1256259-14-9

Upstream product

• 91-44-1 7-diethylamino-4-methylcoumarin 
• 54711-39-6 7-(diethylamino)-2-oxo-2H-1-benzopyran-4-carboxaldehyde 
• 54711-38-5 7-(diethylamino)-4-(hydroxymethyl)-2H-chromen-2-one 

Downstream Products

• 1620751-81-6 N-(1-{[7-(diethylamino)-2-oxo-2H-chromen-4-yl]methoxy}-2,2,6,6-tetramethylpiperidin-4-yl)benzamide 

Relevant academic research and scientific papers

Enantioselective Synthesis and Application of Small and Environmentally Sensitive Fluorescent Amino Acids for Probing Biological Interactions

Environmentally sensitive fluorescent amino acids (FlAAs) have been used extensively to probe biological interactions. However, most of these amino acids are large and do not resemble amino acid side chains. Here, we report the enantioselective synthesis of two small and environmentally sensitive fluorescent amino acids bearing 7-dialkylaminocoumarin side chains by alkylation of a Ni(II) glycine Schiff base complex. These amino acids exhibit a large increase in fluorescence as environment polarity decreases. One of these FLAAs was incorporated into a highly active analog of the cyclic lipopeptide antibiotic paenibacterin by Fmoc solid-phase peptide synthesis via a new and very efficient route. This peptide was used to probe the interaction of the antibiotic with model liposomes, lipopolysaccharides, and live bacteria.

Photolytic Release of a Caged Inhibitor of an Endogenous Transcription Factor Enables Optochemical Control of CREB-Mediated Gene Expression

A direct optochemical method for regulating gene function has been developed based on uncaging of an inactive caged precursor that fragments to produce a CREB (cAMP-response element binding protein) inhibitor that binds to an endogenous transcription factor responsible for regulating CREB-mediated gene expression levels.

Development and cellular application of visible-light-controllable HNO releasers based on caged Piloty's acid

Nitroxyl (HNO) is a gaseous molecule with unique pharmacological functions distinct from those of nitric oxide. Because HNO is highly reactive with biological molecules, spatiotemporally controllable HNO releasers are required. Herein, we report the first visible-light-controllable HNO releasers, based on caged Piloty's acid, and we demonstrate their applicability in living cells.

A Fluorescent Chemodosimeter for Organelle-Specific Imaging of Nucleoside Polyphosphate Dynamics in Living Cells

Nucleoside polyphosphates (NPPs) are mainly produced in mitochondria and used as a universal energy source for various cellular events. Although numerous fluorescent probes for adenosine triphosphate (ATP) have been reported, they are not ideally suited for live monitoring of the subtle variation of the mitochondrial ATP level. A new coumarin-based fluorescent probe is synthesized, and this reagent is utilized for specific recognition of NPPs in mitochondria by super-resolution microscopy in physiological condition. Detailed 31P NMR studies reveal that the probe, L·Zn(II), binds to NPPs through their pendent phosphate functionalities. Such binding leads to a substantial enhancement in the luminescence intensity of L·Zn(II) + ADP or L·Zn(II) + ATP as compared to L·Zn(II). This - as well as 1H NMR spectroscopy - has enabled us to evaluate the probe's binding affinities to these NPPs. Structured illumination and wide field fluorescence microscopy confirmed that this physiologically benign reagent is localized within mitochondria of live RAW 264.7 macrophage cells. This reagent has been utilized to probe real-time changes in ATP concentrations within mitochondria during drug-induced apoptosis.

Spacer-Mediated Control of Coumarin Uncaging for Photocaged Thymidine

Despite its importance in the design of photocaged molecules, less attention is focused on linker chemistry than the cage itself. Here, we describe unique uncaging properties displayed by two coumarin-caged thymidine compounds, each conjugated with (2) or without (1) an extended, self-immolative spacer. Photolysis of 1 using long-wavelength UVA (365 nm) or visible (420, 455 nm) light led to the release of free thymidine along with the competitive generation of a thymidine-bearing recombination product. The occurrence of this undesired side reaction, which is previously unreported, was not present with the photolysis of 2, which released thymidine exclusively with higher quantum efficiency. We propose that the spatial separation between the cage and the substrate molecule conferred by the extended linker can play a critical role in circumventing this unproductive reaction. This report reinforces the importance of linker selection in the design of coumarin-caged oligonucleosides and other conjugates.

Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light

HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor (7) of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene. Light activation to stabilize HIF offers promising potentials for the tissue-specific therapies for HIF-related disease by light irradiation onto target tissues.

Synthesis of a Cytidine Phosphoramidite with Protected Nitroxide Spin Label for EPR Experiments with RNA

Spin labeling of oligonucleotides with nitroxides is hampered by their intrinsic instability under conditions of solid-phase synthesis and enzymatic ligation. Although nitroxide decomposition can be avoided in some cases by postsynthetic introduction or by special reaction conditions, a more general solution would be reversible protection of the radical. We have recently developed such a method based on photolabile protection groups for DNA oligonucleotides and demonstrated their application in EPR spectroscopy. Here, we extend this method to RNA oligonucleotides. By improving the synthetic procedures, the yield of the coumarin-protected phosphoramidite could be increased by a factor of 12. Effective recovery of the nitroxides on a duplex RNA enables pulsed EPR experiments to be performed directly after irradiation and air oxidation. Data at Q-band frequency is shown and distances measured with PELDOR (pulsed electron-electron double resonance) spectroscopy agree well with the calculated values.

Caged Oxime Reactivators Designed for the Light Control of Acetylcholinesterase Reactivation?

Despite its promising role in the active control of biological functions by light, photocaging remains untested in acetylcholinesterase (AChE), a key enzyme in the cholinergic family. Here, we describe synthesis, photochemical properties and biochemical activities of two caged oxime compounds applied in the photocontrolled reactivation of the AChE inactivated by reactive organophosphate. Each of these consists of a photocleavable coumarin cage tethered to a known oxime reactivator for AChE that belongs in an either 2-(hydroxyimino)acetamide or pyridiniumaldoxime class. Of these, the first caged compound was able to successfully go through oxime uncaging upon irradiation at long-wavelength ultraviolet light (365 nm) or visible light (420 nm). It was further evaluated in AChE assays in?vitro under variable light conditions to define its activity in the photocontrolled reactivation of paraoxon-inactivated AChE. This assay result showed its lack of activity in the dark but its induction of activity under light conditions only. In summary, this article reports a first class of light-activatable modulators for AChE and it offers assay methods and novel insights that help to achieve an effective design of caged compounds in the enzyme control.

Remote local photoactivation of morphine produces analgesia without opioid-related adverse effects

Background and Purpose: Opioid-based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e. constipation and dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic-mediated adverse effects. Here, we aimed at developing a morphine photo-derivative (photocaged morphine), which can be activated upon light irradiation both in vitro and in vivo. Experimental Approach: Light-dependent activity of pc-morphine was assessed in cell-based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation and dependence were investigated in vivo using experimental paradigms. Key results: In mice, pc-morphine was able to elicit antinociceptive effects, both using external light-irradiation (hind paw) and spinal cord implanted fibre-optics. In addition, remote morphine photoactivation was devoid of common systemic opioid-related undesired effects, namely, constipation, tolerance to the analgesic effects, rewarding effects and naloxone-induced withdrawal. Conclusion and Implications: Light-dependent opioid-based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid-related undesired effects.

Photorelease of Pyridines Using a Metal-Free Photoremovable Protecting Group

The photorelease of bioactive molecules has emerged as a valuable tool in biochemistry. Nevertheless, many important bioactive molecules, such as pyridine derivatives, cannot benefit from currently available organic photoremovable protecting groups (PPGs). We found that the inefficient photorelease of pyridines is attributed to intramolecular photoinduced electron transfer (PET) from PPGs to pyridinium ions. To alleviate PET, we rationally designed a strategy to drive the excited state of PPG from S1 to T1 with a heavy atom, and synthesized a new PPG by substitution of the H atom at the 3-position of 7-dietheylamino-coumarin-4-methyl (DEACM) with Br or I. This resulted in an improved photolytic efficiency of the pyridinium ion by hundreds-fold in aqueous solution. The PPG can be applied to various pyridine derivatives. The successful photorelease of a microtubule inhibitor, indibulin, in living cells was demonstrated for the potential application of this strategy in biochemical research.