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Final Report Summary - LIGHTLAB-TOOLS (Synthesis of Two-Photon Optimized 'Caged' Compounds for Neuroscienes)

The ‘LIGHTLAB-TOOLS’ project aimed the development of novel two-photon optimized caged compounds for neurophysiological studies. ’Caged compounds’ are light sensitive prodrugs allowing the controlled release of active molecules by using a pulse of light. They are valuable experimental tools for studying complex, dynamic biological processes. Photochemical release of ligands – e.g. neurotransmitters, hormones, second messengers - within tissues has the potential for controlling signalization paths in high spatial resolution at the molecular level when combined with modern microscopy and achieves physiological sub-millisecond temporal resolution. For our studies the quinoline platform, as light sensitive organic platform was selected, described originally by Dore et al. in the 2000’s. In preliminary experiments realized in the laboratory it has been found, that by modifying the substitution pattern, the photophysical properties and the photofragmentation might be significantly improved. During the project the i) optimization of aminoquinoline-derived dipolar structures (by further modifications on the so far most efficient 5-benzoyl-8-DMAQ) and ii) incorporation of different symmetry elements (synthesis of trimeric (octupolar) 2-hydroxymethylene-dimethylaminoquinoline-derived caged compounds) were studied. The evaluation of trimer constructs might help to gain a better understanding of the effect of symmetry on the two-photon efficiency in the quinoline platform, helping the future design of novel caged compounds with improved photophysical and physiological properties. As the result of the synthetic work, a small library of monomeric, dimeric and trimeric 2-hydroxymethylene-dimethylaminoquinoline derived caged compounds were prepared, leading to the first probes having ≥2.5 GM uncaging cross-section (i.e. probes with sufficient efficiency for eventual biological applications). Furthermore, the iii) preparation of caged neurotransmitters, or their receptor specific analogues was addressed. Applications in neurophysiology for the controlled liberation of agonist and inhibitory neurotransmitters are being evaluated. Beyond applications in neurophysiology, the developed probes might be used for masking the biological activity of a large array of small carboxy-ended compounds, such as C-terminal amino acids, olygopeptides as well as phosphate and carbamate ligands. Within a collaborative network in microfluidics, the incorporation of an aminoquinoline as a photosensible unit into a surfactant has been investigated. Droplet-based microfluidics enable high throughput assays for biomedical and biochemical applications, with droplets acting as independent microreactors. Microdroplets stabilized by the aminoquinoline-derived photosensitive surfactants might be merged precisely upon photolysis, offering perspectives for complex mixing processes.
Our results might help the design of new light-sensitive chemical entities and pave the way towards various applications based on the incorporation of photoresponsive units in a variety of constructs, such as photoresponsive block copolymers, photoreconfigurable hydrogels, etc. Moreover, light sensitive prodrugs might play a role in controlled active drug delivery applications as well in the future.

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