Synthesis of deguelin-biotin conjugates and investigation into deguelin's interactions.
Deguelin, a rotenoid, has emerged as an attractive pharmacophore for chemoprevention showing in vivo activity in several xenografts. Recently, several lines of evidence have suggested its mode of action may involve inhibition of HSP90, however binding in a different mode than known pharmacophores. To further probe the target of deguelin and related rotenoids, several biotin conjugates were prepared. None of the conjugates showed significant affinity for HSP90, however two conjugates showed a strong cellular co-localization with mitochondria, consistent with binding to mitochondrial complex 1. Contrarily to rotenone, deguelin and tephrosin were not found to inhibit tubulin polymerization demonstrating a dramatic pharmacological difference between these closely related rotenoids.
Institut de Science et d'Ingénierie Supramoleculaires, Université de Strasbourg, F67000 Strasbourg, France.
José
J
Garcia
Sofia
S
Barluenga
Katarzyna
K
Gorska
Florenz
F
Sasse
Nicolas
N
Winssinger
D000345:Affinity Labels / Q000138:chemical synthesis* / Q000737:chemistry; D001710:Biotin / Q000737:chemistry*; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D012402:Rotenone / Q000031:analogs & derivatives* / Q000737:chemistry; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry
D000345:Affinity Labels; D018841:HSP90 Heat-Shock Proteins; D014404:Tubulin; D050257:Tubulin Modulators; D012402:Rotenone; D001710:Biotin; C107676:deguelin