14003-96-4

Basic information

• Product Name: 7-hydroxy-4-Methyl-2-oxo-2H-1-Benzopyran-8-carboxaldehyde
• Synonyms: 7-hydroxy-4-Methyl-2-oxo-2H-1-Benzopyran-8-carboxaldehyde;4-Methyl-7-hydroxy-8-formylcoumarin;7-Hydroxy-8-formyl-4-methylcoumarin;8-Formyl-7-hydroxy-4-methyl-2H-1-benzopyran-2-one;8-Formyl-7-hydroxy-4-methylcoumarin;2H-1-Benzopyran-8-carboxaldehyde, 7-hydroxy-4-methyl-2-oxo-;8C;4u8C
• CAS NO: 14003-96-4
• Molecular Formula: C₁₁H₈O₄
• Molecular Weight: 204.17882
• Product Categories: Inhibitors
• Mol File: 14003-96-4.mol
• Article Data: 69

Chemical Properties

• Melting Point: 189-190℃ (ethanol )
• Boiling Point: 398.3±42.0 °C(Predicted)
• Appearance: white to beige/
• Density: 1.541
• Refractive Index: 1.641
• Storage Temp.: ?20°C
• Solubility: DMSO: soluble5mg/mL, clear (warmed)
• PKA: 6.22±0.20(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 1 month.
• CAS DataBase Reference: 7-hydroxy-4-Methyl-2-oxo-2H-1-Benzopyran-8-carboxaldehyde(CAS DataBase Reference)
• NIST Chemistry Reference: 7-hydroxy-4-Methyl-2-oxo-2H-1-Benzopyran-8-carboxaldehyde(14003-96-4)
• EPA Substance Registry System: 7-hydroxy-4-Methyl-2-oxo-2H-1-Benzopyran-8-carboxaldehyde(14003-96-4)

Safety Data

• Hazard Codes: Xn
• Statements: 22
• WGK Germany: 3
• Hazardous Substances Data: 14003-96-4(Hazardous Substances Data)

Usage

Description

4μ8C (14003-96-4) is a selective inhibitor of IRE1α ribonuclease (RNase) activity (IC50?= 60 nM). Covalently binds to lysine 907 in the IRE1 endonuclease domain, blocking substrate access to the active site of IRE1α and inactivating both XBP1 splicing and IRE1α-mediated mRNA degradation but not IRE1 kinase activity.1?Inhibits IRE1α in response to hypoxia or other ER stress-inducing agents but has no effect on proliferation or clonogenic survival of hypoxic cells.2?Blocks production of IL-4, IL-5 and IL-13 production in T cells.3?4μ8C prevents the splicing of the XBP1 mRNA in response to ER stress caused by mutant proinsulin production in pancreatic β-cells.4

Uses

8-Formyl-4-methylumbelliferone is an inhibitor that blocks substrate access to the active site of IRE1 and selectively inactivates both Xbp1 splicing and IRE1-mediated mRNA degradation.

General Description

A cell-permeable coumarin o-hydroxyaldehyde compound that inhibits IRE1 RNase activity in a time- and dose-dependent manner (IC50 = 550, 230, 180, 100, and 45 nM, respectively, with 0, 2, 4, 8, 16, min drug preincubation in FRET-based RNA cleavage assays) by covalently targeting IRE1 Lys907 via Schiff base formation, effectively preventing ER stress-induced site-specific mRNA splicing as well as RIDD (Regulated IRE1-Dependent Degradation) mRNA degradation (IC50 = 6.9 and 4.1 μM, respectively, against Xbp1 splicing and Scara3 degradation) in MEF cultures following Tunicamycin (Cat. No. 654380) treatment. Also demonstrated to inhibit ER capacity expansion (Effective conc. 32 μM) and amylase secretion (IC50<2 μM) upon stress induction by Dexamethasone (Cat. No. 265005) treatment in rat AR42J tumoral acinar pancreatic cells. Structural analysis reveals that the reduced water accessibility to Lys907 in IRE1 native conformation accounts for the unusual stability of Lys907 Schiff base formation and forms the basis of selective IRE1 RNase inhibition by 4μ8C and STF083010 (Cat. No. 412510). Although 4μ8C, but not STF083010, is also shown to inhibit IRE1 autophosphorylation by Schiff base formation with IRE1 Lys599 in the absence of ADP, cellular nucleotide prevents 4μ8C from targeting IRE1 Lys599 and inhibiting IRE1 kinase activity intracellularly.

Biochem/physiol Actions

Cell permeable: yes

References

1) Cross?et al. (2012),?The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule; Proc. Natl. Acad. Sci. USA,?109?E869 2) Cojocari?et al. (2013),?New small molecule inhibitors of UPR activation demonstrate that PERK, but not IRE1α signaling is essential for promoting adaptation and survival to hypoxia;? Radiother. Oncol.,?108?541 3) Kemp?et al. (2013),?The serine-threonine kinase inositol-requiring enzyme 1α (IRE1α) promotes IL-4 production in T helper cells; J. Biol. Chem.,?288?33272 4) Zhang?et al. (2014),?IRE1 inhibition perturbs the unfolded protein response in a pancreatic β-cell line expressing mutant proinsulin, but does not sensitize the cells to apoptosis;? BMC Cell Biol.,?15?29

Upstream product

• 90-33-5 7-hydroxy-4-methyl-chromen-2-one 
• 76-05-1 trifluoroacetic acid 
• 141-97-9 ethyl acetoacetate 
• 108-46-3 recorcinol 
• 92646-98-5 7-hydroxy-4-methyl-8-(pyrrolidin-1-ylmethyl)coumarin 
• 3993-57-5 7-allyloxy-4-methyl-2H-chromen-2-one 
• 1402244-59-0 1-((7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methyl)pyrrolidine 1-oxide 
• 64-19-7 acetic acid 
• 68-12-2 N,N-dimethyl-formamide 
• 86290-39-3 7-<(β-chloroallyl)oxy>-8-formyl-4-methylcoumarin 
• 100-97-0 hexamethylenetetramine 

Downstream Products

• 1233766-07-8 7-hydroxy-4-methyl-8-([1,1';4',1'']terphenyl-4-ylimino)methyl-2H-1-benzopyran-2-one 
• 111051-68-4 (8-(4'-chlorophenylimino)methyl)-7-hydroxy-4-methyl-2H-1-benzopyran-2-one 
• 1233766-05-6 8-(4'-acetylphenylimino)methyl-7-hydroxy-4-methyl-2H-1-benzopyran-2-one 
• 111051-69-5 7-hydroxy-4-methyl-8-(4-nitrophenylimino)methyl-2H-1-benzopyran-2-one 
• 1295297-87-8 toluene-4-sulfonic acid 8-formyl-4-methyl-2-oxo-2H-chromen-7-yl ester 

Relevant articles and documents

A selective hydrolytic and restructuring approach through a Schiff base design on a coumarin platform for “turn-on” fluorogenic sensing of Zn2+

A new Schiff base, CMD, designed based on a coumarin platform was synthesized and fully characterized through single crystal X-ray diffraction studies. CMD underwent selective Zn2+-triggered hydrolysis in ethanolic medium followed by restructur

A new coumarin based Schiff base fluorescence probe for zinc ion

Herein, a novel coumarin-based fluorescent probe (FS3) was designed, synthesized, and characterized. It exhibited significant fluorescence quenching in the presence of Zn2+ ions. Just a minor alteration occurred in the fluorescence intensity of

A new strategy for synthesis of 9-benzoyl-4-methylpyrano[2,3-f]chromene-2,8-dione using L-proline as a novel and efficient catalyst

We report the high yield synthesis of novel 9-benzoyl-4-methylpyrano[2,3-f]chromene-2,8-dione derivatives obtained by the reaction of 8-formyl-7-hydroxy-4-methylcoumarin with various active methylene compounds. A mechanism of the tandem Knoevenagel condensation and cyclisation reaction is proposed. Structures of all compounds were elucidated on the basis of 1H and 13C NMR, and mass spectrometry, and elemental analysis.

An enolato-bridged dinuclear Cu(ii) complex with a coumarin-assisted precursor: A spectral, magnetic and biological study

A new, phenoxo-bridged CuII dinuclear complex Cu2[(L)2(DMF)2] (1) has been obtained by employing the coumarin-assisted tridentate precursor, H2L, [benzoic acid(7-hydroxy-4-methyl-2-oxo-2H-chromen-8-yl

A novel coumarin-derived dithioacetal chemosensor for trace detection of Hg2+ in real water samples

A novel coumarin-derived dithioacetal chemosensor, 8-(1,3-dithian-2-yl)-7-hydroxy-4-methylcoumarin (LS), has been designed and synthesized. The sensor LS showed highly selective fluorescent sensing for Hg2+ with a low detection limit of 0.81 nM in the pH range from 6.15 to 9.96 in ethanol/water (1:1, v/v) solution. The sensing mechanism of LS toward Hg2+ was proposed and verified by 1H nuclear magnetic resonance spectroscopy studies. Under an ultraviolet lamp, the fluorescence color changes could be easily detected by the naked eye. In addition, the sensor LS has been applied in the trace detection of Hg2+ in real water samples.

Synthesis, characterization, anti-diabetic potential and DFT studies of 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde oxime

A new compound named 7-hydroxy-4-methyl-2-oxo-2H-chromene-8-carbaldehyde oxime (7-Oxime) was synthesized and characterized by FT-IR, FT-Raman, 1H NMR and 13C NMR techniques. The conformer possibilities were studied to find the most stable conformer and its molecular geometry. Then, the dimer form of the most stable monomer was built and optimized. Density functional theory (DFT) B3LYP method with 6-311++G(d,p) basis set was applied to analyze the molecular electrostatic potential (MEP), HOMO and LUMO orbitals, the vibrational wavenumbers, the infrared intensities, the Raman scattering activities and several thermodynamic properties (at different temperatures). The stability of the molecule derived from hyperconjugative interactions and charge delocalization has been analyzed by using natural bond orbital (NBO) analysis. In order to find the possible inhibitory activity of 7-Oxime, an accurate molecular blind docking simulation was performed. The results indicated that the mentioned compound has a good binding affinity to interact with the active sites of human α-glucosidase and α-amylase. For the first time, our computational finding suggests that this compound has a potential to be used as a supplementary agent in the pre-management of diabetes mellitus.

Synthesis, characterization and biological approach of metal chelates of some first row transition metal ions with halogenated bidentate coumarin Schiff bases containing N and O donor atoms

The impregnation of halogen atoms in a molecule is an emerging trend in pharmaceutical chemistry. The presence of halogens (Cl, Br, I and F) increases the lipophilic nature of molecule and improves the penetration of lipid membrane. The presence of electronegative halogen atoms increases the bio- activity of core moiety. In the present study, Co(II), Ni(II) and Cu(II) complexes are synthesised using Schiff bases (HLI and HLII), derived from 8-formyl-7-hydroxy-4-methylcoumarin/3-chloro-8-formyl-7-hydroxy-4-methylcoumarin with 2,4-difluoroaniline/o-toluidine respectively. The synthesized compounds were characterized by spectral (IR, NMR, UV-visible, Mass, ESI-MS, ESR), thermal, fluorescence and molar conductivity studies. All the synthesized metal complexes are completely soluble in DMF and DMSO. The non-electrolytic nature of the metal complexes was confirmed by molar conductance studies. Elemental analysis study suggest [ML2(H2O)2] stoichiometry, here M = Co(II), Ni(II) and Cu(II), L = deprotonated ligand. The obtained IR data supports the binding of metal ion to Schiff base. Thermal study suggests the presence of coordinated water molecules. Electronic spectral results reveal six coordinated geometry for the synthesized metal complexes. The Schiff bases and their metal complexes were evaluated for antibacterial (Pseudomonas aureginosa and Proteus mirabilis), antifungal (Aspergillus niger and Rhizopus oryzae), anthelmintic (Pheretima posthuma) and DNA cleavage (Calf Thymus DNA) activities.

Synthesis, antioxidant, antibacterial, and DFT study on a coumarin based salen-type Schiff base and its copper complex

Synthesis of new efficient compounds is becoming urgent due to the resistance of organisms to drugs. Salen derivatives have interesting therapeutic and industrial applications. A coumarin based derivative of salen, 7-hydroxy-8-((E)-((2-((E)-((7-hydroxy-5-methyl-2-oxo-3,8a-dihydro-2H-chromen-8-yl)methylene)amino)-4-methylphenyl)imino)methyl)-5-methyl-2H-chromen-2-one (L), and its copper complex, CuL, have been synthesized and characterized. Antibacterial and antioxidant activity of these compounds have been evaluated and electronic, optical and molecular properties have been calculated using density functional theory (DFT) with B3LYP. The results were correlated with the biological activity and reactivity of the compounds. Experimental and theoretical calculations indicate that the studied copper complex has the potential to function as a drug.

Synthesis, characterization, DNA cleavage and in vitro antimicrobial studies of La(III), Th(IV) and VO(IV) complexes with Schiff bases of coumarin derivatives

A series of La(III), Th(IV) and VO(IV) complexes have been synthesized with Schiff bases derived from 8-formyl-7-hydroxy-4-methylcoumarin and o-phenylenediamine/ethylenediamine. The structure of the complexes has been proposed in the light of analytical, spectral (IR, UV-vis, ESR and FAB-mass), Magnetic and thermal studies. The complexes are soluble in DMF and DMSO. The measured molar conductance values indicate that, the complexes are non-electrolytes in nature. The redox behavior of the complexes was investigated by electrochemical method using cyclic voltammetry. The Schiff bases and their complexes have been screened for their antibacterial (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi) and antifungal activities (Aspergillus niger, Aspergillus flavus and cladosporium) by Minimum Inhibitory Concentration method. The DNA cleavage activity of La(III) and VO(IV) metal complexes is studied by agarose gel electrophoresis method.

Photophysical insights and guidelines for blue “turn-on” fluorescent probes for the direct detection of nitric oxide (NO?) in biological systems

Synthesis and photophysical properties of a family of five blue fluorescent “turn-on” probes for the direct detection of nitric oxide (NO?) is reported. The probes CB1-5 feature a substituted 7-hydroxy coumarin chromophore coupled to 2-methyl-8-aminoquinoline, which act as tridentate ligand for Cu(II) and active site for monitoring NO? using a replacement strategy. The UV/vis absorption and fluorescence emission characteristics of the probes are significantly influenced by the substitution pattern on the coumarin ring, as well as by solvent polarity and pH. Time-dependent density functional theory (TD-DFT) calculations for CB4 and CB5 showed that the absorptions are due to π-π* transitions localised on coumarin, with a small charge transfer contribution from the quinoline system at higher pH where the 7-hydroxy coumarin moiety is deprotonated, which leads to a bathochromic shift of the absorption. Complexation of the probes with Cu(II) quenches the fluorescence, which is turned back on upon reaction with NO?, allowing selective detection of this important signalling molecule in μM concentrations. Preliminary experiments revealed that CB4 and CB5 enable to monitor endogenously produced NO? in living bacterial cells in multi-dye imaging experiments.

Design of a coumarinyl-picolinoyl hydrazide Schiff base for the fluorescence turn-on-off sequential sensing of Al3+ and nitroaromatics, and electronic device fabrication

(E)-N′-((7-Hydroxy-4-methyl-2-oxo-2H-chromen-8-yl)methylene)picolinohydrazide (H-CPh), a greenish yellow emitter in the solid state, aggregates in DMSO solution upon increasing the percentage of water (>50%) and the maximized emission intensity was reached at 90% water-DMSO medium. Upon excitation at 400 nm in pure aquatic medium (HEPES buffer, pH 7.2) H-CPh shows fluorescence sensitivity to Al3+ (λem, 470 nm) and forms a 1:1 complex, [(CPh)Al(OH)(H2O)]NO3, with a limit of detection (LOD) of 6.99 nM. The complex, [(CPh)Al(OH)(H2O)]NO3 shows sensitivity to nitroaromatics by quenching the strong emission of the fluorogenic complex and the LODs are: 2,4-dinitrophenol (DNP), 1.67 μM and 2,4,6-trinitrophenol (TNP) 0.99 μM. The H-CPh is electronically a semiconductor and the experimental (2.78 eV) and the DFT derived (2.75 eV) band gaps are comparable. The H-CPh forms a Schottky diode and its photoconductivity (19.98 × 10-4 S m-1) is three times higher than the dark phase conductivity (6.42 × 10-4 S m-1).

L-Proline promoted fluorescent sensor for Mg2+ detection in a multicomponent sensory system

Mg2+ can lead to the fluorescence enhancement of a dye molecule as high as 47.3-fold while l-proline acts as a promoter in this multicomponent sensory system. The fluorescence color could be easily detected by the naked eye under a UV-lamp.

A highly selective and sensitive ESIPT-based coumarin-triazole polymer for the ratiometric detection of Hg2+

A novel fluorescent polymer for Hg2+ recognition was developed based on the phototautomerism mechanism of 7-hydroxycoumarin in aqueous solution. The developed system showed higher sensitivity and specificity towards Hg2+ in the acetonitrile/water mixture over various other metal ions, with a significant fluorescence quenching of the main emission band. It was shown that the presence of Hg2+ affects the chemical equilibrium of the 7-hydroxycoumarin phototautomers through the excited state intramolecular proton transfer (ESIPT) mechanism, which results in ratiometric fluorescence response upon stepwise addition of Hg2+. The occurrence of ESIPT mechanism was explained based on a comparison of the 1H NMR spectra of the starting alkynylated coumarin (4) in a non-polar aprotic solvent (CDCl3) and in a polar aprotic solvent (DMSO-d6). This was further confirmed by 1H NMR of 4 upon stepwise addition of Hg2+ in a polar aprotic solvent (DMSO-d6). From titration experiments, a higher sensitivity with a detection limit at the nanomolar level (50 nM) was observed and the response was fast and reversible. The real applications of the developed system were investigated in real samples and satisfactory results were obtained for both fresh and lake water samples.

Seco-4-methyl-DCK derivatives as potent chemosensitizers

Twenty-five seco-4-methyl-DCK derivatives were designed, synthesized and evaluated for chemoreversal activity when combined with paclitaxel or vincristine in two drug-resistant cancer cell lines (A2780/T and KB-V) respectively. Most of the new compounds displayed moderate to significant MDR reversal activities in the P-gp overexpressing A2780/T and KB-V cells. Especially, compounds 7o and 7y showed the most potent chemosensitization activities with more than 496 and 735 reversal ratios at a concentration of 10 μM. Unexpectedly the newly synthesized compounds did not show chemosensitization activities observed in a non-P-gp overexpressing cisplatin resistant human ovarian cancer cell line (A2780/CDDP), implying that the MDR reversal effects might be associated with P-gp overexpression. Moreover, these compounds did not exhibit significant antiproliferative activities against nontumorigenic cell lines (HUVEC, HOSEC and T29) compared to the positive control verapamil at the tested concentration, which suggested better safety than verapamil. The pharmacological actions of the compounds will be studied further to explore their merit for development as novel candidates to overcome P-gp mediated MDR cancer.

A fluorogenic probe for recognizing 5-hydroxylysine inspired by serine/threonine ligation

The 5-lysyl-hydroxylation has been found among protein post-translational modifications. In this report, we have devised a fluorescence turn-on probe which allows for selectively recognizing 5-hydroxylysine-containing peptides. the Partner Organisations 2014.

A turn-on fluorescent sensor for Zn(II) based on fluorescein-coumarin conjugate

A novel fluorescent sensor, 7-hydroxy-4-methylcoumarin-8-carbaldehyde- (fluorescein) hydrazone was designed and synthesized for selective recognition of Zn2+ in HEPES buffer medium of PH 7.4. This reagent could be used as a probe for Zn2+ by monitoring changes in the absorption and the fluorescence spectral patterns. More importantly, this sensor displays an extreme selectivity, sensitivity and color change for Zn2+ over other earth- and transition metal ions, which was mainly due to the spirolactam ring-opening power of Zn2+. Upon the addition of Zn2+, an overall emission change of 33-fold was observed and the detection limit was low as 6.54 ppb. Photoinduced electron transfer process, coupled with the intramolecular charge transfer process, are proposed to explain the observed spectral response.

Fluorescence sensing and intracellular imaging of Pd2+ ions by a novel coumarinyl-rhodamine Schiff base

Coumarinyl-rhodamine, HCR, served as an extremely selective sensor for Pd2+ ions in ethanol/H2O (8:2, v/v, HEPES buffer, pH 7.2) solution and the limit of detection (LOD) was 18.8 nM (3σ method). The free sensor, HCR, was weakly emissive and in the presence of Pd2+, the colour changed from straw to pink with very strong emission at 598 nm in the presence of eighteen other cations. A plausible mechanism involved opening of the spirolactam ring of rhodamine on interaction with Pd2+, which was justified by structure optimization and transition energy calculations using the DFT technique. HCR underwent 1:1 complexation with Pd2+, which was confirmed via the Job's plot, mass spectra and Benesi-Hildebrand plot (association constant Ka, 9.1 × 104 M-1). A separate in vitro experiment showed that HCR could specifically sense Pd2+ in MCF7 (human breast adenocarcinoma) cell lines.

Synthesis of novel 2H,8H-pyrano[2,3-f]chromene-2,8-diones from 8-formyl-7-hydroxy-4-methylcoumarin

We report the synthesis of novel 2H,8H-pyrano[2,3-f]chromene-2,8-dione based scaffolds by the reaction of 8-formyl-7-hydroxy-4-methylcoumarin with various active methylene compounds. A mechanism of a tandem Knoevenagel condensation and cyclisation reaction is proposed. The structure of all compounds was established on the basis of 1H and 13C NMR data, high resolution mass spectrometry and elemental analysis.

Synthetic studies toward novel pyrrolobenzodiazepine–coumarin hybrids

[Figure not available: see fulltext.] A comprehensive screening of known methods for the synthesis of coumarins was performed in order to obtain a new type of pyrrolobenzodiazepine–coumarin hybrids. A Pechmann condensation turned out to be the method of c

A mitochondria-targeted fluorescent probe based on coumarin-pyridine derivatives for hypochlorite imaging in living cells and zebrafish

Hypochlorite plays a critical role in various physiological processes and is involved in many diseases. Thus, real-time, rapid, and accurate monitoring of hypochlorite has important medical and physiological significance. Herein, a novel coumarin-pyridine derivative (CPD) probe was designed and synthesized, which exhibited fantastic advantages, such as a rapid response (within 10 s), naked eye recognition, large Stokes shift (185 nm), dual-channel detection, and high selectivity and sensitivity toward OCl- (detection limit 0.012 μM, S/N = 3). Furthermore, the current CPD probe was successfully used to image OCl- in the mitochondria of both A549 cells and zebrafish, which further demonstrated its suitability for practical applications in biological systems.

A new coumarin-based “turn-on” fluorescence probe with high sensitivity and specificity for detecting hypochlorite ion

A new type of “turn-on” fluorescence probe coumarin-based DTC was developed for specifically detecting hypochlorite ion (ClO?) with high sensitivity. DTC can display a significant enhancement of fluorescence and emit blue fluorescence at 452 nm after reaction with ClO?. Moreover, probe DTC can detect ClO? without interference from other reactive oxygen species (ROS), and has a low detection limit for ClO? of 96 nM. Meanwhile, DTC can also detect ClO? in the physiological environment, and DTC can be further used as a test paper-strip for portable and rapid detection of ClO?.

Targeting tubulin polymerization and DNA binding of 4-thiazolidinone-umbelliferone hybrids: synthesis and cytotoxicity evaluation

The discovery of a series of combretastatin A-4 inspired novel molecular hybrids of 4-thiazolidinone-umbelliferone as prominent cytotoxic agents is reported. Representative compounds exhibited potent anti-proliferative activities against four human cancer cell lines (A549, MDA-MB-231, THP-1 and HL-60). Amongst the compounds tested,7qshowed the highest potency against A549 cells with an IC50value of 0.96 ± 1.09 μM and a selectivity index of 51.7. The flow cytometric analysis of compound7qtreated A549 cells showed apoptosis induction by the annexin-v/PI dual staining assay and the effect of7qon different phases of the cell cycle was also analyzed. Target based studies demonstrated inhibition of tubulin polymerization by7qat an IC50value of 2.65 ± 0.47 μM and its effective binding with CT-DNA. Further, molecular modelling studies revealed that7qhas a prominent binding affinity towards the α/β-tubulin receptor with remarkable protein-ligand interactions and binding energy.