- Ligand-Directed Approach to Activity-Based Sensing: Developing Palladacycle Fluorescent Probes That Enable Endogenous Carbon Monoxide Detection
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Carbon monoxide (CO) is an emerging gasotransmitter and reactive carbon species with broad anti-inflammatory, cytoprotective, and neurotransmitter functions along with therapeutic potential for the treatment of cardiovascular diseases. The study of CO chemistry in biology and medicine relative to other prominent gasotransmitters such as NO and H2S remains challenging, in large part due to limitations in available tools for the direct visualization of this transient and freely diffusing small molecule in complex living systems. Here we report a ligand-directed activity-based sensing (ABS) approach to CO detection through palladium-mediated carbonylation chemistry. Specifically, the design and synthesis of a series of ABS probes with systematic alterations in the palladium-ligand environment (e.g., sp3-S, sp3-N, sp2-N) establish structure-activity relationships for palladacycles to confer selective reactivity with CO under physiological conditions. These fundamental studies led to the development of an optimized probe, termed Carbon Monoxide Probe-3 Ester Pyridine (COP-3E-Py), which enables imaging of CO release in live cell and brain settings, including monitoring of endogenous CO production that triggers presynaptic dopamine release in fly brains. This work provides a unique tool for studying CO in living systems and establishes the utility of a synthetic methods approach to activity-based sensing using principles of organometallic chemistry.
- Brewer, Thomas F.,Bruemmer, Kevin J.,Chang, Christopher J.,H?fler, Denis,Jurss, Jonah W.,Michel, Brian W.,Morstein, Johannes,Rezgui, Samir P.,Saitoe, Minoru,Ueno, Kohei,Walvoord, Ryan R.
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p. 15917 - 15930
(2020/10/02)
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- Investigations regarding the utility of prodigiosenes to treat leukemia
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Prodigiosenes, possessing a 4-methoxypyrrolyldipyrrin skeleton, are known for their anti-cancer activity. Structural modification of the C-ring resulted in a series of prodigiosenes that displayed promising activity against leukemia cell lines during in v
- Smithen, Deborah A.,Forrester, A. Michael,Corkery, Dale P.,Dellaire, Graham,Colpitts, Julie,McFarland, Sherri A.,Berman, Jason N.,Thompson, Alison
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- One-pot synthesis of asymmetric annulated bis(pyrrole)s
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Condensation of activated functionalized pyrroles with acetone results in asymmetric bis(pyrrole)s, formed via ring annulation. The methodology is somewhat general and can be applied to a variety of ketones, as well as to a range of pyrrolic substrates that do not bear electron-withdrawing groups directly adjacent to the pyrrole ring.
- Smithen, Deborah A.,Cameron, T. Stanley,Thompson, Alison
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supporting information; experimental part
p. 5846 - 5849
(2012/01/13)
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- 5-Substituted pyrido[2,3-d]pyrimidine, an inhibitor against three receptor tyrosine kinases
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NP506, the 3-{2,4-dimethyl-5-[2-oxo-5-(N′-phenylhydrazinocarbonyl)-1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrol-3-yl}-propionic acid, was designed as FGF receptor 1 inhibitor by computational study and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minimum effective dose of 10 μM. NP506 inhibited the tyrosine phosphorylation in FGF, VEGF, and PDGF receptors and the activation of extracellular signal-regulated kinase (ERK), c-Jun-N-terminal-kinase (JNK) and AKT after the rhFGF-2 stimulation. The introduction of the phenyl hydrazide motif to the position 5 of the pyrido[2,3-d]pyrimidine scaffold led to the inhibitory effect in two signaling pathways: inhibition of AKT activation in the phosphatidyl inositol 3′-kinase (PI13K)/AKT signaling pathway and the inhibition of ERK and JNK activation in MAPK pathway.
- Kammasud, Naparat,Boonyarat, Chantana,Sanphanya, Kingkan,Utsintong, Maleeruk,Tsunoda, Satoshi,Sakurai, Hiroaki,Saiki, Ikuo,André, Isabelle,Grierson, David S.,Vajragupta, Opa
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scheme or table
p. 745 - 750
(2009/09/25)
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- PH-SENSITIVE FLUORESCENT PROBE
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A compound represented by the following general formula (I): wherein R1 represents an amino group which may be substituted with one or two alkyl groups; R2, R3, R4 and R5 independently represent an al
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Page/Page column 5-6
(2009/09/26)
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- Cell-based fluorescence screen for K+ channels and transporters using an extracellular triazacryptand-based K+ sensor
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K+ channels and K+-coupled membrane transporters are important targets for drug discovery. We previously developed a triazacryptand (TAC)-based K+ sensor, TAC-Red, and demonstrated its utility to image K+ waves in mouse brain in vivo (Padmawar et al. Nat. Methods. 2005, 2, 825-827). Here, we synthesized a green-fluorescing dextran conjugate of TAC-bodipy ("TAC-Limedex") for use as an extracellular K+ sensor and demonstrated its utility in measuring K+ transport across cell membranes. TAC-Limedex fluorescence increased by 50% with increasing [K+] from 0 to 2 mM and was insensitive to [Na+], [Cl-], or pH. K+ efflux from cells was quantified from increasing extracellular TAC-Limedex fluorescence following cell immersion in K+-free buffer. In HT-29 cells, K+ efflux was 2.0 ± 0.1 μmol/cm2/s, increasing 8-fold following K+ channel activation by ATP; the increase in K+ efflux was inhibited by a K+ channel blocker or by preventing cytoplasmic calcium elevation. Electroneutral K+/Cl- cotransport was demonstrated in SiHa cells, in which K+ efflux was increased 3-fold by hypotonic challenge; the increase in K+ efflux was fully inhibited by a K+/Cl- transport blocker. K+ efflux measurements were adapted to a commercial fluorescence platereader for automated screening. The fluorescence-based K+ transport assay largely replaces assays requiring radioactive rubidium and is suitable for high-throughput identification of K+ transport modulators. Copyright
- Namkung, Wan,Padmawar, Prashant,Mills, Aaron D.,Verkman
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supporting information; experimental part
p. 7794 - 7795
(2009/02/01)
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- WATER-SOLUBLE, FLUORESCENT COMPOUNDS FOR DETECTION OF POTASSIUM IONS
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The invention provides chromoionophore compounds comprising a triazacryptand (TAC) K+ ionophore conjugated to at least a first chromophoric moiety (e.g., xanthylium dyes and derivatives thereof). In related embodiments, the chromoionophore compounds further comprise a second chromophoric moiety which is insensitive to potassium binding by the TAC ionophore, thus providing for dual wavelength detection and absolute determination of K+ concentration. The invention further provides methods and kits for the determination of K+ concentrations in biological systems, either in vitro or in vivo, using embodiments of inventive chromoionophores.
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Page/Page column 63-64
(2008/06/13)
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- Novel inhibitor for fibroblast growth factor receptor tyrosine kinase
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NP603, the 6-dimethoxy phenyl indolin-2-one, was designed as FGF receptor 1 inhibitor by computational study. NP603 was synthesized and found to be more active against endothelial proliferation of HUVEC after the rhFGF-2 stimulation than SU6668 with minim
- Kammasud, Naparat,Boonyarat, Chantana,Tsunoda, Satoshi,Sakurai, Hiroaki,Saiki, Ikuo,Grierson, David S.,Vajragupta, Opa
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p. 4812 - 4818
(2008/02/12)
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- FLUORESCENT PROBES
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A compound represented by the formula (I) wherein R1 and R2 represent amino groups that substitute at adjacent positions on the benzene ring, wherein one of the amino groups may have one alkyl group; R3 and R4 r
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Page/Page column 7
(2008/06/13)
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- Indolinone compounds as kinase inhibitors
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The invention relates to certain indolinone compounds, their method of synthesis, and a combinatorial library consisting of the indolinone compounds of the invention. The invention also relates to methods of modulating the function of protein kinases using indolinone compounds of the invention and methods of treating diseases by modulating the function of protein kinases and related signal transduction pathways.
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Page/Page column 96
(2010/11/30)
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- Highly Sensitive Fluorescence Probes for Nitric Oxide Based on Boron Dipyrromethene Chromophore - Rational Design of Potentially Useful Bioimaging Fluorescence Probe
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Boron dipyrromethene (BODIPY) is known to have a high quantum yield (φ) of fluorescence in aqueous solution but has not been utilized much for biological applications, compared to fluorescein. We developed 8-(3,4-diaminophenyl)-2,6-bis(2-carboxyethyl)-4,4
- Gabe, Yu,Urano, Yasuteru,Kikuchi, Kazuya,Kojima, Hirotatsu,Nagano, Tetsuo
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p. 3357 - 3367
(2007/10/03)
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- Design, synthesis, and evaluations of substituted 3-[(3- or 4- carboxyethylpyrrol-2-yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF receptor tyrosine kinases
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Receptor tyrosine kinases (RTKs) have been implicated as therapeutic targets for the treatment of human diseases including cancers, inflammatory diseases, cardiovascular diseases including arterial restenosis, and fibrotic diseases of the lung, liver, and kidney. Three classes of 3-substituted indolin-2-ones containing propionic acid functionality attached to the pyrrole ring at the C-3 position of the core have been identified as catalytic inhibitors of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF) RTKs. Some of the compounds were found to inhibit the tyrosine kinase activity associated with isolated vascular endothelial growth factor receptor 2 (VEGF-R2) [fetal liver tyrosine kinase 1 (Flk-1)/kinase insert domain- containing receptor (KDR)], fibroblast growth factor receptor (FGF-R), and platelet-derived growth factor receptor (PDGF-R) tyrosine kinase with IC50 values at nanomolar level. Thus, compound 1 showed inhibition against VEGF-R2 (Flk-1/KDR) and FGF-R1 tyrosine kinase activity with IC50 values of 20 and 30 nM, respectively, while compound 16f inhibited the PDGF-R tyrosine kinase activity with IC50 value of 10 nM. Structural models and structure-activity relationship analysis of these compounds for the target receptors are discussed. The cellular activities of these compounds were profiled using cellular proliferation assays as measured by bromodeoxyuridine (BrdU) incorporation. Specific and potent inhibition of cell growth was observed for some of these compounds. These data provide evidence that these compounds can be used to inhibit the function of these target receptors.
- Sun, Li,Tran, Ngoc,Liang, Congxin,Tang, Flora,Rice, Audie,Schreck, Randall,Waltz, Kara,Shawver, Laura K.,McMahon, Gerald,Tang, Cho
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p. 5120 - 5130
(2007/10/03)
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- Haem d1: Development of a new coupling procedure leading to the synthesis of isobacteriochlorins
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A new approach has been developed for construction of the western and eastern lactams, e.g. 2 and 3, needed for synthesis of isobacteriochlorins. It involves acylation of pyrroles with lactonic acids to form ketones. These are then efficiently converted into the desired lactams by a short sequence of reactions. All the steps are high yielding and simple to carry out.
- Mackman, Richard L.,Micklefield, Jason,Block, Michael H.,Leeper, Finian J.,Battersby, Alan R.
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p. 2111 - 2122
(2007/10/03)
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- Synthetic and Biosynthetic Studies of Porphyrins. Part 7. The Action of Coproporphyrinogen Oxidase on Coproporphyrinogen-IV: Syntheses of Protoporphyrin-XIII, Mesoporphyrin XIII, and Related Tricarboxylic Porphyrins
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Coproporphyrinogen-IV (2a) is converted by an enzyme system from chicken blood into a tricarboxylic porphyrinogen (2b) and protoporphyrinogen-XIII (2c).The corresponding porphyrins were isolated as their methyl esters (3b) and (3c) and their structures were deduced by mass and n.m.r. spectrometry (including the use of shift reagents).Confirmation of these conclusions was obtained by total synthesis of the new porphyrins by the MacDonald and ac-biladiene routes.The vinyl groups were introduced either via acetoxyethyl side-chains derived from precursor pyrroles, or by reduction and dehydration of acetyl groups inserted into the porphyrins during the final stages of the syntheses.Mesoporphyrin-XIII dimethyl ester (3m) and the ethyl analogue (3n) of the vinyl tripropionate porphyrin (3b) were also synthesized by the MacDonald route.
- Al-Hazimi, Hassan M. G.,Jackson, Anthony H.,Knight, David W.,Lash, Timothy D.
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p. 265 - 276
(2007/10/02)
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- Structurel Analysis of Tetrapyrroles by Hydrogen Chemical Ionization Mass Spectrometry
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The H2 chemical ionization mass spectra of several standard porphyrins have been determined.Fragmentation proceeds via hydrogenation yielding porphyrinogens, followed by cleavage at the meso (bridge) positions to produce mono-, di-, and tripyrrolic ions.Secondary fragmentation by cleavage of substituent groups attached to the pyrrole rings may then occur.Identification of these fragments and the corresponding molecular ions produces considerable structural information on the parent molecule.In certain cases these data are sufficient to distinguish porphyrin type (positional) isomers.In addition information of substituents at meso positions may be retained.
- Shaw, George J.,Eglinton, Geoffrey,Quirke, J. Martin E.
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p. 2014 - 2020
(2007/10/02)
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