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J Med Chem. 1992 May 15;35(10):1782-91.

4'-modified analogues of aristeromycin and neplanocin A: synthesis and inhibitory activity toward S-adenosyl-L-homocysteine hydrolase.

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1
Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.

Abstract

The carbocyclic adenosine analogues aristeromycin and neplanocin A both display significant S-adenosyl-L-homocysteine (AdoHcy) hydrolase inhibitory activity and broad-spectrum antiviral effects. Since phosphorylation of the 4'-hydroxymethyl substituent has been implicated with the cytotoxicity of these compounds, various analogues modified at this position were synthesized utilizing a key cyclopentenone intermediate 3 which can be derived from several members of the natural chiral pool. Cyclopentenone 3 underwent a highly stereoselective conjugate addition with organocuprate reagents, and the 1,4-adducts so formed were then readily elaborated to the corresponding 4'-modified aristeromycin analogues. Alternatively, quenching the enolate intermediate of the organocuprate conjugate addition with methanesulfinyl chloride followed by pyrolytic syn elimination resulted in the formation of 4'-modified neplanocin A intermediates. Three of the final compounds (1b, 1c, and 1e) displayed inhibitory activity toward AdoHcy hydrolase in the nanomolar range.

PMID:
1588558
DOI:
10.1021/jm00088a013
[Indexed for MEDLINE]

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