- Discovery of Potent Coumarin-Based Kinetic Stabilizers of Amyloidogenic Immunoglobulin Light Chains Using Structure-Based Design
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In immunoglobulin light-chain (LC) amyloidosis, transient unfolding or unfolding and proteolysis enable aggregation of LC proteins, causing potentially fatal organ damage. A drug that kinetically stabilizes LCs could suppress aggregation; however, LC sequences are variable and have no natural ligands, hindering drug development efforts. We previously identified high-throughput screening hits that bind to a site at the interface between the two variable domains of the LC homodimer. We hypothesized that extending the stabilizers beyond this initially characterized binding site would improve affinity. Here, using protease sensitivity assays, we identified stabilizers that can be divided into four substructures. Some stabilizers exhibit nanomolar EC50 values, a 3000-fold enhancement over the screening hits. Crystal structures reveal a key π-πstacking interaction with a conserved tyrosine residue that was not utilized by the screening hits. These data provide a foundation for developing LC stabilizers with improved binding selectivity and enhanced physicochemical properties.
- Yan, Nicholas L.,Santos-Martins, Diogo,Nair, Reji,Chu, Alan,Wilson, Ian A.,Johnson, Kristen A.,Forli, Stefano,Morgan, Gareth J.,Petrassi, H. Michael,Kelly, Jeffery W.
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p. 6273 - 6299
(2021/06/01)
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- Discovery of coumarin-based selective aldehyde dehydrogenase 1A1 inhibitors with glucose metabolism improving activity
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Overexpression of aldehyde dehydrogenase 1A1 (ALDH1A1) is associated with the occurrence and development of obesity and insulin resistance. Herein, a series of coumarin-based ALDH1A1 inhibitors were designed, synthesized and evaluated. Among them, compounds 10, 14 and 26 exhibited potent inhibitory activity against ALDH1A1 and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Optimized compound 10 showed markedly improved pharmacokinetic characters and ADME profiles comparing to the lead compound 1. In vitro study demonstrated that 10 alleviated palmitic acid-induced impairment of glucose consumption in HepG2 cells.
- Liang, Dailin,Fan, Yazhou,Yang, Zhou,Zhang, Zhenguo,Liu, Meiyang,Liu, Li,Jiang, Cheng
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- BENZOPYRANE AND IMIDAZOLE DERIVATIVES USEFUL FOR THE STABILIZATION OF AMYLOIDOGENIC IMMUNOGLOBULIN LIGHT CHAINS
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In immunoglobulin light chain amyloidosis (AL), the unique antibody light chain (LC) protein that is secreted by monoclonal plasma cells in each patient misfolds and/or aggregates, a process leading to organ degeneration. For treating AL patients, such as those with substantial cardiac involvement who have difficulty tolerating existing chemotherapy regimens, provided herein are small molecule compounds of Formula Ia, Formula Ib, and Formula II that are kinetic stabilizers of the native dimeric structure of full-length LCs, which compounds can slow or stop the amyloidogenicity cascade at its origin.
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Paragraph 00105; 00363
(2020/10/19)
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- Acrylamide-Coumarin-Benzaldehyde as a Turn-on Fluorescent Probe Providing an Enhanced Water Solubility for Detection of Cysteine and Homocysteine
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We presented an acrylamide conjugated coumarin (1) as a fluorescent probe for detection of cysteine (Cys) and homocysteine (Hcy). Probe 1 is composed of coumarin as a fluorophore, acrylamide as a reactive site to Cys/Hcy, and benzaldehyde for improvement of the water solubility. To Cys/Hcy, the acrylamide group of 1 readily undergoes Michael addition resulting in a strong fluorescence at 420 nm through an inhibition of photo-induced electron transfer (PET). The turn-on fluorescence change of 1 was observed for Cys and Hcy, but not seen for other biologically abundant thiols (e.g., glutathione, H2S), reactive oxygen and nitrogen species, anions, and metal ions. Moreover, 1 can give strong fluorescence upon the addition of Cys and Hcy in wide pH range and their limits of detection for Cys and Hcy turned out to be 17.25 and 8.69 μM, respectively.
- Chang, Min Jung,Joo, Jin Hui,Lee, Min Hee
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p. 539 - 543
(2019/05/07)
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- 7-substituted amino-4-methylcoumarin derivative, as well as preparation method and medical application thereof
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The invention belongs to the field of medicinal chemistry, and relates to a 7-substituted amino-4-methylcoumarin derivative, as well as a preparation method and application of the 7-substituted amino-4-methylcoumarin derivative as a therapeutic agent in the medical aspect, especially as an ALDH1A1 inhibitor in the aspects of reducing blood glucose and the like.
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Paragraph 0035; 0036; 0037
(2018/12/14)
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- Coumarin-based turn-on fluorescence probes for highly selective detection of Pi in cell culture and Caenorhabditis elegans
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Abstract Two coumarin-based fluorescence probes, 1 and 2, containing a methoxy oxalyl group as a reaction site were developed. These two novel probes displayed an instant turn-on fluorescence response specific towards Pi without interference from ATP and PPi. A selective 23-fold increase in fluorescence for 1 (in DMSO-HEPES) and a 20-fold increase for 2 (in DMSO) were observed. The proposed sensing mechanism for these compounds is Pi-triggered acetamide bond cleavage leading to release of the blue fluorophore coumarin, which was supported by 1H NMR and mass spectrometry data. Probe 1 was successfully used to image endogenous and exogenous Pi in living cells and to trace Pi released from ATP by apyrase in Caenorhabditis elegans.
- Wang, Huan,Guo, Lin E.,Li, Xue Mei,Zhang, Li Mei,Xu, Qiu Lin,Wu, Gao Fen,Zhou, Ying,Zhang, Jun Feng
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p. 293 - 298
(2015/05/20)
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- BODIPY-Coumarin Conjugate as an Endoplasmic Reticulum Membrane Fluidity Sensor and Its Application to ER Stress Models
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An endoplasmic reticulum (ER) membrane-selective chemosensor composed of BODIPY and coumarin moieties and a long alkyl chain (n-C18) was synthesized. The emission ratio of BODIPY to coumarin depends on the solution viscosity. The probe is localized to the ER membrane and was applied to reveal the reduced ER membrane fluidity under ER stress conditions.
- Lee, Hoyeon,Yang, Zhigang,Wi, Youngjin,Kim, Tae Woo,Verwilst, Peter,Lee, Yun Hak,Han, Ga-In,Kang, Chulhun,Kim, Jong Seung
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p. 2474 - 2480
(2015/12/24)
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- A self-calibrating bipartite viscosity sensor for mitochondria
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A self-calibrating bipartite viscosity sensor 1 for cellular mitochondria, composed of coumarin and boron-dipyrromethene (BODIPY) with a rigid phenyl spacer and a mitochondria-targeting unit, was synthesized. The sensor showed a direct linear relationship between the fluorescence intensity ratio of BODIPY to coumarin or the fluorescence lifetime ratio and the media viscosity, which allowed us to determine the average mitochondrial viscosity in living HeLa cells as ca. 62 cP (cp). Upon treatment with an ionophore, monensin, or nystatin, the mitochondrial viscosity was observed to increase to ca. 110 cP.
- Yang, Zhigang,He, Yanxia,Lee, Jae-Hong,Park, Nayoung,Suh, Myungkoo,Chae, Weon-Sik,Cao, Jianfang,Peng, Xiaojun,Jung, Hyosung,Kang, Chulhun,Kim, Jong Seung
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supporting information
p. 9181 - 9185
(2013/07/26)
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- Non-conjugated dendrimers with a porphyrin core and coumarin chromophores as peripheral units: Synthesis and photophysical properties
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Three porphyrin-cored dendrimers with non-conjugated coumarins as dendrons have been synthesized and characterized. The photophysical properties of the title compounds were investigated by means of UV/Vis absorption and fluorescence spectroscopy in dilute CH2Cl2 solutions and in thin neat films. The intramolecular energy transfer from the coumarin units to the porphyrin core clearly reveals two factors influencing energy-transfer efficiency. Firstly, a better spectral overlap between the absorption spectrum of porphyrin core and the emission spectrum of the coumarin moiety results in high energy-transfer efficiency. Secondly, a long alkyl side-chain improves solubility of dendrimers, but also prevents the coumarins from self-quenching. Hence, the dendrimer with N-octyl groups possesses a higher efficiency than that with N-ethyl groups. The dendrimers emit red light with higher fluorescence quantum yields over the free porphyrin.
- Mao, Mao,Song, Qin-Hua
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p. 975 - 981
(2012/03/27)
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- Anticancer drug release from a mesoporous silica based nanophotocage regulated by either a one- or two-photon process
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An excellent mesoporous silica nanoparticle (MSN) based drug deliver system (DDS) was reported for regulated anticancer drug release upon the irradiation of either one- or two-photon excitation. In this system, the coumarin grafted on MSN acted as both the "phototrigger" for the drug release and fluorescence group for cell luminescence imaging. External light manipulations such as changing irradiation wavelength, intensity, and time can regulate the release of the anticancer drug precisely. Biological studies in vitro suggest that the drug carrier can effectively deliver the anticancer drug into intracellular environs and, hence, promote the drug action to kill the cancer cells upon irradiation. We envision that the good biocompatibility, cellar uptake property, and efficient photoregulated drug release will be of great benefit to future controlled release in vivo biomedical applications.
- Lin, Qiuning,Huang, Qi,Li, Chunyan,Bao, Chunyan,Liu, Zhenzhen,Li, Fuyou,Zhu, Linyong
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supporting information; experimental part
p. 10645 - 10647
(2010/11/16)
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- FORMATION OF OLIGOMERS IN THE IRRADIATION OF 7-DIETHYLAMINO-4-METHYLCOUMARIN IN ETHANOL
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In the continuous irradiation of alcoholic solutions of 7-alkylaminocoumarins, oligomers are formed which absorb radiation in the luminescent region of dyes and therefore interfere with the generation of a laser medium.The average molecular weight of the oligomers corresponds with tri- and tetramers.The fractions with higher molecular weights absorb the generated radiation more effectively.The formation of oligomers is observed in oxygen-containing solutions and increases with increase in the dye concentration and degree of conversion.The most likely route for oligomerization seems to be the condensation of the products of the photooxidation of coumarins through the alkylamino group (of amines and amides), and also of acetaldehyde and formaldehyde in a way similar to the formation of amino-aldehyde resins.
- Kalmykova, E. A.,Kuznetsova, N.A.,Kaliya, O.L.,Zhigunova, G.A.,Sergeeva, N.D.
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p. 1361 - 1365
(2007/10/02)
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- SYNTHESIS, SPECTRAL-LUMINESCENCE, AND ACID-BASE PROPERTIES OF 3-FLUORO-7-DIALKYLAMINOCOUMARINS
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The corresponding 3-fluoro-substituted coumarins were obtained by reactions of 7-diethylaminocoumarin, 2,3,6,7-tetrahydro-1H,5H-quinolizinocoumarin, and 2,3,6,7-tetrahydro-9-methyl-1H,5H-quinolizinocoumarin with XeF2, FClO3 or N-fluoropyridinium tetrafluoroborate.A strong mesomeric effect of the fluorine atom on the 7-amino group was established as a result of a study of the absorption and fluorescence spectra and the acid-base properties of the synthesized compounds.
- Gordeeva, N. A.,Kirpichenok, M. A.,Patalakha, N. S.,Khutoretskii, V. M.,Grandberg, I. I.
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p. 491 - 495
(2007/10/02)
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- NEW ASPECTS OF THE MECHANISM OF LASER COUMARIN-DYE PHOTOLYSIS
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Oxygen photooxidizes a concentrated solution of 7-diethylamino-4-methylcoumarin in ethanol to produce photo-N-dealkylation in the substrate and the formation of an oligomer via the intermediate hydroperoxide.Light in the range 254-365 nm causes the reaction to occur with the participation of the first triplet state, and where the rate-limiting step is the interaction between excited and unexcited molecules (k ca. 107 liter/mole*sec), which is followed by the conversion of the radicals to the products in the dark.
- Kalmykova, E. A.,Kuznetsova, N. A.,Kaliya, O. L.,Tavrizova, M. A.
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p. 911 - 916
(2007/10/02)
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- Photodegradation of coumarin-47 in aqueous solutions of β-cyclodextrin
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It is shown that the irradiation of coumarin-47 in aerated aqueous solutions leads to the photodealkylation of the alkylamino-group of the dye via a mechanism involving the self-sensitised photochemical oxidation by singlet oxygen.It was established that the formation of an inclusion complex between coumarin-47 and β-cyclodextrin lowers the rate of photodealkylation by a factor of 12.The observed influence of the complex formation reaction with β-cyclodextrin on the photochemical oxidation of the dye by singlet oxygen under the conditions of sensitised photolysis (sensitiser-sulphonated aluminium-phthalocyanine) leads to the conclusion that the increased photostability of coumarin-47 in the self-sensitised photochemical oxidation reaction on formation of a complex with β-cyclodextrin is caused mainly by the shielding of the substrate and to a lesser extent by change in the quantum field of the singlet oxygen generated by the dye and in the lifetime of such oxygen.
- Kalmykova, E. A.,Kuznetsova, N. A.,Kaliya, O. L.
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p. 1821 - 1822
(2007/10/02)
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- REACTIONS OF 4-METHYL-7-DIETHYLAMINOCOUMARIN THAT PROCEED WITH ELECTRON TRANSFER
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The reactions of 4-methyl-7-diethylaminocoumarin with various oxidizing agents, viz., nitrous acid, nitromethane in the presence of Lewis acids, tetranitromethane, lead tetraacetate, phenyliodosodiacetate, and p-benzoquinone, as well as with typical one-electron oxidizing agents +SbCl6-, NOBF4, NOSbCl6, (ClO4)3>, were studied.It was shown that most of the reactions can be interpreted as proceeding with the intermediate formation of the cation radical of the starting coumarin and lead to new substituted 7-aminocoumarins when suitable substrates (unsaturated compounds, radicals, etc.) are present.
- Kirpichenok, M. A.,Gorozhankin, S. K.,Grandberg, I. I.
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p. 737 - 745
(2007/10/02)
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- PHOTOCHEMICAL REACTIONS OF 7-AMINOCOUMARINS. 4. REACTION OF 4-METHYL-7-DIETHYLAMINOCOUMARIN WITH COMPOUNDS TENDING TO PHOTOLYTIC DISSOCIATION
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The photochemical reactions of 4-methyl-7-diethylaminocoumarin with a series of alkyl halides including isopropyl iodide, allyl iodide, bromoacetone, α-bromoethyl acetate, phenacyl bromide, p-bromophenacyl bromide, and chloroacetonitrile, and aryl iodides including iodobenzene, 2-nitroiodobenzene, 3,4-dimethoxyiodobenzene, and 3-iodo-4-methyl-7-diethylaminocoumarin proceed by a radical addition mechanism to give 3-substituted aminocoumarins.A series of 3-substituted 7-aminocoumarins was also obtained as a result of the photochemical reactions of 4-methyl-7-diethylaminocoumarin, with other reagents, having photolabile chemical bonds such as dioxanyl peroxide, phenyl iodosodiacetate, and nitromethane.The luminescence characteristics of the compounds synthesized were studied.
- Kirpichenok, M. A.,Mel'nikova, L. M.,Denisov, L. K.,Grandberg, I. I.
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p. 380 - 388
(2007/10/02)
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- Effect of Oxygen in Photodegradation of 7-Diethylamino-4-methylcoumarin at 350 nm
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Photodegradation of 7-diethylamino-4-methylcoumarin (C-1) at 350 nm has been investigated in methanolic solutions at = 1E-5 mol dm-1.The parent dye remaining undecomposed after photolysis has been estimated by HPLC separation and analysis with a fluoromonitor.At a photon intensity of ca. 1E16 cm-3s-1 the time for 50percent decomposition of the dye is found to be 1,2 and 6 hr, respectively in oxygenated, aerated and oxygen-free solutions.In oxygenated solutions three photoproducts are detected, one of which has been identified as 7-ethylamino-4-methylcoumarin (C-445) formed by monodealkylation of the parent dye.The bis-dealkylated product (C-120) is not formed even after prolonged photolysis; monodealkylation does not occur in oxygen-free solutions.The significance of these observations for dye laser operation is discussed.
- Priyadarsini, K. Indira,Kunjappu, Joy T.,Moorthy, P. N.
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p. 899 - 901
(2007/10/02)
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- REACTIONS OF 4-METHYL-7-DIETHYLAMINOCOUMARIN WITH ELECTROPHILIC REAGENTS
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The reactions of 4-methyl-7-diethylaminocoumarin with various electrophilic reagents - acetic anhydride, complexes of unsaturated compounds (styrene, dihydropyran, phenylacetylene) with Lewis acids, and copper halides - were used to synthetize 3-, 6-, and 8-substituted coumarins.It was shown that the selectivity of reactions involving substitution in the 3 position increases with an increase in the "softness" of the Lewis acid.
- Kirpichenok, M. A.,Levchenko, S. L.,Grandberg, I. I.
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p. 1059 - 1067
(2007/10/02)
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