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

• Published in: European journal of medicinal chemistry 2022-12, Vol.244, p.114844-114844, Article 114844
• Main Authors: Li, Meng, She, Xianlan, Ou, Yufei, Liu, Jiangxin, Yuan, Zaifeng, Zhao, Qin-shi
• Format: Article
• Language: English
• Subjects: Antitumor; Hsp90 inhibitor; Natural product; Vibsanin C
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2022.114844

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 μM 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. [Display omitted] • •A series of novel vibsanin C analogues were synthesized and biologically evaluated for the Hsp90 inhibitory activity.• •29 and 31 showed the most potent Hsp90 inhibitory activity.• •Mechanism of action and direct interaction between Hsp90 and lead compounds were demonstrated.• •29 suppressed tumor growth in H22 tumor-bearing mice model.