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.
- 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: [email protected].
- 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: [email protected].
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.