Structure-activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity

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• 作者：Xiaoli Xu^a ; ^b ; Yue Wu^a ; ^b ; Mingyang Hu^a ; ^b ; Xiang Li^a ; ^b ; Congying Gu^a ; ^c ; Qidong You^a ; ^b ; ^{youqd@163.com" class="auth_mail" title="E-mail the corresponding author} ; Xiaojin Zhang^a ; ^c ; ^{zxj@cpu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Caged xanthones ; Hsp90 inhibitor ; Antitumor ; Anti-angiogenesis ; Gambogic acid
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：24
• 期：19
• 页码：4626-4635
• 全文大小：2527 K

文摘

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 compound 25, with a simplified skeleton, had an improved inhibitory effect toward Hsp90. Compound 25 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, compound 25 induced the degradation of Hsp90 client proteins including Akt and Erk1/2 without causing the heat shock response. Additionally, compound 25 inhibited angiogenesis in HUVEC cells through Hsp90 regulation of the HIF-1α pathway. These results demonstrate that compound 25 as an Hsp90 inhibitor with a new structure could be further studied for the development of tumor therapy.