2. Academic Validation
  3. Structure-activity relationship of Garcinia xanthones analogues: Potent Hsp90 inhibitors with cytotoxicity and antiangiogenesis activity

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

  • Bioorg Med Chem. 2016 Oct 1;24(19):4626-4635. doi: 10.1016/j.bmc.2016.07.067.
Xiaoli Xu 1,  Yue Wu 1,  Mingyang Hu 1,  Xiang Li 1,  Congying Gu 2,  Qidong You 3,  Xiaojin Zhang 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
  • 2 State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China.
  • 3 State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China. Electronic address: youqd@163.com.
  • 4 State Key Laboratory of Natural Medicines and Jiang Su Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China. Electronic address: zxj@cpu.edu.cn.
PMID: 27527413 DOI: 10.1016/j.bmc.2016.07.067
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 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±0.18μM. 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.

Keywords

Anti-angiogenesis; Antitumor; Caged xanthones; Gambogic acid; Hsp90 inhibitor.

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