Synthesis and Biological Evaluation of 2-Aminopurine Derivatives as Heat Shock Protein 90 Inhibitors

Title
Synthesis and Biological Evaluation of 2-Aminopurine Derivatives as Heat Shock Protein 90 Inhibitors
Authors
금교창이주현신상철유경호강순방김은경
Keywords
Hsp90; structure based
Issue Date
2012-09
Publisher
EFMC; ISMC 2012 XXIInd International Symposium on Medicinal Chemistry
Citation
, 266-266
Abstract
Heat shock protein 90 (Hsp90) is a molecular chaperone involved in the correct folding, stabilization, and activation of various proteins by forming multimeric protein complexes with ADP/ATP, its co-chaperones, and many client proteins which are essential in cell activation and proliferation. Because Hsp90 also stabilizes a number of oncogenic proteins that are mutated or overexpressed in tumor cells and drive cancer cell growth, a number of Hsp90 inhibitors are currently undergoing clinical evaluation in cancer patients.[1] Among them, we are interested in the purine-based inhibitors such as PUH71, CUDC-305, MPC-3100, and BIIB021. We synthesized a series of 2-aminopurine derivatives containing amino or oxy modifications at the 6-position to introduce an additional pharmacophore. The prepared compounds showed good binding affinity to Hsp90 in ITC assays and exhibited good antiproliferative activities against MCF-7 and HCT-116 cancer cell lines. X-ray crystallographic data of the ligand–Hsp90 complex showed the inhibitors bind in the ATPase site of the Hsp90 N-terminal domain with an L-shaped conformation. The aryl ring at position N9 showed π–π stacking interactions with Phe138 in the hydrophobic pocket by reserving the conformation of outer helix.
URI
http://pubs.kist.re.kr/handle/201004/44296
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KIST Publication > Conference Paper
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