 to
provide precise information about their interaction with RNA.
This information is useful for us to design and synthesize lead
candidate having suitable properties for clinical development.
We have employed ESI-MS RNA binding assay to evaluate
the binding affinities of compounds 4, 6, 7, 9, and 10–20 for a
27-mer RNA representing the 16S A-site, and the resulting es-
timated dissociation constants (based on a 1 point Kd determina-
tion) are reported in Table 1. During the binding assay, neamine
and 2-deoxystreptamine were used as the standard compounds.
Compounds 6 and 9 were found to exhibit higher binding
affinities. Based on their structures, design and synthesis of
more complex aminoglycoside mimetics for new antibiotics is
on the progress.
In conclusion, through an efficient synthetic strategy, we
are able to synthesize several different types of 4-heterocyclic
2-deoxystreptamine derivatives as neamine mimetics, which
provide an excellent method for the synthesis of heterocyclic
carbohydrate libraries. By using ESI-MS RNA binding assay,
we are able to find out some useful RNA binding motifs for lead
optimization, even they failed in biological screening assay.
8
9
10 M. T. Goulet, S. R. McAlpine, M. J. Staruch, S. Koprak, F. J.
Dumont, J. G. Cryan, G. J. Wiederrecht, R. Rosa, M. B. Wilusz,
L. B. Peterson, M. J. Wyvratt, and W. H. Parsons, Bioorg. Med.
Chem. Lett., 8, 2253 (1998).
11 M. R. Grimmett, in ‘‘Comprehensive Heterocyclic Chemistry,’’ ed.
by A. R. Katritzky, C. W. Rees, and K. T. Potte, Pergamon Press,
New York (1984), Vol. 5, p 457.
12 R. H. Griffey, K. A. Sannes-Lowery, J. J. Drader, V. Mohan, E. E
Swayze, and S. A. Hofstadler, J. Am. Chem. Soc., 122, 9933
(2000).
13 Spectral data for selected compounds. 2: 13C NMR (CDCl3,
100 MHz) ꢀ 112.7, 79.5, 74.7, 74.0, 62.5, 57.2, 32.0, 26.7, 27.8.
4: 1H NMR (D2O, 400 MHz) ꢀ 8.30 (1H, s), 5.15 (1H, d,
J ¼ 12:4), 4.93 (1H, d, J ¼ 12:8), 3.50 (3H, m), 3.27 (1H, m),
3.12 (1H, td), 2.34 (1H, dt), 1.72 (1H, q, J ¼ 10:8); 13C NMR
(D2O, 100 MHz) ꢀ 171, 80.4, 75.6, 72.5, 65.0, 49.7, 49.2, 34.3.
6: 1H NMR (CDCl3, 400 MHz) ꢀ 4.93 (1H, d, J ¼ 13:6), 3.54–
3.38 (3H, m), 3.30 (1H, td, J ¼ 12:8, 4.4), 3.16 (1H, td,
J ¼ 13:2, 4.0), 2.32 (1H, dt, J ¼ 12:4, 4.4), 1.70 (1H, q,
J ¼ 12:8); 13C NMR (D2O, 100 MHz) ꢀ 176.7, 150.3, 81.2, 75.2,
72.5, 63.8, 50.0, 49.2, 28.2. 7: 1H NMR (D2O, 400 MHz) ꢀ 7.26
(5H, m), 4.35 (1H, d, J ¼ 2:8), 4.29 (1H, s), 4.28 (1H, d,
J ¼ 2:8), 4.24 (1H, s), 3.51–3.35 (4H, m), 3.29 (1H, td,
J ¼ 12:8, 4.4), 2.31 (1H, dt, J ¼ 12:0, 4.0), 1.68 (1H, q,
J ¼ 12:4); 13C NMR (D2O, 100 MHz) ꢀ 172.4, 137.9, 129.2,
129.0, 127.4, 81.4, 75.3, 72.5, 70.8, 49.9, 49.0, 42.8, 28.2. 9: 1H
NMR (D2O, 400 MHz) ꢀ 7.16 (2H, s), 4.97 (1H, d, J ¼ 13:6),
4.91 (1H, d, J ¼ 14:0), 3.53–3.23 (4H, m), 3.14 (1H, m), 2.30
(1H, dt, J ¼ 12:0, 4.0), 1.68 (1H, q, J ¼ 12:8); 13C NMR (D2O,
100 MHz) ꢀ 120.0, 81.3, 75.3, 72.6, 64.9, 49.9, 49.1, 28.4. 10:
1H NMR (D2O, 400 MHz) ꢀ 7.35 (5H, m), 4.95 (1H, d,
J ¼ 12:6), 4.69 (1H, d, J ¼ 12:8), 3.52–3.44 (3H, m), 3.29–3.17
(2H, m), 2.34 (1H, dt, J ¼ 12:4, 4.4), 1.71 (1H, q, J ¼ 12:4). 11:
1H NMR (D2O, 400 MHz) ꢀ 7.56 (1H, t), 7.44 (1H, t), 7.31 (1H,
q), 7.19 (1H, q), 4.99 (1H, d), 4.72 (1H, d), 3.60-3.45 (3H, m),
3.32–3.18 (2H, m), 2.37 (1H, m), 1.75 (1H, q). 12: 1H NMR
(D2O, 400 MHz) ꢀ 7.57 (1H, s), 7.48 (1H, m), 7.34 (1H, m),
7.25 (1H, q), 4.89 (1H, d), 4.69 (1H, d), 3.60–3.48 (3H, m),
3.35–3.22 (2H, m), 2.35 (1H, m), 1.75 (1H, q). 13: 1H NMR
(D2O, 400 MHz) ꢀ 7.46 (2H, d, J ¼ 8:4), 7.24 (2H, d, J ¼ 8:4),
4.83 (1H, d, J ¼ 11:2), 4.62 (1H, d, J ¼ 11:2), 3.50–3.41 (3H,
m), 3.29–3.15 (2H, m), 2.34 (1H, dt, J ¼ 12:4, 4.4), 1.71 (1H, q,
J ¼ 12:0). 14: 1H NMR (D2O, 400 MHz) ꢀ 7.70 (1H, s), 7.58
(1H, d, J ¼ 7:6), 7.29 (1H, d, J ¼ 7:2), 7.03 (1H, t, J ¼ 7:2),
4.78 (1H, d, J ¼ 11:2), 3.45 (3H, m), 3.29–3.15 (2H, m), 2.31
(1H, dt), 1.71 (1H, q, J ¼ 12:8).
Table 1. The dissociation constants of 16S-ligand complexes
based on gas phase measurements of the ratio of free and bound
RNA target
Compounds
4a
Dissociation constants (mM)
714.3
6
7
9
10
11
12
13
14
15
16
17
18
19
20
57.7
117.2
73.5
605.8
247.7
150.4
245.3
173.2
181.9
1328.1
339.9
203.4
240.4
166.4
24.0
Neamine
2-deoxystreptamine
600.0
aCompound 4 was run at 50 mM, and other compounds were
run at 75 mM.
Published on the web (Advance View) September 8, 2003; DOI 10.1246/cl.2003.908