1842
C. Dini et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1839±1843
Scheme 4. (a) 2, Hg(CN)2, CH2Cl2, MS 4 A, rt; (b) MeONa, MeOH, rt; (c) 2-methoxypropene, PTSA, acetone, rt; (d) MsCl, TEA, CH2Cl2, rt; (e)
Pd/C, H2, MeOH, rt; (f) NaN3, DMF, 70 ꢀC; (g) 60% AcOH aq. 70 ꢀC; (h) Ac2O, Pyr., rt; (i) O,O0-bis(trimethylsilyl)uracil,TMSOTf, CH3CN, rt; (j)
MeONa, MeOH, rt; (k) PPh3, H2O, THF, rt.
4. Boyle, D. S.; Donachie, W. D. J. Bacteriol. 1998, 180, 6429.
5. For a recent review see Lee, V. J.; Hecker, S. J. Med. Chem.
Table 2.
Res. Rev. 1999, 19, 521, and references cited therein.
6. Brandish, P. E.; Kimura, K.; Inukai, M.; Southgate, R.;
Lonsdale, J. T.; Bugg, T. D. H. Antimicrob. Agents Chemother.
1996, 40, 1640.
Compound no. Tunicamycins Mureidomycin B
IC50 (mM) 0.48 0.065
I
XIV XV
50 425
5
7. Kimura, K.; Ikeda, Y.; Kagami, S.; Yoshihama, M.;
Suzuki, K.; Osada, H.; Isono, K. J. Antibiot. 1998, 51, 1099.
8. Inukai, M.; Isono, F.; Takatsuki, A. Antimicrob. Agents
and Chemother. 1993, 37, 980.
9. Spada, M. R.; Ubukata, M.; Isono, K. Heterocycles 1992,
34, 1147.
10. Knapp, S.; Nandan, S.; Resnick, L. Tetrahedron Lett.
1992, 33, 5485.
11. Kim, K. S., Cho, I. H., Ahn, Y. H., Park, J. I. J. Chem.
Soc., Perkin Trans. 1 1995, 1783.
introduction of the uracil moiety was performed using
the standard Vorbruggen procedure.24 Subsequent
hydrolysis of the crude compound led to the nucleoside
18. The azido group was reduced in the presence of
PPh3 and H2O in THF to give the desired isomers XIV25
and XV.26
The inhibitory activity (IC50) of XIV and XV on trans-
locase was determined and ®nal results are summarised
in Table 2.
12. Kim, K. S.; Lim, J. W.; Joo, Y. H.; Kim, K. T.; Cho, I.
H.; Ahn, Y. H. J. Carbohydr. Chem. 1995, 14, 439.
13. Moore, W. J.; Luzzio, F. A. Tetrahedron Lett. 1995, 36,
6599.
14. Gravier-Pelletier, C.; Charvet, L.; Le Merrer, Y.; Depe-
zay, J. C. J. Carbohydr. Chem. 1997, 16, 129.
15. Le Merrer, Y.; Gravier-Pelletier, C.; Gerrouache, M.;
Depezay, J. C. Tetrahedron Lett. 1998, 39, 385.
16. Kim, K. S.; Ahn, Y. H. Tetrahedron: Asymmetry 1998, 9,
3601.
17. Ubukata, M.; Kimura, K.; Isono, K.; Nelson, C. C.;
Gregson, J. M.; Mc Closkey, J. A. J. Org. Chem. 1992, 57,
6392.
18. Dinur, U.; Hagler, A. T. Approaches to Empirical Force
Fields. In Reviews of Computational Chemistry; Lipkowitz,
K. B., Boyd, D. B., Eds.; VCH: New York, 1991; Vol. 2,
Chapter 4.
19. Analytical data for I (formic acid salt): 1H NMR
(300 MHz, D2O): 3.05 (dd, 1H, J=9, 13 Hz, H500a), 3.40 (dd,
1H, J=2.5, 13 Hz, H500b), 3.76 to 4.37 (m, 8H, H400, H300, H200,
H40), 5.12 (s, 1H, H100), 5.87 (d, 1H, J=3.5 Hz, H10), 5.90 (d,
1H, J=8 Hz, H5), 7.74 (d, 1H, J=8 Hz, H6), 8.46 (s, 1H,
formic acid salt); MS (FAB): 376+ (M+H+).
20. Vosberg, H. P.; Homann-Berling, H. J. Mol. Biol. 1971,
58, 739.
Only the (S) isomer XV displays an ecient inhibitory
activity on the enzyme. This result is in agreement with
the molecular model we propose, and also with the
con®guration proposed by Isono's group for liposido-
mycin. Moreover, modi®cation of I to give XV resulted
in a 10-fold improvement of the inhibitory activity.
In conclusion, the model based on stable conformations
of two highly potent enzyme inhibitors (TCMs and
LPMs) with that of the natural substrate (UMA5) has
led to the synthesis of smaller molecules which still dis-
play useful enzyme inhibitory activity. The model also
supports Isono's work on the con®guration of the 50
chiral centre. The next step will be to elucidate the role
of each functional group in such molecules.
Acknowledgement
We are grateful to the Analytical Department (HMR,
Romainville) for performing spectral analysis.
21. Maas, D.; Pelzer, H. Arch. Microbiol. 1981, 130, 301.
22. Kishi, Y.; Fang, F.; Forsyth, C. J.; Scola, P. M.; Yoon, S.
K. Patent WO 9317690, 1993.
23. Nagashima, N.; Ohno, M. Chem. Pharm. Bull. 1991, 39,
1972.
References and Notes
24. Niedballa, U.; Vorbruggen, H. J. Org. Chem. 1974, 39,
3668.
1. Plattner, J. J. Annual Reports in Medicinal Chemistry 1997,
32, 111.
2. Struve, G. W.; Sinha, R. K.; Neuhaus, F. C. Biochemistry
1966, 5, 82.
3. Kandler, O. Cell wall structure and their phylogenis impli-
cations, Zbl. Bakt. Hyg., I Abt. Orig. 1982, C3, 149.
25. Analytical data for XIV (acetate salt): 1H NMR
(400 MHz, D2O): 1.91 (s, 3H, CH3 acetate salt), 3.09 (dd, 1H,
J=9, 13 Hz, H500a), 3.36 (dd, 1H, J=2.5, 13 Hz, H500b), 3.74
(dd, 1H, J=5, 12.5 Hz, H60a), 3.89 (dd, 1H, J=3.5, 12.5 Hz,
H60b), 4.06 (dt, 1H, J=3.5, 5 Hz, H50), 4.10 to 4.20 (m, 4H,