New novobiocin analogues as antiproliferative agents in breast cancer cells and potential inhibitors of heat shock protein 90.
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.
Le Bras
Gaëlle
G
University of Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, and University of Paris-Sud, 5 rue J.-B. Clément, Châtenay-Malabry, France.
Radanyi
Christine
C
Peyrat
Jean-François
JF
Brion
Jean-Daniel
JD
Alami
Mouâd
M
Marsaud
Véronique
V
Stella
Barbara
B
Renoir
Jack-Michel
JM
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; D020169:Caspases; D051358:Cyclin-Dependent Kinase 4; D004958:Estradiol; D047628:Estrogen Receptor alpha; D018841:HSP90 Heat-Shock Proteins; D009675:Novobiocin; D046988:Proteasome Endopeptidase Complex; D019908:Proto-Oncogene Proteins c-raf; D018719:Erb-b2 Receptor Tyrosine Kinases