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

Article Details

Citation

Wolfe MS, Lee Y, Bartlett WJ, Borcherding DR, Borchardt RT

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

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

PubMed ID
1588558 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
(1'R,2'S)-9-(2-Hydroxy-3'-Keto-Cyclopenten-1-yl)AdenineAdenosylhomocysteinaseKi (nM)49N/AN/ADetails