title: Structure-activity studies of non-steroid analogues structurally-related to neuroprotective estrogens.
abstract: Estrone and 17β-estradiol are phenolic steroids that are known to be neuroprotective in multiple models of neuronal injury. Previous studies have identified the importance of their phenolic steroid A-ring for neuroprotection and have identified ortho substituents at the C-2 and C-4 positions on the phenol ring that enhance this activity. To investigate the importance of the steroid ring system for neuroprotective activity, phenolic compounds having the cyclopent[b]anthracene, cyclopenta[b]phenanthrene, benz[f]indene, benz[e]indene, indenes linked to a phenol, and a phenolic spiro ring system were prepared. New synthetic methods were developed to make some of the cyclopent[b]anthracene analogues as well as the spiro ring system. Compounds were evaluated for their ability to protect HT-22 hippocampal neurons from glutamate neurotoxicity and their activity relative to a potent neuroprotective analogue of 17β-estradiol was determined. An adamantyl substituent placed ortho to the phenolic hydroxyl group gave neuroprotective analogues in all ring systems studied.
authors.affiliation: Department of Developmental Biology, Campus Box 8103, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA. dcovey@wustl.edu.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Qian
authors.affiliation: Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Elizabeth B
authors.initials: EB
authors.lastname: Engler-Chiurazzi
authors.affiliation: Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Lewis
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience, University of Missouri-St. Louis, St. Louis, MO 63121, USA.
authors.forename: Nigam P
authors.initials: NP
authors.lastname: Rath
authors.affiliation: Center for Basic and Translational Stroke Research, West Virginia University, Morgantown, WV 26506, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
authors.affiliation: Department of Developmental Biology, Campus Box 8103, Washington University in St. Louis, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA. dcovey@wustl.edu and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA and Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Covey
mesh_terms: D002460:Cell Line; D004967:Estrogens / Q000737:chemistry* / Q000494:pharmacology*; D006624:Hippocampus / Q000166:cytology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology*; D013141:Spiro Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D004967:Estrogens; D018696:Neuroprotective Agents; D013141:Spiro Compounds