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WO2014092544A1 - Capteur permettant de détecter des ions de calcium - Google Patents

Capteur permettant de détecter des ions de calcium Download PDF

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Publication number
WO2014092544A1
WO2014092544A1 PCT/MY2013/000245 MY2013000245W WO2014092544A1 WO 2014092544 A1 WO2014092544 A1 WO 2014092544A1 MY 2013000245 W MY2013000245 W MY 2013000245W WO 2014092544 A1 WO2014092544 A1 WO 2014092544A1
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WO
WIPO (PCT)
Prior art keywords
group
hydroxyl
amine
hydrogen
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/MY2013/000245
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English (en)
Inventor
Mohd Rais BIN AHMAD
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mimos Bhd
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Mimos Bhd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mimos Bhd filed Critical Mimos Bhd
Publication of WO2014092544A1 publication Critical patent/WO2014092544A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
    • G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
    • G01N27/28—Electrolytic cell components
    • G01N27/30—Electrodes, e.g. test electrodes; Half-cells
    • G01N27/305—Electrodes, e.g. test electrodes; Half-cells optically transparent or photoresponsive electrodes

Definitions

  • the present invention relates to a sensor for determining calcium ions in a sample and a method of preparing optical-chemical sensor for determining calcium ions in a sample.
  • Biosensors are devices which utilize biological reactions to identify biological-relevant analytes such as glucose, deoxyribonucleic acid (DNA), proteins, hormones, or even microorganisms. These devices couple a biological recognition element, called the probe, with the physiochemical transducer which translates the biorecognition event into a measurable signal.
  • the probes in these systems take advantage of the selectivity and specificity (affinity) of biomolecular interactions such as DNA-DNA hybridization in gene chips or antibody- antigen interactions in immunoassays.
  • affinity specificity
  • fluorescence is an absolute measurement, it possesses an inherent sensitivity that is among the highest of all analytical instruments.
  • the high sensitivity of fluorescence spectroscopy for biochemically interesting molecules has led to an increasing popularity in biomedical and life science research.
  • Ion selective electrodes have been used for determining calcium ions in body fluids for many years. Serious drawbacks of electrochemical measuring arrangements are the requirement of a reference element, sensitivity towards electrical potentials and electromagnetic interference. While ion-selective electrodes are rugged and reliable, they are expensive to use in a disposable device application. In addition, these electrodes require an electrical connection of the sample measurement device to the instrument.
  • a sensor for determining calcium ions in a sample particularly optical- chemical sensor which does not require a reference element and a method of preparing optical-chemical sensor for determining calcium ions in a sample.
  • the present invention further introduces calcium sensing receptor active compounds having fluorescence properties.
  • the present invention provides a considerable reduction of materials with even greater efficiency and economically during operation.
  • the present invention provides compound selected from the group consisting of a compound having the general formula I:
  • X and Z are heteroatoms selected from a group at least or combination of oxygen, nitrogen, sulphur;
  • Y is heteroatom selected from a group at least or combination of oxygen and nitrogen;
  • M is selected from a group consisting of alkyl having 0-12 carbon atoms
  • R. ! is selected from a group consisting of hydrogen, hydroxyl, methyl, methoxy, and ethoxy;
  • R 2 is selected from a group consisting of hydrogen, hydroxyl and amine;
  • R 3 is selected from a group consisting of hydrogen, amine, thiocyanate, methylamine and ethylamine;
  • R 4 is selected from a group consisting of hydroxyl, amine, dimethylamine and diethylamine.
  • An optical-chemical sensor for determining calcium ions in a sample comprising a substrate, a carbon layer as conductor layer provided on the substrate, a transducer layer for converting a chemical activity to an electrical signal; and a sensing membrane for detecting calcium ions having a matrix comprising a compound having a luminophoric moiety.
  • the transducer is an electrochemical transducer and deposited on the carbon layer and luminophoric moiety is diglycolic fluorescein derivative.
  • At least 0.1 weight percent of diglycolic fluorescein derivative as a sensing membrane cocktail and at least 0.2 microliter of the sensing cocktail on the transducer layer comprising depositing an electrochemical transducer on a carbon layer placed on a substrate, preparing and purifying a luminophoric moiety having diglycolic fluorescein derivative having a compound selected from the group consisting of a compound having the general formula I:
  • X and Z are heteroatoms selected from a group at least or combination of oxygen, nitrogen, sulphur;
  • Y is heteroatom selected from a group at least or combination of oxygen and nitrogen;
  • M is selected from a group consisting of alkyl having 0-12 carbon atoms
  • F? ! is selected from a group consisting of hydrogen, hydroxyl, methyl, methoxy, and ethoxy;
  • R.2 is selected from a group consisting of hydrogen, hydroxyl and amine;
  • R 3 is selected from a group consisting of hydrogen, amine, thiocyanate, methylamine and ethylamine;
  • R 4 is selected from a group consisting of hydroxyl, amine, dimethylamine and diethylamine; preparing a sensing membrane cocktail having at least 0.1 weight of the luminophoric moiety in a polymer matrix solution, dispersing at least 0.2 microliter of the sensing membrane cocktail on the electrochemical transducer layer; and testing a characteristic of the sensor on the detection of calcium ions.
  • the diglycolic fluorescein derivative having compound selected from the group consisting of a compound having the general formula I:
  • X and Z are heteroatoms selected from a group at least or combination of oxygen, nitrogen, sulphur;
  • Y is heteroatom selected from a group at least or combination of oxygen and nitrogen;
  • M is selected from a group consisting of alkyl having 0-12 carbon atoms
  • Ri is selected from a group consisting of hydrogen, hydroxyl, methyl, methoxy, and ethoxy;
  • R 2 is selected from a group consisting of hydrogen, hydroxyl and amine
  • R 3 is selected from a group consisting of hydrogen, amine, thiocyanate, methylamine and ethylamine;
  • R 4 is selected from a group consisting of hydroxyl, amine, dimethylamine and diethylamine; is prepared according to the following method comprising alkylating a phenol hydroxyl group with a hydrocarbon chain having heteroatom, adding diglycoiic anhydride to an intermediate formation in an organic base, isolating the diglycoiic from the formation in an organic acid buffer; andexchanging the oxygen heteroatom Y in general formula I with at least one of the reagents selected from hydroxylamine, hydrazine, methylamine and ethylamine.
  • the organic acid buffer is selected at least one of citric acid, formic acid, oxalic acid and acetic acid.
  • the electrochemical transducer is selected at least one or in combination of silver-silver chloride, polypyrrole and polythiophene.
  • Figure l illustratesa schematic diagram of calcium sensor in accordance of the present invention.
  • Figure 2 illustratesa flow chart for process flow of the preparation of calcium sensor in accordance of the present invention.
  • ions such as calcium, magnesium, and sodium play an important physiological role in regulating a wide variety of cellular functions. For a better understanding of that role, it is necessary to measure the ion concentrations inside living cells. Calcium, magnesium, sodium, and similar species do not naturally fluoresce. They can be measured indirectly, however, by complexing them with fluorescent molecules. Molecules that bestow fluorescence properties on non-fluorescent species are called probes, indicators, or dyes. Fluorescent probes can be designed to exhibit a high affinity for a specific ion. Thus, calcium and other ions can be quantitatively measured by rationing the fluorescence intensity of the calcium-bound dye and that of the calcium-free dye.
  • the present invention relates to a sensor for determining calcium ions in a sample particularly optical-chemical sensor which does not require a reference element and a method of preparing optical-chemical sensor for determining calcium ions in a sample.
  • a novel calcium sensing receptor active compounds which is use as optical-chemical sensor for detecting calcium ions in a sample by an optical change due to a fluorescence properties possess by the compound of general Formula I.
  • X and Z are heteroatoms selected from a group at least or combination of oxygen, nitrogen, sulphur; Y is heteroatom selected from a group at least or combination of oxygen and nitrogen; M is selected from a group consisting of alkyl having 0-12 carbon atoms;
  • Ri is selected from a group consisting of hydrogen, hydroxyl, methyl, methoxy, and ethoxy;
  • R 2 is selected from a group consisting of hydrogen, hydroxyl and amine
  • R 3 is selected from a group consisting of hydrogen, amine, thiocyanate, methylamine and ethylamine;
  • R 4 is selected from a group consisting of hydroxyl, amine, dimethylamine and diethylamine.
  • the construction of the said compound is based on the mixing of a fluorescence molecule with the biological recognition elements/sensors active ingredient and is dissolved in an organic solvent and isolated with organic acid.
  • the compound of general Formula I is prepared according to the following method comprising by first alkylating a p eno) hydroxyl group with a hydrocarbon chain having heteroatom. Then, diglycolic anhydride is added to an intermediate formation in the previous reaction in an organic base.
  • organic bases is selected from pyridine, 4-dimethylaminopyridine, triethylamine and 1 ,8- diazabicycloundec-7-ene.
  • the following example illustrates functionalization of the lipophilic alcohol intermediate with diglycolic moiety.
  • the organic acid buffer is selected at least one of citric acid, formic acid, oxalic acid and acetic acid.
  • the oxygen heteroatom Y in general formula l is exchanged with at least one of the reagents selected from hydroxylamine, hydrazine, methylamine and ethylamine.
  • FIG. 1 illustrates a schematic diagram of calcium sensorin accordance of the present invention.
  • the calcium sensor of the present invention is an optical-chemical sensor(100) for determining calcium ions in a sample.
  • This optical-chemical sensor (l OO) comprising a substrate (102), a carbon layer (103) as conductor layer provided on the substrate (102), a transducer layer (104) for converting a chemical activity to an electrical signal and a sensing membrane (105) for detecting calcium ions having a matrix comprising a compound having a luminophoric moiety.
  • the substrate (102) of the optical-chemical sensor(100) is used to provide mechanical strength to the sensor tip. Meanwhile, an electrochemical transducer is used and deposited on the carbon layer.
  • the electrochemical transducer is selected at least one or in combination of silver-silver chloride, polypyrrole and polythiophene.
  • the luminophoric moiety of the optical-chemical sensor (100)of the present invention is diglycolic fluorescein derivative having a compound selected from the group consisting of a compound having the general Formula I as mentioned above.
  • the sensing membrane (105) of the optical-chemical sensor (100) of the present invention at least 0.1 weight percent of diglycolic fluorescein derivative is provided as a sensing membrane cocktail and at least 0.2 microliter of the sensing cocktail is provided on the transducer layer(104).
  • Figure 2 illustrates a flow chart for process flow of the preparation of calcium sensor of the present invention.
  • a method of preparing optical-chemical sensor for determining calcium ions in a sample of the present invention comprising by depositing an electrochemical transducer on a carbon layer placed on a substrate. Then, a luminophoric moiety having diglycolic fluorescein derivative having a compound selected from the group consisting of a compound having the general Formula I is prepared and purified. A sensing membrane cocktail having at least 0.1 weight of the luminophoric moiety in a polymer matrix solution is then prepared accordingly. Next, at least 0.2 microliter of the sensing membrane cocktail is dispersed on the electrochemical transducer layer. Finally, a characteristic of the sensor on the detection of calcium ions is tested in different concentration.
  • the preparation of the calcium sensor having a compound having the general Formula I as the calcium recognizing agent is as follow:
  • Carbon paste (100 micrometer dry thickness, 0.4mm diameter) is printed on 1-mm thick FR4 board and cured by heat treatment at 120 °C for 30 minutes.
  • a compound having the general Formula I (1 mg) and potassium para-chloro tetraphenyl borate (1mg) are added into a tetrahydrofuran solution of 40mg polyvinyl chloride and 60mg dioctyl sebacate.
  • the calcium sensor cocktail (10microliter) is dispensed on the carbon electrode, already pre- deposited with chloride doped polypyrrole. The solvent is evaporated under continuous flow of nitrogen.
  • the sensor coupled with Orion double-junction reference electrode (lithium acetate external junction) is immersed into calcium chloride solutions (10 "1 to 10 “4 M) and the potential difference readings are recorded.
  • the plot of sensor response (mV) versus logarithmic of analyte concentration shows that the sensor based on a compound having the general Formula I gives desirable response towards calcium ion and sufficient linear range.
  • One of the advantages of the present invention provides a sensor for determining calcium ions in a sample particularly optical-chemical sensor which does not require a reference element. Another advantage of the present invention is that it introduces calcium sensing receptor active compounds having fluorescence properties. In further advantages of this invention include fluorescent and lipophilic calcium receptor molecule that can be used as calcium ion recognizing agent in electrochemical and opto-chemical sensor.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Electrochemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Investigating Or Analyzing Non-Biological Materials By The Use Of Chemical Means (AREA)
  • Investigating Or Analysing Materials By The Use Of Chemical Reactions (AREA)
  • Investigating Or Analysing Biological Materials (AREA)

Abstract

La présente invention concerne un capteur permettant de détecter des ions de calcium dans un échantillon, et un procédé de préparation de capteur opto-chimique permettant de détecter des ions de calcium dans un échantillon. L'un des avantages de la présente invention permet de produire un capteur permettant de détecter des ions de calcium dans un échantillon, notamment un capteur opto-chimique qui n'exige pas d'élément de référence. Un autre avantage de la présente invention est qu'elle introduit des composés actifs du récepteur de détection du calcium ayant des propriétés de fluorescence. Selon d'autres avantages de cette invention, une molécule de récepteur de calcium fluorescente et lipophile peut être utilisée comme agent de reconnaissance d'ions de calcium dans un capteur électrochimique et opto-chimique.
PCT/MY2013/000245 2012-12-11 2013-12-10 Capteur permettant de détecter des ions de calcium Ceased WO2014092544A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MYPI2012005346 2012-12-11
MYPI2012005346 2012-12-11

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Publication Number Publication Date
WO2014092544A1 true WO2014092544A1 (fr) 2014-06-19

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006130551A2 (fr) * 2005-05-31 2006-12-07 Promega Corporation Composes luminogenes et fluorogenes, procedes de detection de molecules ou de conditions

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006130551A2 (fr) * 2005-05-31 2006-12-07 Promega Corporation Composes luminogenes et fluorogenes, procedes de detection de molecules ou de conditions

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
SHORTREED M ET AL: "FLUORESCENT FIBER-OPTIC CALCIUM SENSOR FOR PHYSIOLOGICAL MEASUREMENTS", ANALYTICAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 68, no. 8, 15 April 1996 (1996-04-15), pages 1414 - 1418, XP000584513, ISSN: 0003-2700, DOI: 10.1021/AC950944K *
SONIA TAKTAK ET AL: "Electrode Chemistry Yields a Nanoparticle-Based NMR Sensor for Calcium", LANGMUIR, vol. 24, no. 14, 1 July 2008 (2008-07-01), pages 7596 - 7598, XP055005336, ISSN: 0743-7463, DOI: 10.1021/la8006298 *

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WO2014092544A1 (fr) Capteur permettant de détecter des ions de calcium

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