(3R,5S,7as)-(3,5-Bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol, a novel neuroprotective agent.
Compounds that interact with microtubules, such as paclitaxel, have been shown to possess protective properties against beta-amyloid (Abeta) induced neurodegeneration associated with Alzheimer's disease. In this work, the novel agent (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol was investigated for effectiveness in protecting neurons against several toxic stimuli and its interaction with the microtubule network. Exposure of neuronal cultures to Abeta peptide in the presence of 5 nM (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol resulted in a 50% increase in survival. Neuronal cultures treated with other toxic stimuli such as staurosporine, thapsigargin, paraquat, and H(2)O(2) showed significantly enhanced survival in the presence of (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol. Microtubule binding and tubulin assembly studies revealed differences compared to paclitaxel but confirmed the interaction of (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol with microtubules. Furthermore, in vitro studies using bovine brain microvessel endothelial cells experiments suggest that (3R,5S,7as)-(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo[3,4-c]oxazol-7a-yl)methanol can readily cross the blood-brain barrier in a passive manner.
Desino
Kelly E
KE
Department of Pharmaceutical Chemistry, The University of Kansas, 2095 Constant Avenue, Lawrence, Kansas 66047, USA.
Ansar
Sabah
S
Georg
Gunda I
GI
Himes
Richard H
RH
Michaelis
Mary Lou
ML
Powell
Douglas R
DR
Reiff
Emily A
EA
Telikepalli
Hanumaiah
H
Audus
Kenneth L
KL
D016229:Amyloid beta-Peptides / Q000633:toxicity; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D002417:Cattle; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010539:Permeability; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability; D051381:Rats; D020112:Rhodamine 123 / Q000378:metabolism; D013237:Stereoisomerism
C545992:(3,5-bis(4-fluorophenyl)tetrahydro-1H-oxazolo(3,4-c)oxazol-7a-yl)methanol; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D010080:Oxazoles; D020112:Rhodamine 123