New Novobiocin Analogues as Antiproliferative Agents in Breast Cancer Cells and Potential Inhibitors of Heat Shock Protein 90

Citations Over TimeTop 10% of 2007 papers

Abstract

Selective hsp90 inhibitors simultaneously destabilize and deplete key signaling proteins involved in cell proliferation and survival, angiogenesis, and metastasis. Investigation of novobiocin analogues lacking the noviose moiety as novel inhibitors of hsp90 was carried out. A novel series of 3-aminocoumarin analogues has been produced and screened in cell proliferation, and the molecular signature of hsp90 inhibition was assessed by depletion of estrogen receptor, HER2, Raf-1, and cdk4 in human breast cancer cells. This structure-activity relationship study highlights the crucial role of the C-4 and/or C-7 positions of coumarin which appeared to be essential for degradation of hsp90 client proteins. Removal of the noviose moiety in novobiocin together with introduction of a tosyl substituent at C-4 or C-7 coumarins provides 6e and 6f as lead 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 suggest stimulation of the extrinsic apoptosis pathway.

Related Papers

• → Hsp90 Inhibitors Identified from a Library of Novobiocin Analogues(2005)171 cited
• → Novobiocin Induces a Distinct Conformation of Hsp90 and Alters Hsp90−Cochaperone−Client Interactions(2004)100 cited
• → Modulation of Hsf1 activity by novobiocin and geldanamycin(2009)77 cited
• → Heat Shock Protein 90 (Hsp90) Chaperone Complex: A Molecular Target for Enhancement of Thermosensitivity and Radiosensitivity.(2002)1 cited
• The Research Advancement of Heat Shock Protein 90 in Tumor Prevention and Therapy(2008)