New Novobiocin Analogues as Antiproliferative Agents in Breast Cancer Cells and Potential Inhibitors of Heat Shock Protein 90
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- 作者：Gaë ; lle Le Bras ; Christine Radanyi ; Jean-Franç ; ois Peyrat ; Jean-Daniel Brion ; Mouâ ; d Alami ; Vé ; ronique Marsaud ; Barbara Stella ; Jack-Michel Renoir
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：November 29, 2007
- 年：2007
- 卷：50
- 期：24
- 页码：6189 - 6200
- 全文大小：382K
- 年卷期：v.50,no.24(November 29, 2007)
- ISSN：1520-4804
文摘
Selective hsp90 inhibitors simultaneously destabilize and deplete key signaling proteins involved in cellproliferation and survival, angiogenesis, and metastasis. Investigation of novobiocin analogues lacking thenoviose moiety as novel inhibitors of hsp90 was carried out. A novel series of 3-aminocoumarin analogueshas been produced and screened in cell proliferation, and the molecular signature of hsp90 inhibition wasassessed by depletion of estrogen receptor, HER2, Raf-1, and cdk4 in human breast cancer cells. Thisstructure-activity relationship study highlights the crucial role of the C-4 and/or C-7 positions of coumarinwhich appeared to be essential for degradation of hsp90 client proteins. Removal of the noviose moiety innovobiocin together with introduction of a tosyl substituent at C-4 or C-7 coumarins provides 6e and 6f aslead structures which compared favorably with novobiocin as demonstrated by enhanced rates of cell death.The processing and activation of caspases 7 and 8 and the subsequent cleavage of PARP by 6e suggeststimulation of the extrinsic apoptosis pathway.