Structure-activity studies of non-steroid analogues structurally-related to neuroprotective estrogens

Mingxing Qian, Elizabeth B. Engler-Chiurazzi, Sara E. Lewis, Nigam P. Rath, James W. Simpkins, Douglas F. Covey

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5 Scopus citations

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.

Original languageEnglish
Pages (from-to)9790-9805
Number of pages16
JournalOrganic and Biomolecular Chemistry
Volume14
Issue number41
DOIs
StatePublished - 2016

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