Design, synthesis and biological evaluation of a new class of Hsp90 inhibitors vibsanin C derivatives

Hsp90, an ATP-dependent chaperone that is essential for a wide range of protein assembly and folding processes, has long been recognized as a potential target for cancer. Hsp90 has more recently been identified as having a significant pathogenic role in viral infection, neurodegenerative disease, and inflammation, therefore, the development of the agents to inhibit the chaperone could potentially treat such intractable diseases. Here, on the basis of primary structure-activity relationships and docking analysis, a series of novel vibsanin C analogues with an emphasis on the C18 position was first designed, synthesized and biologically evaluated. The most effective Hsp90 inhibitory activity among these analogues was demonstrated by 29 and 31, with IC50 values of 0.39 and 0.27 mu M respectively. Direct interaction between Hsp90 and its inhibitors were further confirmed. Mechanism studies indicated that 29 promoted HL-60 cell apoptosis by mitochondrial-mediated apoptosis pathway. In addition, 29 suppressed tumor growth in the H22 tumor-bearing mice model and revealed low acute toxicity in mice (LD50 > 500 mg/kg), suggesting its potential for further investigations.

Automated summary

Hsp90 is an ATP-dependent chaperone that plays a crucial role in protein assembly and folding. It has been found to be involved in cancer, viral infection, neurodegenerative disease, and inflammation. In this study, a series of novel analogues were designed, synthesized, and evaluated for their inhibitory activity against Hsp90. Among these analogues, compound 29 and 31 showed the most potent inhibitory activity. Mechanism studies revealed that compound 29 promoted cell apoptosis through the mitochondrial-mediated pathway. Furthermore, compound 29 exhibited anti-tumor activity in a mouse model and showed low acute toxicity. These findings suggest that compound 29 has potential for further development as a therapeutic agent.