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Scheme 2. Synthesis of the Three Cage-GABA Derivatives, iDMPO-GABA (2a), iDMBO-GABA (2b), and DNI-CO-GABA (3)
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In this paper, we present an additional, new cage-GABA compound, called 4-amino-1-(4′-dimethylaminoisopropoxy-5′,7′-dinitro-2′,3′-dihydro-indol-1-yl)-1-oxobutane-γ-aminobutyric acid (iDMPO-DNI-GABA), and currently, this compound is the only photoreagent, which can be applied for GABA uncaging without experimental compromises. By a systematic theore...
Citations
... Since the 1970s, a considerable effort has been dedicated both to the development of novel photoactivatable chemical probes and their applications in various experimental studies. Regarding the scope of PPG applications, the caged substrate could be as Encyclopedia 2022, 2 1227 simple as a proton or an inorganic species or ion (e.g., Ca 2+ [15], Zn 2+ [16], CO [17], NO [18], H 2 S [19]), it could be a small molecule (e.g., second messenger (such as inositol-1,4,5-triphosphate (IP 3 ) [20]), neurotransmitter (notably GABA and glutamate [21,22]), nucleotide [23], peptide [24], drug molecule [25] (such as antibiotics [26], analgesics [27] or anticancer agents [28]) or a more complex biomolecule (e.g., enzymes [29], RNA [30] or DNA [31]) ( Figure 3). ...
... Since the 1970s, a considerable effort has been dedicated both to the development of novel photoactivatable chemical probes and their applications in various experimental studies. Regarding the scope of PPG applications, the caged substrate could be as simple as a proton or an inorganic species or ion (e.g., Ca 2+ [15], Zn 2+ [16], CO [17], NO [18], H2S [19]), it could be a small molecule (e.g., second messenger (such as inositol-1,4,5-triphosphate (IP3) [20]), neurotransmitter (notably GABA and glutamate [21,22]), nucleotide [23], peptide [24], drug molecule [25] (such as antibiotics [26], analgesics [27] or anticancer agents [28]) or a more complex biomolecule (e.g., enzymes [29], RNA [30] or DNA [31]) ( Figure 3). [32], (B) neurotransmitter glutamate caging with MNI [21], (C) caging the anticancer agent vemurafenib with a nitrobenzyl PPG [33], (D) a coumarin PPG-caged antibiotic agent [34], (E) a coumarin PPG-caged analgesic [27]. ...
Photoremovable protecting groups (PPGs) (also often called photocages in the literature) are used for temporary inactivation of biologically active substrates. By photoirradiation the PPG could be cleaved off and the biological activity could be restored on-demand, with a high spatiotemporal precision. The on-site liberation of the biologically active substrate could be exploited for studying dynamic biological processes or for designing targeted pharmacological interventions in vitro or in vivo. Several chemical scaffolds have been described and tested as PPGs, operating at different wavelengths. The scope of potential substrates is very broad, spanning from small molecules to proteins. In a wider context, PPGs could be used for the design of various light-responsive materials as well, for diverse applications.
... To assess the application of cobalamin conjugates as drug delivery systems, a cobalamin-doxorubicin conjugate was prepared (12) [47]. Cytotoxicity was studied in HeLa (cervical cancer) cells (MTT assay at 10 µM), following different illumination times (30,45, and 75 s at 530 nm). The cobalamin-conjugate affected cell viability in an irradiation-dependent manner (neither the construct without light nor the light irradiation without the construct had an effect on cell viability), with similar efficacy at the end point as that of the parent doxorubicin. ...
Cancer chemotherapy is affected by a modest selectivity and toxic side effects of pharmacological interventions. Among novel approaches to overcome this limitation and to bring to therapy more potent and selective agents is the use of light for selective activation of anticancer compounds. In this review, we focus on the anticancer applications of two light-activated approaches still in the experimental phase: photoremovable protecting groups (“photocages”) and photoswitches. We describe the structural considerations behind the development of novel compounds and the plethora of assays used to confirm whether the photochemical and pharmacological properties are meeting the stringent criteria for an efficient in vivo light-dependent activation. Despite its immense potential, light activation brings many challenges, and the complexity of the task is very demanding. Currently, we are still deeply in the phase of pharmacological tools, but the vivid research and rapid development bring the light of hope for potential clinical use.
Citation: Csomos, A.; Madarász, M.; Turczel, G.; Cseri, L.; Katona, G.; Rózsa, B.; Kovács, E.; Mucsi, Z. A Molecular Hybrid of the GFP Chromophore and 2,2 ′-Bipyridine: An Accessible Sensor for Zn 2+ Detection with Fluorescence Microscopy. Int. J. Mol. Sci. 2024, 25, 3504. These authors contributed equally to this work. Abstract: The few commercially available chemosensors and published probes for in vitro Zn 2+ detection in two-photon microscopy are compromised by their flawed spectroscopic properties, causing issues in selectivity or challenging multistep syntheses. Herein, we present the development of an effective small molecular GFP chromophore-based fluorescent chemosensor with a 2,2 ′-bipyridine chelator moiety (GFZnP BIPY) for Zn 2+ detection that has straightforward synthesis and uncompro-mised properties. Detailed experimental characterizations of the free and the zinc-bound compounds within the physiologically relevant pH range are presented. Excellent photophysical characteristics are reported, including a 53-fold fluorescence enhancement with excitation and emission maxima at 422 nm and 492 nm, respectively. A high two-photon cross section of 3.0 GM at 840 nm as well as excellent metal ion selectivity are reported. In vitro experiments on HEK 293 cell culture were carried out using two-photon microscopy to demonstrate the applicability of the novel sensor for zinc bioimaging.
An asymmetric cyanine-type fluorescent dye was designed and synthesized in a versatile, multi-step process, aiming to conjugate to Her2+ receptor specific antibody by azide alkyne click reaction. The aromaticity and the excitation and relaxation energetics of the fluorophore was characterized by computational methods. The synthesized dye exhibited excellent fluorescent properties for confocal microscopy, offering efficient applicability in in vitro imaging, such as a high molar absorption coefficient (36816 M-1cm-1) as well as brightness, optimal wavelength (627 nm), larger stokes shift (26 nm) and appropriate photostability compared to cyanines. The conjugated cyanine-trastuzumab was constructed via an effective, metal-free, strain-promoted azide-alkyne click reaction leading to regulated number of dyes conjugated. This novel cyanine-labelled antibody was successfully applied for in vitro confocal imaging and flow cytometry of Her2+ tumor cells.
A novel family of julolidine-containing fluorescent rhodols equipped with a wide variety of substituents was synthesized in a versatile two-step process. The prepared compounds were fully characterized and exhibited excellent fluorescence properties for microscopy imaging. The best candidate was conjugated to the therapeutic antibody trastuzumab through a copper-free strain-promoted azide-alkyne click reaction. The rhodol-labeled antibody was successfully applied for in vitro confocal and two-photon microscopy imaging of Her2+ cells.
Shape memory polymers (SMPs) are suitable substrate materials for soft neural interfaces due to their tunable elastic characteristics. The stability and biocompatibility of intracortical SMP probes are demonstrated. In this work, a SMP‐based cortical implant capable of recording high‐density micro‐electrocorticography is utilized in a multimodal neuroimaging scheme. The transparent nature of thiol‐ene/acrylate substrate is exploited, and the feasibility of measuring intracranial electroencephalogram and fluorescent GCaMP6 signals with two‐photon imaging through the device is presented in mice. The potential influence of the optical properties of the microdevice is investigated using fluorescent microbeads, hippocampal brain slices, and awake animals. It is found that neurites and cell soma can be efficiently detected with sufficient resolution to follow changes in the calcium signal. These chronically implanted devices do not suppress the quality of optical signals exceeding 22 weeks after implantation. These results indicate that thiol‐ene/acrylate ECoG is an appropriate tool to combine electrophysiology with two‐photon imaging while leveraging the inherent tissue‐friendly properties of SMPs. Soft, transparent thiol‐ene/acrylate‐based neural microimplant is utilized to concurrently record cortical electrophysiology and optical signals with two‐photon calcium imaging. Ca signals of individual neurons can be recorded for at least 22 weeks in awake animals at high spatial resolution. Integrated gold and iridium‐oxide electrodes provide stable signal‐to‐noise ratio during the long‐term in vivo experiment.
Versatile, two-step synthesis of dihydro-dibenzo[c,e]azepine, carbazole derivatives and other alkaloid type drug-like scaffolds, by in situ generated azomethine ylide induced intramolecular electrocyclization reaction from commercially available materials are presented. The reaction mechanisms of transition metal-free carbon–carbon bond formation and the role of the kinetic control, resulting in the good regioselectivity, were confirmed by theoretical calculations.
Novel small‐molecular analogues the green fluorescence protein (GFP) chromophore were synthesised to expand and improve this fluorophore family and to deepen the understanding of their fluorescence mechanism. The introduction of an aminophenyl substituent and the repositioning of the hydroxyl group, to enable strong intramolecular hydrogen bonding, not only enhanced fluorescence emission but also resulted in an increased Stokes shift and a considerable redshift. Experimental and computational results described dual fluorescence involving both excited‐state intramolecular proton transfer and internal charge transfer (ESIPT‐ICT) mechanisms. Screening of the pH and the solvent medium revealed a complicated equilibrium involving hydrogen bonding, protonation and deprotonation that influences the absorption and emission spectra. Further improvement of the photophysical properties via the systematic variation of dialkylamino substituents at a single position of the chromophore led to a two‐orders of magnitude enhancement in the quantum yields. In addition, the novel compounds also have significant two‐photon absorption, which widens the possibilities for applications in the field of bioimaging.
