Date of Award
12-2024
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Chemistry and Chemical Engineering
First Advisor
Nasri Nesnas
Second Advisor
Yi Liao
Third Advisor
Roberto Peverati
Fourth Advisor
Peshala Thibbotuwawa Gamage
Abstract
In recent biomedical research, the precise control of molecular dynamics through light activation has emerged as a powerful tool, particularly in the field of neurobiology. This approach involves the use of photocleavable cages or photoprotective groups (PPGs) that are chemically tethered to biologically active molecules such as neurotransmitters or calcium chelators. These cages remain inert until exposed to specific wavelengths of light, typically in the visible range, triggering the release of the active compound with high spatiotemporal precision.
For neurotransmitter systems, such as glutamate (Glu), which plays a critical role in synaptic transmission and memory formation, researchers have developed novel cage designs. These include thiocoumarin-based cages activated by light at 467 nm and BODIPY-based cages activated at 515–540 nm. The choice of these wavelengths is deliberate to avoid the cytotoxic effects associated with UV light while ensuring efficient activation and release of Glu molecules. Quantum efficiencies (QEs) of these cages, which measure the efficiency of conversion upon light exposure, range up to 0.65, with notable advancements achieving high QE for precise control of neurotransmitter release patterns in vivo, aiding in the study of neuronal circuitry and potentially leading to targeted therapies for neurological disorders.
Beyond neurotransmitters, the application of light-mediated control extends to calcium chelators like BAPTA, crucial for modulating intracellular calcium levels implicated in diseases such as Alzheimer's and Parkinson's. Thiocoumarin-based BAPTA cages demonstrate high efficiency (0.39-0.83 QE) in releasing BAPTA upon light activation, enabling researchers to selectively target neurons experiencing abnormal calcium influx during neuronal activity.
Moreover, advancements in chemogenetic technologies, such as TC-DREADD-21 cages, allow for non-invasive manipulation of neuronal activity using longer wavelengths of light (467 nm), minimizing cellular damage. These tools are pivotal for studying complex brain behaviors and neuronal signaling pathways in vivo, offering insights into behaviors ranging from basic motor functions to higher cognitive processes.
Additionally, the synthesis and evaluation of anti-inflammatory compounds are critical for developing new therapeutic agents. This study focused on the synthesis of 4-arylidene-2-phenyloxazol-5(4H)-ones using the Erlenmeyer–Plöchl reaction, characterized by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Their in vitro anti-inflammatory activities were assessed using the heat-induced human red blood cell (HRBC) membrane stabilization assay, revealing concentration-dependent inhibitory effects. Docking studies against human cyclooxygenase (COX) 1 and 2 demonstrated the compounds' affinity for COX enzyme binding cavities. These compounds exhibited significant anti-inflammatory activity, indicating potential as therapeutic agents.
In parallel, the synthesis of functionalized nanoparticles, such as silver nanoparticles (AgNPs), via light-controlled reactions has expanded their antimicrobial efficacy. These nanoparticles, functionalized with organic ligands like benzothiazole derivatives, exhibit potent antibacterial properties against pathogens like E. coli, demonstrating their potential in biomedical applications.
Recommended Citation
Egodawaththa Arachchilage Don, Nishal Madujith, "Synthesis of Photocleavable Molecules for Neurological Applications" (2024). Theses and Dissertations. 1487.
https://repository.fit.edu/etd/1487
Included in
Chemical Actions and Uses Commons, Complex Mixtures Commons, Heterocyclic Compounds Commons, Inorganic Chemicals Commons, Laboratory Medicine Commons, Macromolecular Substances Commons, Medicinal and Pharmaceutical Chemistry Commons, Medicinal-Pharmaceutical Chemistry Commons, Nanomedicine Commons, Natural Products Chemistry and Pharmacognosy Commons, Neurology Commons, Organic Chemicals Commons, Organic Chemistry Commons, Other Chemicals and Drugs Commons, Other Pharmacy and Pharmaceutical Sciences Commons, Pharmaceutical Preparations Commons, Pharmaceutics and Drug Design Commons, Physical Chemistry Commons, Polycyclic Compounds Commons, Polymer Chemistry Commons, Radiology Commons