ORGANIC
LETTERS
2001
Vol. 3, No. 11
1621-1623
An Efficient Synthesis of Mimetics of
Neamine for RNA Recognition
Yili Ding,* Steven A. Hofstadler, Eric E. Swayze, and Richard H. Griffey
Ibis Therapeutics, a DiVision of Isis Pharmaceuticals, 2292 Faraday AVenue,
Carlsbad, California 92008
Received March 5, 2001
ABSTRACT
As mimetics of neamine, several 4-heterocyclic 2-deoxystreptamine derivatives were chemically synthesized for RNA recognition. Conversion
of 4-methylthiomethyl-5,6-di-O-acetyl-diazido-2-deoxystreptamine to the 4-chloromethyl derivative followed by reactions with different nuclophilic
reagents gave the 4-heterocyclic 2-deoxystreptamine derivatives in satisfactory yields.
Several aminoglycosides are known to interact with RNA
and interfere with its function.1 For example, neomycin B
induces translational misreading, most likely as a result of
an interaction with 16S rRNA in the A site of the ribosome.2
Direct use of neomycin B as a drug, however, has been
discouraged as a result of its high toxicity, instability, and
poor oral bioavailability.3 The structures of the amino-
glycosides are synthetically challenging and do not lend
themselves to the rapid preparation necessary for a medicinal
chemistry program.4 Therefore, it is highly desirable to
synthesize mimetics of aminoglycosides that are smaller,
simpler structures and retain the activity of the larger parent
structures.
Most naturally occurring aminoglycosides share a common
pseudodisaccharide known as neamine. Therefore, mimetics
of neamine would be an ideal starting point for the synthesis
of new potential antibiotics. In this communication, we report
an efficient strategy for the synthesis of mimetics of neamine.
Computer modeling studies indicated that if the A ring of
neomycin B was replaced by a benzyl group, then the
resulting compound would keep the conformation of neo-
mycin B.5 We assumed that the conformation of neomycin
B plays a very important role in its RNA binding affinity
and specificity. So, we chose the 4-heterocyclic 2-deoxy-
streptamine derivatives as target compounds. Two approaches
could be used for synthesis of target compounds (Scheme
1).
One approach is simple alkylation of diacetylated 2-deoxy-
streptamine derivative 1 with different Het-CH2X (X ) Cl,
Br, CNHCCl3).6 By a second approach, 4-chloromethyl-5,6-
di-O-acetyl-diazido-2-deoxystreptamine (2) can be coupled
with different heterocycles such as HetYH (Y ) N, S) to
provide the heterocyclic 2-deoxystreptamine derivatives.
Alkylation of compound 1 with several Het-CH2X (X )
Cl, Br) under different base conditions failed as a result of
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J.; Boykin, D. W.; Wilson, W. D. Bioorg. Med. Chem. 1995, 3, 785. (d)
Fernandez-Saiz, M.; Schneider, H. J.; Sartorius, J.; Wilson, W. D. J. Am.
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(3) Aminoglycoside Antibiotics; Umezawa, H., Hooper, I. R., Eds., Spring-
Verlag: New York, Herdelberg, 1982.
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(5) Mohan, V.; Griffey, R. H. Unpublished results.
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10.1021/ol015794g CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/02/2001