Inhibition of heat shock protein 90 (Hsp90) by diterpenoids from roots of Zhumeria majdae

Zhumeria majdae Rech.f. & Wendelbo is an endemic plant in Iran. and an unique member of Zhumeria genus. The constituents of this genus are rarely studied. Roots of Z. majdae were extracted with n-hexane, ethyl acetate, and methanol, respectively. The phytochemical investigation of the n-hexane extract by different chromatographic techniques, such as Silica gel and Sephadex LH-20 chromatography, and RP-HPLC, led to the isolation and identification of two new abietane diterpenes, 1-hydroxysahandone and 1-hydroxy-11-demethylsahandone, and 18 known abietane derivatives [1], [2]. The structures of the isolated compounds were elucidated by 1D and 2D NMR and MS techniques and absolute configurations were established by circular dichroism spectroscopy. A surface plasmon resonance analysis (SPR), MTT assay (Hela & MCF 7 cancer cell lines) western blot (WB) analysis on HSP-90 and several of its client proteins, including HSP-70, p-Akt, Akt, Cyclin A, p-Erk1 and Erk1, along with ATPase activity were implemented to screen a small diterpene library towards HSP90. This chaperone is involved in the turnover, trafficking, and folding of a large number of proteins, including oncoproteins. Thus, there is an interest in the development of new anticancer drugs targeting HSP90 [3]. Results showed that among all isolated diterpenes, lanugon Q showed higher affinity towards HSP90, with SPR KD of 2.98±1.97 nM. The results of WB and MTT assays were in agreement with SPR analysis. However, in the ATPase assay, lanugon Q did not show any inhibition.