Synthesis and HIV-1 integrase inhibitory activity of spiroundecane(ene) derivatives

Fifteen 2,4-dioxaspiro[5.5]undecane ketone and 2,4-dioxa-spiro[5.5]undec-8-ene (spiroundecane(ene)) derivatives were synthesized using the Diels–Alder reaction. Inhibition of human immunodeficiency virus integrase (IN) was examined. Eight spiroundecane(ene) derivatives inhibited both 3′-processing a...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2007-03, Vol.17 (5), p.1362-1368
Main Authors: Shults, Elvira E., Semenova, Elena A., Johnson, Allison A., Bondarenko, Svetlana P., Bagryanskaya, Irina Y., Gatilov, Yuri V., Tolstikov, Genrikh A., Pommier, Yves
Format: Article
Language:English
Subjects:
Alkanes - chemical synthesis
Alkanes - pharmacology
Anti-HIV Agents - chemical synthesis
Catalysis - drug effects
Crystallography, X-Ray
HIV Integrase - drug effects
HIV Integrase Inhibitors - chemical synthesis
HIV Integrase Inhibitors - chemistry
HIV Integrase Inhibitors - pharmacology
Humans
Inhibitory Concentration 50
Protein Binding - drug effects
Spiro Compounds - chemical synthesis
Spiro Compounds - pharmacology
Structure-Activity Relationship
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Summary:Fifteen 2,4-dioxaspiro[5.5]undecane ketone and 2,4-dioxa-spiro[5.5]undec-8-ene (spiroundecane(ene)) derivatives were synthesized using the Diels–Alder reaction. Inhibition of human immunodeficiency virus integrase (IN) was examined. Eight spiroundecane(ene) derivatives inhibited both 3′-processing and strand transfer reactions catalyzed by IN. SAR studies showed that the undecane core with at least one furan moiety is preferred for IN inhibition. Moreover, crosslinking experiments showed that spiroundecane derivatives did not affect IN–DNA binding at concentrations that block IN catalytic activity, indicating spiroundecane derivatives inhibit preformed IN–DNA complex. The moderate toxicity of spiroundecane(ene) derivatives encourages the further design of therapeutically relevant analogues based on this novel chemotype of IN inhibitors.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2006.11.094