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1.
Org Biomol Chem ; 21(29): 5977-5984, 2023 07 26.
Article in English | MEDLINE | ID: mdl-37434538

ABSTRACT

While γ-glutamylcyclotransferase (GGCT) has been implicated in cancer-cell proliferation, the role of GGCT enzymatic activity in the regulation of cancer-cell growth remains unclear. Toward further understanding of GGCT in vivo, here we report a novel cell-permeable chemiluminogenic probe "MAM-LISA-103" that detects intracellular GGCT activity and apply it to in vivo imaging. We first developed a chemiluminogenic probe LISA-103, which simply and sensitively detects the enzymatic activity of recombinant GGCT through chemiluminescence. We then designed the cell-permeable GGCT probe MAM-LISA-103 and applied it to several biological experiments. MAM-LISA-103 successfully detected the intracellular GGCT activity in GGCT-overexpressing NIH-3T3 cells. Moreover, MAM-LISA-103 demonstrated tumor-imaging ability when administered to a xenograft model using immunocompromised mice inoculated with MCF7 cells.


Subject(s)
gamma-Glutamylcyclotransferase , Animals , Humans , Mice , gamma-Glutamylcyclotransferase/chemistry , MCF-7 Cells , Fluorescent Dyes/chemistry
2.
Chembiochem ; 23(24): e202200556, 2022 12 16.
Article in English | MEDLINE | ID: mdl-36285893

ABSTRACT

Some types of dioxetanes are called chemiluminophores because they produce luminescence light without the use of enzymes. Here, we designed and synthesized a novel carboxy group-containing chemiluminophore derivative, which enabled the simple introduction of such a chemiluminophore to the molecule of interest. Furthermore, we demonstrate that the in vivo imaging system (IVIS imaging system) can recognize tagged chemicals, indicating that such a chemiluminophore could be employed as a tracer molecule for biological studies.


Subject(s)
Heterocyclic Compounds, 1-Ring , Heterocyclic Compounds , Heterocyclic Compounds/chemistry , Luminescent Measurements , Indicators and Reagents , Luminescence
3.
Luminescence ; 28(5): 696-704, 2013.
Article in English | MEDLINE | ID: mdl-22997052

ABSTRACT

Bicyclic dioxetanes 2a-c bearing a 2'-alkoxy-2-hydroxy-1,1'-binaphthyl-7-yl moiety were effectively synthesized and their base-induced chemiluminescent decomposition was investigated by the use of alkaline metal (Na(+) and K(+) ) or Mg(2+) alkoxide in MeOH. When 2a-c were treated with tetrabutylammonium fluoride (TBAF) in dimethyl sulfoxide (DMSO) as a reference system, they showed chemiluminescence as a flash of orange light (maximum wavelength λmax (CL) = 573-577 nm) with efficiency Φ(CL) = 6-8 × 10(-2) . On the other hand, for an alkaline metal (Na(+) or K(+) ) alkoxide/MeOH system, 2a-c decomposed slowly to emit a glow of chemiluminescence, the spectra of which were shifted slightly toward red from the TBAF/DMSO system, and Φ(CL) (= 1.4-2.3 × 10(-3) ) was considerably decreased. In addition, Mg(OMe)2 was found to play a characteristic role as a base for the chemiluminescent decomposition of 2a-c through coordination to the intermediary oxidoaryl-substituted dioxetanes 13. Thus, Mg(2+) increased Φ(CL) to more than twice those with Na(+) or K(+) , while it shifted λmax (CL) considerably toward blue (λmax (CL) = 550-566 nm).


Subject(s)
Bridged Bicyclo Compounds/chemistry , Heterocyclic Compounds/chemistry , Luminescence , Magnesium/chemistry , Naphthalenes/chemistry , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds, 1-Ring , Luminescent Measurements , Molecular Structure
4.
J Org Chem ; 77(10): 4725-31, 2012 May 18.
Article in English | MEDLINE | ID: mdl-22524301

ABSTRACT

Charge-transfer-induced decomposition (CTID) of bicyclic dioxetanes 1b-d bearing a 3-hydroxylphenyl moiety substituted with a benzothiazol-2-yl group at the 2-, 6-, or 5-position was investigated, and their chemiluminescence properties were compared to each other, based on those for a 4-benzothiazolyl analogue 1a. Dioxetanes 1c and 1d underwent CTID to give the corresponding oxido anions of keto esters 8c or 8d in the singlet excited state with high efficiencies similarly to the case of 1a. On the other hand, 1b showed chemiluminescence with quite low efficiency, though it gave exclusively keto ester 2b. The marked decline of chemiluminescence efficiency for 1b was attributed to 1b mainly being decomposed to 8b through a radiationless pathway, in which intramolecular nucleophilic attack of nitrogen in the benzothiazolyl group to dioxetane O-O took place to give cyclic intermediate cis-11.

5.
J Org Chem ; 77(1): 632-9, 2012 Jan 06.
Article in English | MEDLINE | ID: mdl-22136154

ABSTRACT

Diphenylparabanic acid was found to react with >2 equiv of organolithiums at -78 °C to effectively give the corresponding symmetrical α-diketones. However, upon treatment with 1 equiv of organolithium, the parabanic acid gave mainly 5-substituted 5-hydroxyimidazolidine-2,4-diones. On the other hand, Grignard reagents were less reactive toward the parabanic acid at low temperature, and selectively gave the corresponding 5-hydroxyimidazolidine-2,4-diones even if more than 1 equiv of the reagents was used. A tandem process in which the parabanic acid was first reacted with a Grignard reagent and then reacted in one-pot with an organolithium effectively gave the unsymmetrical α-diketone. 5-Substituted 5-hydroxyimidazolidine-2,4-diones were useful as versatile precursors for preparing α-ketocarboxylic acids as well as unsymmetrical α-diketones.

6.
Phys Chem Chem Phys ; 13(35): 16005-14, 2011 Sep 21.
Article in English | MEDLINE | ID: mdl-21829826

ABSTRACT

The chemiluminescence (CL) mechanism of oxidophenyl-substituted 1,2-dioxetane was investigated by performing TD-DFT calculations on biradicals of three model compounds. We propose a novel mechanism of CL in which excitation of a dissociative intermediate by infrared radiation (IRE) of the surrounding solvent is considered. The excitation energies and oscillator strengths (f-values) were estimated for intermediates along the reaction coordinate (Rx). The difference in efficiencies of CL between syn- and anti-isomers of m-oxidophenyl-dioxetane is explained using the difference in potential curves of the singlet excited states (S) and the IRE mechanism. At the point where the biradical of the anti-isomer decomposes into two fragments, the interaction between the S and triplet (T) states is induced by a significant back electron transfer (BET) from the dioxetane group to the oxido-phenyl group and the S(1) excited state is stabilized and CL efficiency is enhanced. In the syn-isomer, the barrier in the S(1) potential curve to reach the final CL state is higher than for the anti-isomer, which reduces the efficiency. The poor CL yield for the p-isomer is ascribed to a much higher barrier in the potential curve of the S(1) state.

7.
J Org Chem ; 76(12): 5006-17, 2011 Jun 17.
Article in English | MEDLINE | ID: mdl-21574649

ABSTRACT

Thermally stable rotamers of bicyclic dioxetanes bearing 6-hydroxynaphthalen-1-yl (anti-5a and syn-5a), 3-hydroxynaphthalen-1-yl (anti-5b and syn-5b), and 5-hydroxy-2-methylphenyl groups (anti-5c and syn-5c) were synthesized. These dioxetanes underwent TBAF (tetrabutylammonium fluoride)-induced decomposition accompanied by the emission of light in DMSO and in acetonitrile at 25 °C. For all three pairs of rotamers, the chemiluminescence efficiency Φ(CL) for anti-5 was 8-19 times higher than that for syn-5, and the rate of CTID (charge-transfer-induced decomposition) for anti-5 was faster than that for syn-5. The chemiluminescence spectra of the rotamers for 5a and 5c, respectively, were different. This discrepancy in the chemiluminescence spectra between rotamers can presumably be attributed to the difference in the structures of de novo keto imide anti-14 and syn-14 in an excited state, which inherit the structures of the corresponding intermediary anionic dioxetanes anti-13 and syn-13. The important difference in chemiluminescence efficiency between anti-5 and syn-5 is discussed from the viewpoint of a chemiexcitation mechanism for CTID of oxidophenyl-substituted dioxetane.


Subject(s)
Ethers, Cyclic/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Luminescence , Models, Molecular , Molecular Conformation
8.
J Org Chem ; 76(3): 902-8, 2011 Feb 04.
Article in English | MEDLINE | ID: mdl-21192637

ABSTRACT

Bicyclic dioxetanes 3a-d bearing a 4-(benzothiazol-2-yl)-3-hydroxyphenyl group decomposed to give the corresponding keto esters 4a-d accompanied by the emission of bright light when simply dissolved in an aprotic polar solvent such as N-methylpyrrolidone (NMP) or DMF at 50-100 °C. This solvent-promoted decomposition (SPD) was effectively a chemiluminescence process caused by the hydrogen bonding of a phenolic OH with a solvent molecule(s). The characteristics of the chemiluminescence in SPD resembled those in base-induced decomposition (BID), which occurs through an oxidoaryl-substituted dioxetane 5 by an intramolecular charge-transfer-induced decomposition (CTID) mechanism. Both free energies of activation, ΔG(doubledagger)(SPD) and ΔG(doubledagger)(BID), increased in the order 3a < 3b < 3c < 3d, and were linearly correlated with each other. However, SPD showed features different from those of BID in terms of enthalpy of activation and entropy of activation. SPD had large negative values for ΔS(doubledagger) (ca. -71 J mol(-1) K(-1)) regardless of the substituent R at the 5-position for 3a-d, while the ΔS(doubledagger) values for BID changed from 0.5 to -22 J mol(-1) K(-1) as R became smaller. The enthalpy of activation ΔH(doubledagger) for SPD was 14-21 kJ mol(-1) smaller than that for BID.

9.
Rapid Commun Mass Spectrom ; 24(18): 2715-22, 2010 Sep.
Article in English | MEDLINE | ID: mdl-20814977

ABSTRACT

A dioxetane bearing a hydroxyphenyl group produces an unstable oxidoaryl anion by deprotonation which rapidly decomposes with accompanying emission of light effectively by the intramolecular charge-transfer-induced decomposition (CTID) mechanism. Although several mechanisms have been proposed to explain chemi-excitation in CTID, strong experimental evidence is still lacking. In the course of our investigation to clarify the chemi-excitation process, negative-mode matrix-assisted laser desorption/ionization time-of-flight collision-induced dissociation tandem mass spectrometry (MALDI-TOF-CID-MS/MS) was used to investigate the decomposition of bicyclic dioxetanes bearing a 4-(benzothiazol-2-yl)-3-hydroxyphenyl moiety 1 and their related keto esters 2 in a gas phase. Dioxetanes 1 decomposed to give 2 in an electronically excited state, which underwent alpha-cleavage of a ketone moiety, while authentic 2 (ground state) hardly showed fragmentation in MS. On the other hand, 2 displayed fragment ions in CID-MS/MS, though the fragmentation pattern was significantly different between 2a (R = tert-butyl) and 2b-2d (R = isopropyl, ethyl and methyl, respectively): 2a exhibited mainly alpha-cleavage of a ketone moiety, while 2b-2d showed beta-cleavage of the aromatic ester moiety. The marked difference in fragmentation between 2 (electronically excited state) produced directly from 1 and authentic 2 under CID was most likely due to the difference in the excitation processes: chemi-excitation of 2 by CTID of 1 versus vibrational excitation of 2 induced by collision in MS/MS.

10.
J Org Chem ; 75(17): 5920-6, 2010 Sep 03.
Article in English | MEDLINE | ID: mdl-20681740

ABSTRACT

Hydroxyaryl-substituted dioxetanes 2-4 fused with a pyrrolidine ring were selectively synthesized by singlet oxygenation of the corresponding dihydropyrroles 5-7. These N-acylamino-substituted bicyclic dioxetanes were quite stable thermally, and 2a and 2b were estimated to possess half-lives of 32 and 34 y at 25 degrees C. When treated with TBAF (tetrabutylammonium fluoride) in DMSO, these dioxetanes underwent charge-transfer-induced decomposition (CTID) to emit yellow-orange light. The chemiluminescence efficiencies Phi(CL) for dioxetanes 2 ranged from 10(-6) to 10(-2). On the other hand, dioxetane 4 bearing a 4-(benzothiazol-2-yl)-3-hydroxyphenyl moiety showed chemiluminescent decomposition with high efficiency (Phi(CL) = 0.15) comparable to its oxy-analogue 26. Prominent characteristics for CTID of the present dioxetanes were that the N-acylamino-group influenced the color of chemiluminescence as well as the rate of decomposition k(CTID), and furthermore an N-acyl substituent could decisively affect the singlet-chemiexcitation efficiency, as observed for the case of 2b.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Heterocyclic Compounds/chemical synthesis , Temperature , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Heterocyclic Compounds/chemistry , Heterocyclic Compounds, 1-Ring , Luminescent Measurements , Molecular Structure , Stereoisomerism
11.
J Org Chem ; 75(11): 3678-84, 2010 Jun 04.
Article in English | MEDLINE | ID: mdl-20455570

ABSTRACT

Uncatalyzed thermal decomposition (TD) and charge-transfer-induced decomposition (CTID) of dioxetanes were investigated to determine their thermodynamic characteristics. The dioxetanes examined were a series of 1-[4-(benzothiazol-2-yl)-3-hydroxyphenyl]-4,4-dimethyl-2,6,7-trioxabicyclo[3.2.0]heptanes, 1a-d, bearing an alkyl substituent R, e.g., methyl, ethyl, isopropyl, or tert-butyl, at the 5-position and a parent dioxetane 1e with R = H. X-ray single crystallographic analysis was achieved for 1a-d. Both free energies of activation, DeltaG(double dagger)(TD) and DeltaG(double dagger)(CTID), increased in the order 1a < or = 1b < 1c < 1d. The free energy difference DeltaDeltaG(double dagger) = DeltaG(double dagger)(TD) - DeltaG(double dagger)(CTID) was ca. 27 kJ mol(-1) regardless of the substituent R. However, the use of Taft's dual-substituent parameter suggested that CTID was more sensitive to the polarity of the substituent R than TD. The entropy term for CTID, DeltaS(double dagger)(CTID), decreased from zero to a large negative value in the order of tert-butyl, isopropyl, ethyl, and methyl, whereas DeltaS(double dagger)(TD) did not show a similar tendency.

12.
J Org Chem ; 75(3): 879-84, 2010 Feb 05.
Article in English | MEDLINE | ID: mdl-20073481

ABSTRACT

The singlet oxygenation of 4-tert-butyl-3,3-dimethyl-5-(3-oxyphenyl)-2,3-dihydrothiophenes 5c-e bearing an acetoxy or methoxy group at the 2-position exclusively gave the corresponding sulfanyl-substituted bicyclic dioxetanes 2c-e, while that of 5a without 2-substituent mainly gave sulfoxide 11 along with a small amount of dioxetane 2a. These dioxetanes were sufficiently stable thermally to permit handling at room temperature. Sulfanyl-substituted dioxetanes, 2c and 2e, were further oxidized with m-chloroperbenzoic acid to afford the corresponding sulfinyl-substituted dioxetanes 3c, 3e and sulfonyl-substituted dioxetanes 4c, 4e. X-ray single crystallographic analysis was performed for 2c and 4e. Base-induced decomposition of the dioxetanes in DMSO gave light with a maximum wavelength lambda(max)(CL) at 554 nm for 2a and 565 nm for 2e in moderate light yields, while sulfinyl-derivative 3e gave weak light with lambda(max)(CL) = 795 nm and sulfonyl-derivative 4e gave very weak light with lambda(max)(CL) = 848 nm.

13.
Chem Rec ; 8(4): 213-28, 2008.
Article in English | MEDLINE | ID: mdl-18752319

ABSTRACT

Dioxetanes bearing an aromatic electron donor decompose with an accompanying emission of light by an intramolecular charge-transfer-induced chemiluminescence (CTICL) mechanism. The color of the chemiluminescence from CTICL-active aryl-substituted dioxetanes is controlled by the design of the aromatic moiety and its substitution pattern, and the substituent on the carbon of the dioxetane ring. In addition to these color modulations, a change in the conformation of dioxetanes bearing a biaryl group was also found to cause a change in the color of CTICL in the coordination sphere of a crown ether complex. This new color modulation system was further developed for optically active dioxetanes bearing 2-hydroxy-1,1'-binaphthyl, the CTICL of which took place under the chiral recognition of optically active crown ether complexes. The spectra of the chemiluminescence from biaryl-type dioxetanes did not coincide with the fluorescence spectrum from the authentic emitter in the coordination sphere, but they did coincide with each other in a completely homogeneous system. This finding suggests that the emitter of CTICL possesses a transient structure, which retains the afterimage of the conformation of the dioxetane.


Subject(s)
Heterocyclic Compounds/chemistry , Luminescence , Color , Heterocyclic Compounds, 1-Ring , Luminescent Measurements/methods , Models, Molecular , Molecular Structure , Stereoisomerism
14.
Luminescence ; 23(5): 344-9, 2008.
Article in English | MEDLINE | ID: mdl-18509844

ABSTRACT

A bicyclic dioxetane 1 bearing a 4-(4-cyanophenyl)iminomethyl-3-hydroxyphenyl group was found to undergo base-induced decomposition with the accompanying emission of light, the colour of which changed depending on the base used and its concentration. When 1 was triggered with tetrabutylammonium fluoride (TBAF), 1 displayed an emission of glowing orange light. On the other hand, on treatment with a high concentration of potassium t-butoxide complexed with 18-crown-6 ether, 1 afforded a flash of blue light. The mechanistic study of this unprecedented phenomenon revealed that the emission of glowing orange light was due to the normal oxido anion of keto ester 11, whereas the emission of a flash of blue light was attributed to another species that was produced by addition of a nucleophile to an iminomethyl of unstable oxido anion of dioxetane 10.


Subject(s)
Heterocyclic Compounds/chemistry , Luminescent Measurements/methods , Color , Heterocyclic Compounds, 1-Ring , Indicators and Reagents
15.
Article in English | MEDLINE | ID: mdl-18401042

ABSTRACT

1,2-Dioxetanes bearing an aromatic electron donor undergo intramolecular charge-transfer-induced chemiluminescence (CTICL). Although there has been some controversy regarding the mechanisms involved, there is little experimental evidence to strongly support any of the proposed mechanisms. In the course of our investigations, to clarify these mechanisms, we tried to effectively ionize dioxetanes bearing a phenolic group and found that poly(3-octylthiophene-2,5-diyl) was a promising matrix for negative-mode matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF-MS). Electron-transfer ionization was found to take place for dioxetanes bearing a hydroxyphenyl moiety that had been further substituted with an aromatic group, which acted as an antenna to catch an electron from the matrix. Furthermore, the characteristic fragmentation of dioxetanes 3c-3d was thought to occur by the elimination of 2-methyl-1-propene (56 u) and pivalaldehyde (86 u) from deprotonated ion [M - H](-) of dioxetanes, based on the results of muliple mass spectrometry measurements of dioxetanes using MALDI quadrupole ion trap ToF-MS. Based on a comparison of fragmentation in dioxetanes and the corresponding keto esters, dioxetanes were presumed to initially generate excited keto esters from which fragmentation took place.

16.
Luminescence ; 22(5): 420-9, 2007.
Article in English | MEDLINE | ID: mdl-17492631

ABSTRACT

Bicyclic dioxetanes bearing a 3-(carbazol-9-yl)-5-hydroxyphenyl 2a, 3-hydroxy-5-(indol-1-yl)phenyl 2b, or 3-(benzotriazol-1-yl)-5-hydroxyphenyl group 2c were synthesized. Base-induced decomposition of dioxetane 2a displayed intense light, the maximum wavelength (lambda(max) (CTICL)) of which changed depending on the crown ether complex of potassium t-butoxide used as a base, although the magnitude of lambda(max) (CTICL) change was considerably smaller than the case of dioxetane bearing a 3-(anthracen-9-yl)-5-hydroxyphenyl group 1. Chemiluminescence (CL) from 2b resembled closely that from 2a in response to the crown ether complexes. On the other hand, dioxetane 2c exhibited emission of red light on treatment with tetrabutylammonium fluoride. The colour of light changed significantly and exhibited two peaks in the CL spectrum when treated with complex of bulky dibenzyldiazacrown ether 13.


Subject(s)
Bridged Bicyclo Compounds, Heterocyclic/chemistry , Carbazoles/chemistry , Heterocyclic Compounds/chemistry , Indoles/chemistry , Phenols/chemistry , Triazoles/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Crystallography, X-Ray , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds, 1-Ring , Luminescence , Luminescent Measurements/instrumentation , Luminescent Measurements/methods , Models, Chemical , Molecular Structure , Stereoisomerism
17.
Luminescence ; 20(2): 63-72, 2005.
Article in English | MEDLINE | ID: mdl-15803504

ABSTRACT

Bicyclic dioxetanes bearing 5-(t-butyldimethylsiloxy)inden-2-yl, 3, or 5-(t-butyldimethylsiloxy)benzo(b)thiazol-2-yl, 4, were synthesized. On treatment with large excess of tetrabutylammonium fluoride in DMSO, dioxetane, 3, decomposed rapidly with accompanying emission of red (vermilion) light (lambda(max) (CL) = 637 nm). Comparing the chemiluminescent properties for 3 with those for related dioxetane, 1, in which pi-conjugation system is not fixed in plane, both CIEEL-decay rate and chemiluminescent efficiency were found to be improved for 3. Chemiluminescent decomposition of dioxetane, 4, was similarly induced to emit crimson light (lambda(max) (CL) = 725 nm), though the chemiluminescent efficiency was low.


Subject(s)
Heterocyclic Compounds/chemical synthesis , Indenes/chemistry , Luminescence , Luminescent Measurements , Thiazoles/chemistry , Benzothiazoles , Bridged Bicyclo Compounds/chemical synthesis , Heterocyclic Compounds, 1-Ring , Light
19.
Chem Commun (Camb) ; (4): 483-5, 2005 Jan 28.
Article in English | MEDLINE | ID: mdl-15654377

ABSTRACT

N-substituted pyridones (1) easily undergo singlet oxygenation to give exclusively the corresponding endoperoxides (2), which decompose to give pyridones again while liberating 1O2 in high yield.

20.
Chem Commun (Camb) ; (4): 482-3, 2003 Feb 21.
Article in English | MEDLINE | ID: mdl-12638960

ABSTRACT

A new type of dioxetane bearing a 3-(cyanomethyl)phenyl (1a), 3-(methoxycarbonylmethyl)phenyl (1b), 3-(benzoylmethyl)phenyl (1c), or 3-[cyano(methoxycarbonyl)methyl]phenyl group (1d) decomposed through an intermediary dioxetane bearing a benzylic carbanion to afford crimson to yellow light on treatment with TBAF in DMSO.

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