J. M. Berge et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1811±1814
1813
tion to 3 being about equipotent to SB-219383, the proton
NMR spectra of 2 and 14 are almost identical (with the
exception of the obvious dierences resulting from the
omission of the methyleneoxy unit in 14) (Table 1, Fig. 2)
Thus, the stereostructure of SB-219383 is most likely to be
as shown in 18 (Fig. 3). Potent inhibition by 14 also
con®rms that neither the tetrahydrofuran ring of 1 nor the
pendant hydroxymethyl group of 2 are important for
YRS recognition. Synthesis and activity of further
analogues of these compounds will be reported in due
course.
Figure 2.
References and Notes
Table 1. Proton NMR data (400 MHz, D2O) of compounds 14 and 2
(Fig. 3)
1. Stefanska, A. L.; Coates, N. J.; Mensah, L. M.; Pope, A. J.;
Ready, S. J.; Warr, S. R. J. Antibiotics 2000, 53, 345.
H
14
2
2. Walker, G.; Brown, P.; Forrest, A. K.; O'Hanlon, P.; Pons,
J. E. Recent Advances in the Chemistry of Anti-infective Agents;
Royal Society of Chemistry: London, 1993; p 106.
3. Houge-Frydrych, C. S. V.; Readshaw, S. A.; Bell, D. J. J.
Antibiotics 2000, 53, 351.
1
3.18 (dd, J=10.1, 1.1 Hz)
2.83 (dd, J=11.8, 1.2 Hz)
3.34 (dd, J=11.7, ca. 3 Hz)
4.01 (ddd, J ca. 4.9, 1.5, 1.5 Hz) 4.06 (dd, J=2.9, 2.2 Hz)
3.55 (dd, J=9.7, 3.5 Hz)
3.41 (dd, J=10.5, 1.3 Hz)
3.06 (dd, J=12.4, 2.1 Hz)
3.39 (dd, J=12.4, 3.2 Hz)
3ax
3eq
4
5
Ð
CH2OH Ð
CH2OH Ð
3.90 (d, J=12.6 Hz)
3.96 (d, J=12.6 Hz)
3.52 (bd, J=9.5 Hz)
4.65 (d, J=1.1 Hz)
4.11 (dd, J=7.9, 4.7 Hz)
3.04 (dd, J=14.4, 7.9 Hz)
3.24 (dd, J=14.4, 4.9 Hz)
7.25 (d, J=8.5 Hz)
6.94 (d, J=8.5 Hz)
4. Berge, J. M.; Broom, N. J. P.; Houge-Frydrych, C. S. V.;
Jarvest, R. L.; Mensah, L. M.; McNair, D. J.; O'Hanlon, P. J.;
Pope, A. J.; Rittenhouse, S., submitted for publication.
5. For examples of sugar derived nitrones see e. g.: Herczegh, P.;
Kovacs, I.; Szilagyi, L.; Varga, T.; Dinya, Z.; Sztaricskai, F.
Tetrahedron Lett. 1993, 34, 1211. Van den Broek, L. A. G. M.
Tetrahedron 1996, 52, 4467. Ishikawa, T.; Tajima, Y.; Fukui, M.;
Saito, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1863.
6
7
3.4 (bt, J=9.8 Hz)
4.82 (d, J=1.0 Hz)
10
20
20
30
40
4.36 (dd, J=8.6, 5.2 Hz)
3.05 (dd, J=14.8, 8.6 Hz)
3.32 (dd, J=14.8, 5.2 Hz)
7.19 (d, J=8.6 Hz)
6.85 (d, J=8.6 Hz)
6. For examples of additions of organometallics to nitrones,
see e.g.: Lantos, I.; Flisak, J.; Liu, L.; Matsuoka, R.; Mendel-
son, W.; Stevenson, D.; Tubman, K.; Tucker, L.; Zhang, W.-
Y.; Adams, J.; Sorenson, M.; Garigipati, R.; Erhardt, K.;
Ross, S. J. Org. Chem. 1997, 62, 5385. Dondoni, A.; Junquera,
F.; Merchan, L.; Merino, P.; Scherrmann, M.-C.; Tejero, T. J.
Org. Chem. 1997, 62, 5484. Fiumana, A.; Lombardo, M.;
Trombini, C. J. Org. Chem. 1997, 62, 5623.
7. Kiso, M.; Hasegawa, A. Carbohydr. Res. 1976, 52, 95.
8. O'Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663.
Ghosez, L.; Antoine, J.-P.; Deense, E.; Navarro, M.; Libert,
V.; O'Donnell, M. J.; Bruder, W. A.; Willey, K.; Wojcie-
chowski, K. Tetrahedron Lett. 1982, 23, 4255.
9. X-ray crystal structure determination of the opposite enan-
tiomer to 10. Crystals were grown via the evaporation of a
CDCl3/DMSO-d6 solution at reduced pressure. Crystal data:
colourless blade, 0.63Â0.27Â0.05 mm; C29H38N2O5Si, Mr=
522.70, monoclinic, C2 (no. 5), a=30.105(5), b=8.7694(16),
Figure 3. Likely stereostructure of SB-219383.
deprotection of the amino terminus gave the target
dipeptide 14 in acceptable overall yield. Similar treat-
ment of compound 10 gave rise to the analogous dipep-
tide 15 with d-con®guration of the C-terminal amino
acid. Additionally, compounds 16 and 17 with inverted
chirality of the C-terminal amino acid were obtained
when d( )-arabinose was used as the starting material.
c=11.421(2) A, ꢀ=103.431(12) ꢀ, V=2932.7(10) A3, Z=4,
1
Dx=1.184 Mg m 3, ꢁ (Cu Ka, l=1.54178 A)=1.019 mm
.
Data collection: Nonius MACH3 diractometer, GX21 rotating
copper anode generator, graphite monochromator, 293 K,
ꢂ
max=58.91 ꢀ, !/2ꢂ scans, Nref=4794, Nuniq=4220. Data
reduction: corrections for Lorentz and polarisation eects; psi-
scan absorption correction, Tmin=0.6774, Tmax=0.9206;
decay correction, four standard re¯ections, maximum varia-
tion=13.0%; Rint=0.0325. Solution and re®nement: SHELXTL
V5.10 IRIX package; direct methods; full-matrix least-squares
re®nement on F2; coordinates and anisotropic displacement
parameters re®ned for the non-hydrogen atoms; hydrogen atoms
in idealised positions, riding or as rigid rotating groups, with
isotropic atomic displacement parameters which were an
appropriate multiple of Ueq for the >bonded atom;
The four stereoisomers were tested in a standard amino-
acylation assay of YRS activity.11 Dipeptide 14 was
found to be a potent inhibitor of bacterial YRS (IC50
1.2 nM) with good selectivity over the mammalian
enzyme (11% inhibition at 3 mM) whereas epimer 15
showed signi®cantly weaker inhibition (IC50 21.3 nM;
the presence of up to 5% 14 in 15 (which would account
for this level of inhibition) cannot be ruled out). Isomers
16 and 17 were inactive when tested up to 3 mM. In addi-
Nref=4220, Npar=343, R1 (3545 data with I>2 ꢃ(I))=0.0434,
3
wR2 (all data)=0.1069, S=1.023; Áꢄmin= 0.103 e A
,
Áꢄmax=0.148 e A 3; extinction coecient=0.00113(9); abso-