S. E. Kim et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3389–3393
3393
Figure 2. Proposed model of compound 9 bound to the Escherichia coli MetRS binding site.
5. Forrest, A. K.; Jarvest, R. L.; Mensah, L. M.; OÕHanlon,
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¨
of compound 9 may be acquired by the formation of
an extra hydrogen bond between the oxygen atom of
the ribose ring and His24.
In summary, we have synthesized 20-deoxy, 30-deoxy,
and 20,30-dideoxyribosyl surrogates of isoleucyl and
methionyl sulfamate adenylates, which were previously
described as potent IRS and MRS inhibitors, from
adenosine and 20-deoxyadenosine to identify the phar-
macophoric importance of the two hydroxyl groups on
the ribose for the inhibition of the E. coli methionyl-
tRNA and isoleucyl-tRNA synthetases. All of the deoxy
analogues displayed reduced potencies as compared to
the parent compounds. Interestingly, the 20,30-dideoxyri-
bosyl analogues were found to be much more potent
than the 20-deoxy or 30-deoxy analogues in both IRS
and MRS. The molecular modeling study of 20,30-dide-
oxyribosyl Met-NHSO2-AMP (9) with the crystal struc-
ture of E. coli MRS revealed that an extra hydrogen
bond between the ring oxygen of 9 and His24 compen-
sated for the dramatic loss of activity, due to the lack
of the two hydroxyl groups on ribose, resulting in only
a small reduction in the activity.
M.; Cusack, S. Science 1994, 263, 1432.
15. Lee, J.; Kim, S. E.; Lee, J. Y.; Kim, S. Y.; Kang, S. U.;
Seo, S. H.; Chun, M. W.; Kang, T.; Choi, S. Y.; Kim, H.
O. Bioorg. Med. Chem. Lett. 2003, 13, 1087.
Acknowledgment
16. US patent 5,726,195.
This work was supported by a grant (03-PJ2-PG4-
BD02-0001) from the Ministry of Health & Welfare,
Republic of Korea.
17. Jo, Y. J.; Lee, S. W.; Jo, M. K.; Lee, J.; Kang, M.-K.;
Yoon, J. H.; Kim, S. J. Biochem. Mol. Biol. 1999, 32, 547.
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Vaughan, M. D.; Honek, J. F.; Blanquet, S. J. Mol. Biol.
2003, 332, 59.
References and notes
19. Compound 9 was modeled in the binding pocket of E. coli
MetRS, using the X-ray structure of the MetRS–com-
pound 3 complex. All of the hydrogen atoms were added
to MetRS, and then the obtained complex was fully
optimized by energy minimization using the Tripos force
1. Ibba, M.; So¨ll, D. Annu. Rev. Biochem. 2000, 69, 617.
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field and Gasteiger–Huckel partial atomic charges. All
¨
computational work was done on a Silicon Graphics O2
R10000 workstation.