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 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.
Shults
Elvira E
EE
N.N. Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russian Federation. schultz@nioch.nsc.ru
Semenova
Elena A
EA
Johnson
Allison A
AA
Bondarenko
Svetlana P
SP
Bagryanskaya
Irina Y
IY
Gatilov
Yuri V
YV
Tolstikov
Genrikh A
GA
Pommier
Yves
Y
D000473:Alkanes / Q000138:chemical synthesis* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis*; D002384:Catalysis / Q000187:drug effects; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000187:drug effects*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D011485:Protein Binding / Q000187:drug effects; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000473:Alkanes; D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D013141:Spiro Compounds; D019427:HIV Integrase; C022884:undecane