Synthesis and evaluation of fluorescently linked polycyclic cage derivatives for application in neurodegenerative disorders
Year: 2020
Type: article
Abstract: Neurodegenerative diseases (ND) are chronic and progressive in nature, and characterized by the gradual loss of neurons in various regions of the central nervous system (CNS).ND include Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and cerebral ischemia/reperfusion (CIR).They have various progressive neurodegenerative pathologies that can result in several severe functional impairments for patients, and ultimately lead to serious health-related issues.According to more recent data, AD accounts for the most common cause of dementia and is believed to contribute to approximately 60-70% of cases.AD is thus seen as the most common form of dementia.There are various mechanisms involved in neuronal cell death, whether necrotic or apoptotic in nature, but one of the most notable is the lethal triplet.This triplet consists of metabolic compromise, oxidative stress, and excitotoxicity.Although not the only processes that can cause cell death, one or a combination of these processes are usually involved.A large part of this triplet involves excessive Ca 2+ influx through Voltage gated calcium channels (VGCC) and N-Methyl-D-Aspartate (NMDA) receptor overstimulation.Polycyclic cage derivatives are hydrocarbon chemical compounds that resemble a cage like shape or structure.Well known chemical structures such as PCP, amantadine and NGP1-01 are all cage like moieties.These cages have been proven to exhibit neuroprotective properties, while also inhibiting NMDA receptors and/ or calcium channels.Furthermore, they tend to exhibit a generally low side effect profile.These cages also have the potential to cross the blood brain barrier (BBB) permeability.Moreover the use of fluorescent molecules in ND can be highly advantageous, as they can generate high-resolution images; they tend to have a high sensitivity and can be a cost-effective way of monitoring diseases.Combining the neuroprotective, NMDA and VGCC activity of cage moieties with fluorophores can result in multi-functional agents in ND.For this purpose six compounds were synthesised, including polycyclic cage derivatives, fluorophores and fluorophore-cage conjugates.The structures of these http://etd.uwc.ac.za/ ix compounds were confirmed using NMR, IR and MS.The synthesised compounds were evaluated for cytotoxicity, neuroprotection and most importantly NMDA and VGCC inhibitory activity.For the VGCC inhibition assay Nimodipine and NGP1-01 were used as reference compounds, yielding 69.55% and 59.14% inhibition respectively, while all the test compounds showed a moderate to high degree of inhibition.Compound 3 had the highest inhibition at 77.76%.The assay proved to be statistically significant (P <0.0001).MK-801 and NGP1-01 were used as reference compounds for the NMDA assay.They showed a percentage inhibition of 59,57% and 42,27% respectively.Again compound 3 showed the best activity at 73.68% inhibition.For this assay most compounds also showed significant results and the assay was found to be statistically significant (P < 0.01).Compound 3, 4 and 7 were fluorophore-cage conjugates and all proved to have moderate to high degrees of dual VGCC and NMDA activity.The true potential use of these compounds as neuroprotective, NMDA and VGCC inhibitory agents have been proven to some degree, however the efficiency of these compounds and safety in patients is yet to be established and should be further researched.It has also been proven that these compounds maintained the fluorescent nature of the fluorophores conjugated to the cage moieties, and as such have potential as fluorescent ligands in disease monitoring and detection.The compounds could serve as lead structures in studies with a more comprehensives series for the development of novel fluorescent polycyclic agents in ND.
Author: Locarno Lawrence Fourie
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W3163858753