Structure–activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity. Issue 19 (1st October 2016)

• Record Type: Journal Article
• Authors: Xu, Xiaoli; Wu, Yue; Hu, Mingyang; Li, Xiang; Gu, Congying; You, Qidong; Zhang, Xiaojin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 19(2016)
• Page Start: 4626
• Page End: 4635
• Publication Date: 2016-10-01
• Subjects: Caged xanthones -- Hsp90 inhibitor -- Antitumor -- Anti-angiogenesis -- Gambogic acid; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2016.07.067
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Hsp90 has long been recognized as an attractive and crucial molecular target for cancer therapy. Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported as a natural inhibitor of Hsp90. Here, we present the structure–activity relationship of Garcinia xanthones analogues as Hsp90 inhibitors and identify that compound25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound25 inhibited the ATPase activity of Hsp90 with an IC50 value of 3.68 ± 0.18 μM. It also exhibited potent antiproliferative activities in some solid tumor cells. In SK-BR-3 cells with high Hsp90 expression, compound25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy.