Abstract
A variety of isosteres of the DNA polymerase inhibitor aphidicolin were synthesized as potential antiherpes agents. Modeling studies indicated that the bicyclooctane C, D rings of aphidicolin could be replaced by an aromatic moiety while maintaining the spatial arrangement of the hydroxyl group equivalent to the essential C18 hydroxyl group of aphidicolin. Of the racemic isosteres synthesized only 13, the compound with the greatest structural similarity to aphidicolin, showed any significant antiviral activity in primary assays. An enantioselective synthesis of the compound was carried out and the 4aS isomer 36 was shown to account for the observed antiviral activity noted against herpes simplex virus 1 and human cytomegalovirus.
MeSH terms
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Antiviral Agents / chemistry*
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Aphidicolin / analogs & derivatives*
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Aphidicolin / chemistry
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Aphidicolin / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Cytomegalovirus / drug effects
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Cytomegalovirus / enzymology
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Deoxycytosine Nucleotides / metabolism
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Herpesvirus 1, Human / drug effects
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Herpesvirus 2, Human / drug effects*
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Herpesvirus 2, Human / enzymology
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Models, Molecular
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Molecular Structure
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Nucleic Acid Synthesis Inhibitors*
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Phenanthrenes / chemical synthesis*
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Phenanthrenes / chemistry
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Phenanthrenes / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Antiviral Agents
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Deoxycytosine Nucleotides
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Nucleic Acid Synthesis Inhibitors
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Phenanthrenes
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1,7-bis(hydroxymethyl)-1,4a-dimethyl-1,2,3,4,4a,9,10,10a-octahydro-2,6-phenanthrenediol
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2'-deoxycytidine 5'-triphosphate
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Aphidicolin