A chimera composed of the natural products radicicol and geldanamycin has been prepared through an amide linkage connecting the resorcinol moiety of radicicol to the quinone ring of geldanamycin. The inhibitory activity of these compounds was determined by their ability to inhibit Hsp90's inherent ATPase activity along with degradation of the Hsp90 client protein, HER-2 in MCF-7 breast cancer cells. [reaction: see text]
Inhibition of the 90 kDa heat shock proteins (Hsp90) represents a promising new chemotherapeutic approach for the treatment of several cancers. Hsp90 is essential to the survival of cancer cells and is inhibited by members of the ansamycin family of antibiotics. In particular, the quinone-containing antibiotics geldanamycin (GDA) and herbimycin A inhibit Hsp90 function in vitro at low micromolar concentrations via interaction with an ATP binding domain. Many proteins bind ATP, and the discovery of selective Hsp90 inhibitors requires the identification of other proteins that bind GDA and may cause undesired effects. Biotinylated analogues of GDA with varying tether lengths have been synthesized to elucidate other proteins that competitively bind GDA. Analogues containing a photolabile tether have also been prepared as a complementary method for the removal of GDA-bound proteins from neutravidin-containing resin. Preliminary studies indicate several proteins other than Hsp90 are isolated with biotinylated GDA.
Methyl 2,4-Bis(tert-butyldimethylsilanyloxy)-6methyl-benzoate (3): A slurry of NaH (4.2 g, 105 mmol, 60% dispersion) in THF (50 mL) was cooled to 0 °C before addition of methyl benzoate 2 1 (7.1 g, 39.06 mmol) in THF (10 mL). The mixture was warmed to 25 ˚C and stirred 30 min. tert-Butyldimethylsilyl chloride (14.72 g, 97.65 mmol) in THF (10 mL) was added dropwise to the slurry at 0 ˚C. The mixture was warmed to 25 ˚C and stirred for 10 h. H 2 O (50 mL) and EtOAc (200 mL) were added to the mixture and the aqueous layer removed. The organic layer was washed with H 2 O (2 x 50 mL) and saturated aqueous NaCl (50 mL), dried (Na 2 SO 4 ), filtered and concentrated. Chromatography (SiO 2 , 5 cm x 10 cm, 25% toluene in hexanes) afforded 3 (16 g, 94%) as a colorless oil: 1 H NMR (CDCl 3 , 400 MHz) δ 6.29 (d, J = 2.
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