Project 3 - Bio-inspired Synthesis of Steroidal-Heterocyclic Hybrids as Neuroprotective Agents
Applying for Summer 2025
Supervisor: Dr Amr Eldemerdash
School/Institute: School of Chemistry, Pharmacy and Pharmacology, UEA
Introduction: The global rise in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, poses a significant challenge as aging populations grow. These disorders, caused by protein misfolding, oxidative stress, and inflammation, lead to cognitive and motor impairments, straining healthcare systems and caregivers1.
Natural products have long been a valuable source of therapeutic agents for neurodegenerative diseases, offering diverse bioactive compounds with unique structures and mechanisms of action. Numerous naturally occurring compounds including alkaloids, polyphenols, and terpenoids, offer neuroprotective potential by reducing oxidative stress, inhibiting protein aggregation, and modulating neuroinflammation. Compounds like curcumin and resveratrol have shown promise in preclinical models of Alzheimer’s and Parkinson’s, inspiring drug discovery2-4. Intriguingly, natural and synthetic steroid-containing compounds have garnered attention for their significant neuroprotective effects. These compounds have shown potential in modulating various neurodegenerative pathways, such as reducing oxidative stress, inhibiting neuroinflammation, and protecting against neuronal cell death5-6. For example, steroidal alkaloids [e.g. (+)-O6-buxafurandiene (1)7 and conessine (2)8], along with steroidal saponins [e.g. ginsenoside Rb1 (3)9] are being explored for their ability to enhance neuroprotection and promote neuronal regeneration. Additionally, a plenty of synthetic DHEA-like alkaloids (e.g. 4-7) featuring different heterocyclic moieties have displayed potent neuroprotection activity, where their unique structural diversification makes them promising candidates for the development of novel treatments for neurodegenerative diseases10-14.
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Figure 1 – Images of steroidal alkaloids (+)-O6-buxafurandiene (1)7 and conessine (2)8, along with a steroidal saponin named ginsenoside.
Objectives: This research aims to design, synthesize, and evaluate novel DHEA-heterocyclic hybrids as potential neuroprotective agents using computer-aided approaches. Molecular docking and dynamics simulations will guide the in-silico design of a library of hybrids, identifying structural modifications that enhance binding to neurodegeneration-related targets and predicting drug-target stability and like AChE, BuChE, P2X and P2X7. Promising analogues with optimal efficacy and pharmacokinetic properties will be prioritized for chemical synthesis using advanced organic methods to improve neuroprotective activity. These compounds will then be preliminary evaluate for in vitro neuroprotection in neuronal cell lines, focusing on pathways that prevent neuronal loss. Finally, a comprehensive structure-activity relationship (SAR) analysis will correlate chemical structures with biological activity, providing insights for optimizing promising therapeutics neurodegenerative diseases.
Skills gained and outcomes: The student will gain training/experience in a range of experimental methods [e.g. synthetic organic chemistry, different chromatographic and analytical techniques, including flash chromatography, HPLC, NMR, LC-HR-ESI-MS (El-Demerdash Lab), evaluation of synthesized compounds for the AChE, BuChE, P2X and P2X7 (Stokes Lab), and scientific report writing] as well as analyzing and collectively interpreting the outcomes of these different datasets to provide a clearer insight into the therapeutic potential of these saponins. The preliminary data from this project may be used to support a full research grant application to the Medical Research Council.
References: (1) Science 2015, 349, 1255555. (2) Neurosignals 2005, 14, 6. (3) Cells 2021, 10, 1309. (4) Int. J. Mol. Sci 2023, 24, 8827. (5) Oxidative Medicine and Cellular Longevity. 2022, 1, 6873874. (6) Frontiers in Neuroendocrinology 2009, 30, v. (7) Steroids 2024, 109468. (8) Steroids 2006, 71, 1045. (9) Life sciences 2012, 90, 929. (10) Brain research bulletin 2016, 125, 30. (11) Steroids 2013, 78, 1200. (12) Steroids 2020, 154, 108548. (13) ACS Chemical Neuroscience 2017, 8,186. (14) Steroids 2019, 148, 114.