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.

Detecting Key Functional Components Group and Speculating the Potential Mechanism of Xiao-Xu-Ming Decoction in Treating Stroke

“…In addition, molecular docking indicated that KFCG could bind the proteins involved in comprehensive pathways effectively, such as COM14, MOL000114, MOL002516, MOL001755, MOL010921, COM52, and MOL000953 (Figure 10D 1 -10I 2 , Supplementary Figure S2A1-S2D21). These components in KFCG showed a potential contribution to the treatment of stroke by KFCG (Figure 9) (Li et al, 2015;Li et al, 2016;Qian et al, 2016;Kempuraj et al, 2020). It is indicated that KFCG can represent the key function of XXMD in treating stroke and the CCR model used in our study was effective for XXMD optimization.…”

Effect of experimentally induced hypertension on cerebellum of postmenopausal rat

“…Therefore, the significant increase in number of astrocytes in OVX-group in this study could be a compensatory response of the cerebellum to maintain (Laouafa et al, 2017). Another study mentioned that estrogen acts as hydroxyl scavengers because of their hydrophobic phenolic compounds which has the ability to donate hydrogen (Qian et al, 2016). In addition, ROS react with antioxidants which results in its consumption and makes them lose their free radical scavenging activity (Samantaray et al, 2016).…”

“…Estradiol could provide protection against toxic insults and impact a variety of health related cerebellar functions by down regulating the expression of important subunits of mitochondrial NADPH oxidase; the ROS generator (Laouafa et al, 2017). Another study mentioned that estrogen acts as hydroxyl scavengers because of their hydrophobic phenolic compounds which has the ability to donate hydrogen (Qian et al, 2016). In addition, ROS react with antioxidants which results in its consumption and makes them lose their free radical scavenging activity (Samantaray et al, 2016).…”

Neuroprotective effects of estrogen in CNS injuries: insights from animal models

“… 22 What specific signaling pathway that E2 takes when it is protecting the CNS cells and other cells from injuries is still debatable; however, it is found that the hydroxyl group in the phenolic steroid ring is what produces the antioxidant effects of E2. 21 – 23 It is now well established that quinol-based cyclic antioxidant mechanism of E2 is responsible for its neuroprotective effects. 24 Exciting recent studies show that most of the neurosteroids including E2 are highly capable of improving mitochondrial bioenergetics in neurons by increasing the ATP levels, mitochondrial membrane potential, and basal mitochondrial respiration.…”