Gedunin, a novel hsp90 inhibitor: semisynthesis of derivatives and preliminary structure-activity relationships

Abstract

Gedunin (1), a tetranortriterpenoid isolated from the Indian neem tree ( Azadirachta indica), was recently shown to manifest anticancer activity via inhibition of the 90 kDa heat shock protein (Hsp90) folding machinery and to induce the degradation of Hsp90-dependent client proteins similar to other Hsp90 inhibitors. The mechanism of action by which gedunin induces client protein degradation remains undetermined, however, prior studies have demonstrated that it does not bind competitively versus ATP. In an effort to further probe the mechanism of action, 19 semisynthetic derivatives of gedunin were prepared and their antiproliferative activity against MCF-7 and SkBr3 breast cancer cells determined. Although no compound was found to exhibit antiproliferative activity more effective than the natural product, functionalities critical for antiproliferative activity have been identified.

Figure 1

Chemical structures of GDA, gedunin (1), and novobiocin.

Figure 2

Western blot analysis of compounds 1, 3f, and 4 in SKBr3 breast cancer cells after 24 h of incubation at given concentrations.

Scheme 1^a

^a Reagents and conditions: (a) alkyl iodide, KO^tBu, THF, 0°C; (b) propionyl chloride, DMAP, Et₃N, CH₂Cl_2, 0 °C; (c) trichloroacetyl isocyanate, CH₂Cl₂; (d) PCC, CH₂Cl₂.

Scheme 2^a

^a Reagents and conditions: (a) NaOH, H₂O₂, acetone.

Scheme 3^a

^a Reagents and conditions: (a) NMO, OsO₄, acetone, H₂O, 0 °C; (b) 1,2-dimethoxypropane, pTsOH, acetone; (c) 10% Pd/C, MeOH; (d) NaBH₄, CeCl₃, MeOH/CHCl_3; (e) ⁱPrOH, Al(OⁱPr)₃, toluene, 70 °C; (f) acyl chloride, DMAP, Et₃N, CH₂Cl₂; (g) NaBH₄, EtOH; (h) alkoxyamine hydrochloride, pyridine, 70 °C.

Scheme 4^a

^a Reagents and conditions: (a) hydroxylamine hydrochloride, pyridine, 70 °C.