Abstract
The effect of introduction of a lipophilic phosphodiester amidate moiety on the HIV activity of inactive unsaturated nucleoside analogues was investigated. Phosphodiester alaninates 5a, 5b, and 6 derived from unsaturated nucleoside analogues 3b, 3c, and 4a were synthesized and investigated as inhibitors of cytopathic effect and replication of HIV-1 in ATH-8 cells. Compound 5a is an inhibitor of HIV-1 whereas analogue 6 is inactive with cytotoxicity appearing above 10 microM and 5b is both inactive and nontoxic. Alkaline or enzymic hydrolysis of 5a gave phosphomonoester alaninate 14, a putative product of intracellular metabolism. Compound 14 as well as adenallene derivative 15c were devoid of anti-HIV activity, and they also failed to inhibit HIV reverse transcriptase. A new regioselective method for preparation of (Z)-4-(benzoyloxy)-1-hydroxy-2-butene, 7, a key intermediate for the synthesis of unsaturated nucleoside analogues of cis configuration such as 3a, 3b, and 3c, is also described.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Anti-HIV Agents / chemical synthesis*
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Anti-HIV Agents / chemistry
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Anti-HIV Agents / pharmacology
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Cell Line
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Cell Survival / drug effects
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Esterases / metabolism
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HIV Reverse Transcriptase / antagonists & inhibitors*
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HIV-1 / drug effects*
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HIV-1 / pathogenicity
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HIV-1 / physiology
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Humans
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Liver / enzymology
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Molecular Structure
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Nucleosides / chemical synthesis*
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Nucleosides / chemistry
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Nucleosides / pharmacology
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Organophosphorus Compounds / chemical synthesis*
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Organophosphorus Compounds / chemistry
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Organophosphorus Compounds / pharmacology
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Purines / chemical synthesis*
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Purines / chemistry
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Purines / pharmacology
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Pyrimidinones / chemical synthesis*
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Pyrimidinones / chemistry
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Pyrimidinones / pharmacology
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Structure-Activity Relationship
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Swine
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Virus Replication / drug effects*
Substances
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Anti-HIV Agents
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Nucleosides
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Organophosphorus Compounds
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Purines
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Pyrimidinones
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HIV Reverse Transcriptase
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Esterases