Rapid Combinatorial Synthesis of Aminoglycoside Antibiotic Mimetics:  Use of a Polyethylene Glycol-Linked Amine and a Neamine-Derived Aldehyde in Multiple Component Condensation as a Strategy for the Discovery of New Inhibitors of the HIV RNA Rev Responsive Element

A library of neomycin B mimetics has been prepared rapidly without chromatography using a neamine-derived aldehyde, tert-butyl isocyanide or isocyanoacetic acid methyl ester, a glycine-conjugated polyethylene glycol (PEG) methyl ether, and various Cbz-N-protected amino acids as substrates in a Ugi-t...

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Bibliographic Details
Published in:Journal of the American Chemical Society 1996-10, Vol.118 (42), p.10150-10155
Main Authors: Park, William K. C., Auer, Manfred, Jaksche, Herbert, Wong, Chi-Huey
Format: Article
Language:English
Subjects:
human immunodeficiency virus 1
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Summary:A library of neomycin B mimetics has been prepared rapidly without chromatography using a neamine-derived aldehyde, tert-butyl isocyanide or isocyanoacetic acid methyl ester, a glycine-conjugated polyethylene glycol (PEG) methyl ether, and various Cbz-N-protected amino acids as substrates in a Ugi-type one-pot reaction. The product linked to PEG was isolated by precipitation in ether. A simultaneous base-catalyzed hydrolysis and de-O-acetylation followed by hydrogenation provided an easy access to a library of neomycin B mimetics, which were screened for binding to the Rev responsive element of HIV mRNA (RRE). Several products were found to be more active than neamine with the IC50 values in the micromolar range.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja9612817