147963-30-2

Upstream product

• 638-07-3 ethyl (2-chloroaceto)acetate 
• 7664-93-9 sulfuric acid 
• 609-15-4 ethyl 2-chloro-3-oxo-butyrate 
• 7159-96-8 ethyl N-(3-hydroxyphenyl)carbamate 
• 591-27-5 m-Hydroxyaniline 

Downstream Products

• 147963-22-2 7-amino-4-(chloromethyl)-2H-1-benzopyran-2-one 
• 1270046-30-4 7-anilino-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 
• 1270046-64-4 4-chloromethyl-7-phenylamino-2H-chromen-2-one 

Relevant academic research and scientific papers

Targeting of glut5 for transporter-mediated drug-delivery is contingent upon substrate hydrophilicity

Specific link between high fructose uptake and cancer development and progression highlighted fructose transporters as potential means to achieve GLUT-mediated discrimination between normal and cancer cells. The gained expression of fructose-specific transporter GLUT5 in various cancers offers a possibility for developing cancer-specific imaging and bioactive agents. Herein, we explore the feasibility of delivering a bioactive agent through cancer-relevant fructose-specific transporter GLUT5. We employed specific targeting of GLUT5 by 2,5-anhydro-D-mannitol and investigated several drug conjugates for their ability to induce cancer-specific cytotoxicity. The proof-of-concept analysis was carried out for conjugates of chlorambucil (CLB) in GLUT5-positive breast cancer cells and normal breast cells. The cytotoxicity of conjugates was assessed over 24 h and 48 h, and significant dependence between cancer-selectivity and conjugate size was observed. The differences were found to relate to the loss of GLUT5-mediated uptake upon increased conjugate size and hydrophobicity. The findings provide information on the substrate tolerance of GLUT5 and highlight the importance of maintaining appropriate hydrophilicity for GLUT-mediated delivery.

Novel coumarin-based pH sensitive fluorescent probes for the highly alkaline pH region

The design, synthesis and spectroscopic properties of novel polymerizable coumarin-based pH indicators are reported. They show a fluorescence response to pH in the highly alkaline pH region with calculated pKa values in the range of 12.2–12.5. Covalent immobilization of the indicators to polymer supports provides novel pH-sensitive materials that possess excellent photostability. The materials are sensitive to pH in a similar range and can be applied in optical pH sensors for measuring pH in various alkaline media.

Photolytic release of bioactive carboxylic acids from fused pyran conjugates

New ester cages bearing the coumarin (2H-benzopyran-2-one) skeleton with extended π-systems as phototriggers, for glycine and β-alanine, as models of carboxylic acid bifunctional molecules with biological relevance, were evaluated under photolysis conditions at 254, 300, 350 and 419 nm of irradiation in a RPR-100 photochemical reactor. The processes were followed by HPLC-UV detection and 1H NMR with collection of kinetic data. The results showed a correlation between the photolysis efficiency and the increasing extension of the conjugation for both glycine and β-alanine, showing that the 7-aminocoumarin afforded the best results at all wavelengths tested. From a study of the time-resolved fluorescence behaviour, these compounds were also found to exhibit more complex fluorescence decay kinetics. This was attributed to the presence of conjugated and non-conjugated coumarin species.

PET-dependent fluorescence sensing of enzyme reactions using the large and tunable pKa shift of aliphatic amines

A fluorescence sensing system exploiting the large and finely tunable pKa shift of aliphatic amines was developed. The amine-containing fluorescent probes with distinct pKa values in a wide pH range were successfully applied to detect a variety of enzyme reactions with a large and real-time fluorescence enhancement.

Design, synthesis, and biological evaluation of imidazolyl derivatives of 4,7-disubstituted coumarins as aromatase inhibitors selective over 17-α-hydroxylase/C17-20 lyase

The design, synthesis, and biological evaluation of a series of new aromatase (AR, CYP19) inhibitors bearing an imidazole ring linked to a 7-substituted coumarin scaffold at position 4 (or 3) are reported. Many compounds exhibited an aromatase inhibitory potency in the nanomolar range along with a high selectivity over 17-α-hydroxylase/C17-20 lyase (CYP17). The most potent AR inhibitor was the 7-(3,4-difluorophenoxy)-4-imidazolylmethyl coumarin 24 endowed with an IC50 = 47 nM. Docking simulations on a selected number of coumarin derivatives allowed the identification of the most important interactions driving the binding and clearly indicated the allowed and disallowed regions for appropriate structural modifications of coumarins and closely related heterocyclic molecular scaffolds.

Synthesis, enzymatic evaluation, and docking studies of fluorogenic caspase 8 tetrapeptide substrates

The synthesis, enzymatic evaluation, and molecular modeling studies of new fluorogenic tetrapeptide-based substrates selective for caspase 8, having the general structure Ac-IETD-AXX, are described. Various fluorescent reporter groups (AXX), i.e., 3- and 4-substituted coumarins and quinolin-2(1H)-ones were synthesized by von Pechmann condensation. They were subsequently coupled with the caspase-8-selective tetrapeptide Ac-IETD-OH under newly developed synthetic conditions to give the desired substrates in good yields and in high enantiomeric purity. Based on KM and Vmax values, the new compounds proved to be excellent substrates for recombinant human caspase 8. In contrast, the KM values for the same compounds as substrates for human caspase 3 were approximately 10-20-fold higher. Molecular modeling studies based on the X-ray crystal structures of both human caspases 3 and 8 revealed that there is sufficient room within both active sites to accommodate substrates with moderately bulky substituents in the 3- and 4-positions of the fluorogenic coumarins and quinolin-2(1H)-ones. Automated docking of the substrates into the active sites of both human caspases 3 and 8 with the program Auto-Dock 3 gave structures similar to the published crystallographic structures for the same tetrapeptide bound to caspase 8 in the form of an irreversible inhibitor. The calculated binding energies for the new substrates to either caspase 3 or 8 showed little difference between the substrates, consistent with the K M data. In addition, the calculated binding energies (ΔG) to caspase 8 were considerably more negative than those to caspase 3, also consistent with the KM data. A possible molecular interaction that might explain the selectivity of the IETD tetrapeptide motif for caspase 8 over caspase 3 is discussed.

A macrocyclic coumarin-containing tripeptide via CuAAC chemistry

A Cu-catalysed macrocyclisation was performed to obtain a macrocyclic coumarin-containing tripeptide for use in thrombin activity measurements.

Synthesis, photophysical, photochemical and biological properties of caged GABA, 4-[[(2H-1-benzopyran-2-one-7-amino-4-methoxy) carbonyl] amino] butanoic acid

The photorelease of a caged neurotransmitter can be used to investigate the function of neuronal circuits in tissues. We have designed and synthesized a stable, caged γ-aminobutyric acid (GABA) derivative, 4-[[(2H-l-benzopyran- 2-one-7-amino-4-methoxy)carbonyl]amino] butanoic acid (BC204), that releases the neurotransmitter in physiological medium when irradiated with UV light at 300-400 nm in PBS at pH 7.4. The release of GABA occurs with the formation of the major photoproduct, 7-amino-4-(hydroxymethyl)-2H-1-benzopyran-2-one, via a solvolytic photodegradation mechanism of the coumarin moiety and was confirmed by electrospray mass spectrometry/mass spectrometry (ESI MS/MS). BC204 is chemically stable and shows no intrinsic activity after many hours under physiological dark conditions. These properties suggest that BC204 is an excellent form of caged GABA that is well suited for long-term biological studies.

Haloalkyl derivatives of reporter molecules used to analyze metabolic activity in cells

The subject invention provides substrates useful for analyzing the metabolic activity in cells by improving the retention of a detectable reporter molecule only in intact cells where a particular enzyme is present. In particular, improved retention results from a two part process involving conjugation of haloalkyl-substituted derivatives of a reporter molecule with intracellular cysteine-containing peptides while unblocking the reporter molecule. The substrates have the form wherein -BLOCK is a group selected to be removable by action of a specific analyte, to give REPORTER spectral properties different from those of the substrate, -REPORTER- is a molecule that, when no longer bound to BLOCK by a BLOCK-REPORTER bond, has spectral properties different from those of the substrate, -SPACER- is a covalent linkage, and XR- is a haloalkyl moiety that can covalently react with an intracellular thiol (Z-S-H) to form a thioether conjugate (Z-S-R-). After the substrate enters the cells, the analyte removes BLOCK to make REPORTER detectable by the change in spectral properties, and the haloalkyl XR reacts with the intracellular thiol to form the thioether conjugate inside the cells, which is well-retained in the cells.

Fluorescent haloalkyl derivatives of reporter molecules well retained in cells

The subject invention provides a method for analyzing the metabolic activity in cells by improving the retention of a detectable reporter molecule only in intact cells where a particular enzyme is present. In particular, improved retention results from a two part process involving conjugation of haloalkyl-substituted derivatives of a reporter molecule with intracellular cysteine-containing peptides while unblocking the reporter molecule. The method for analyzing metabolic activity of cells involves the use of a substrate having the form wherein -BLOCK is a group selected to be removable by action of a specific analyte, to give REPORTER spectral properties different from those of the substrate, -REPORTER- is a molecule that, when no longer bound to BLOCK by a BLOCK-REPORTER bond, has spectral properities different from those of the substrate, and XR-- is a haloalkyl moiety that can covalently react with an intracellular thiol (Z--S--H) to form a thioether conjugate (Z--S--R--). After the substrate enters the cells, the analyte removes BLOCK to make REPORTER detectable by the change in spectral properties, and the haloalkyl XR reacts with the intracellular thiol to form the thioether conjugate inside the cells, which is well-retained in the cells.