Electrochemically active agents for pH modulation in biological buffers

• US 10,011,549 B2
• Filed: 07/06/2015
• Issued: 07/03/2018
• Est. Priority Date: 07/06/2015
• Status: Active Grant

• Current Assignee: Robert Bosch GmbH
• Original Assignee: Robert Bosch GmbH
• Inventors: Johnson, Christopher, Kavusi, Sam, Fomina, Nadezda, Ahmad, Habib, Maruniak, Autumn, Lang, Christoph, Raghunathan, Ashwin
• Primary Examiner(s): NOGUEROLA, ALEXANDER STEPHAN
• Application Number:
  US14/792,553
• Publication Number:
  US 20170008825A1
• Time in Patent Office: 1,093 Days
• CPC Class Codes: C07C 37/00 Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 37/07 with simultaneous reduction of C=O group in that ring
• CPC Class Codes: C07C 39/10 Polyhydroxy benzenes; Alkylated derivatives thereof C07C39/08 takes precedence
• CPC Class Codes: C07C 39/11 Alkylated hydroxy benzenes containing also acyclically bound hydroxy groups, e.g. saligenol
• CPC Class Codes: C07C 41/01 Preparation of ethers
• CPC Class Codes: C07C 41/24 by elimination of halogens, e.g. elimination of HCl
• CPC Class Codes: C07C 41/30 by increasing the number of carbon atoms, e.g. by oligomerisation
• CPC Class Codes: C07C 43/1783 with hydroxy or -O-metal groups bound to the aromatic rings
• CPC Class Codes: C07C 43/2055 containing more than one ether bond
• CPC Class Codes: C07C 43/225 containing halogen
• CPC Class Codes: C07C 43/23 containing hydroxy or O-metal groups
• CPC Class Codes: C07C 45/42 by hydrolysis
• CPC Class Codes: C07C 46/06 of at least one hydroxy group on a six-membered aromatic ring
• CPC Class Codes: C07C 49/82 containing hydroxy groups
• CPC Class Codes: C07C 49/84 containing ether groups, groups, groups, or groups
• CPC Class Codes: C12Q 1/001 Enzyme electrodes
• CPC Class Codes: C12Q 1/004 mediator-assisted
• CPC Class Codes: G01N 27/302 pH sensitive, e.g. quinhydron, antimony or hydrogen electrodes ion selective electrodes G01N27/333, glass electrodes G01N27/36
• CPC Class Codes: G01N 27/327 Biochemical electrodes , e.g. electrical or mechanical details for in vitro measurements
• CPC Class Codes: G01N 27/3275 Sensing specific biomolecules, e.g. nucleic acid strands, based on an electrode surface reaction
• CPC Class Codes: G01N 27/4163 : checking the operation of, or calibrating, the measuring apparatus G01N27/3274, G01N27/4175 and G01N33/0006 take precedence
• CPC Class Codes: G01N 27/4167 : pH electrodes therefor G01N27/302, G01N27/36
• CPC Class Codes: G01N 33/5438 : Electrodes

Abstract

Device and methods for use in a biosensor comprising a multisite array of test sites, the device and methods being useful for modulating the binding interactions between a (biomolecular) probe or detection agent and an analyte of interest by modulating the pH or ionic gradient near the electrodes in such biosensor. An electrochemically active agent that is suitable for use in biological buffers for changing the pH of the biological buffers. Method for changing the pH of biological buffers using the electrochemically active agents. The methods of modulating the binding interactions provided in a biosensor, analytic methods for more accurately controlling and measuring the pH or ionic gradient near the electrodes in such biosensor, and analytic methods for more accurately measuring an analyte of interest in a biological sample.

Claims

1. An apparatus comprising:

an electrochemically active composition that includes a quinone derivative; and

at least one electrode, wherein;

a reactivity between a nucleophile and the quinone derivative is reduced compared to a reactivity between the nucleophile and an unsubstituted quinone from which the quinone derivative is derived;

the apparatus is configured to control the at least one electrode to modulate a pH of at least a portion of the composition to predefined levels by the manipulation of the at least one electrode electrochemically reacting the quinone derivative in a targeted manner to thereby produce H⁺ ions or OH⁻

ions;

the quinone derivative is defined by a chemical formula selected from the group consisting of;

2. The apparatus of claim 1, wherein all of the R groups of the quinone derivative are different from each other.

3. The apparatus of claim 1, wherein two or more of the R groups of the quinone derivative are the same.

4. The apparatus of claim 1, wherein the reactivity between the nucleophile and the quinone derivative is reduced compared to the reactivity between the nucleophile and the unsubstituted quinone from which the quinone derivative is derived due to:

(i) increased steric hindrance of a nucleophile binding site by one or more of the R groups;

(ii) elimination of the nucleophile binding site by covalent bonding between the nucleophile binding site and one of the R groups;

or

(iii) both (i) and (ii).

5. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

6. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

7. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

8. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

9. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

10. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

11. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

12. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

13. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

14. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

15. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

16. The apparatus of claim 1, wherein the quinone derivative has the chemical formula:

17. An apparatus comprising:

an electrochemically active composition that includes;

a quinone derivative, wherein a reactivity between a nucleophile and the quinone derivative is reduced compared to a reactivity between the nucleophile and an unsubstituted quinone from which the quinone derivative is derived; and

an additive selected from the group consisting of;

an aqueous buffer, an organic solvent, an electrolyte, a buffer salt, a bioreagent, a biomolecule, a surfactant, a preservative, a cryoprotectant, and a combination of two or more thereof; and

at least one electrode, which the apparatus is configured to control to modulate a pH of at least a portion of the composition to predefined levels by the control of the at least one electrode electrochemically reacting the quinone derivative in a targeted manner to thereby produce H⁺ ions or OH⁻

ions.

18. The apparatus of claim 17, wherein the composition is an aqueous solution.

19. An apparatus comprising:

an electrochemically active composition that includes a quinone derivative; and

at least one electrode, wherein;

a reactivity between (a) a nucleophile selected from the group consisting of;

amines, thiols, amino acids, peptides, proteins, and a combination of two or more thereof, and (b) the quinone derivative is reduced compared to a reactivity between the nucleophile and an unsubstituted quinone from which the quinone derivative is derived; and

the apparatus is configured to control the at least one electrode to modulate a pH of at least a portion of the composition to predefined levels by the manipulation of the at least one electrode electrochemically reacting the quinone derivative in a targeted manner to thereby produce H⁺ ions or OH⁻

ions.

20. The apparatus of claim 19, wherein:

the quinone derivative is derivable from the unsubstituted quinone by substituting one or more R groups of the unsubstituted quinone with a substituent selected from the group consisting of;

H, C_nH_2n+1, Cl, F, I, Br, OM, NO₂, OH, OC_nH_2n, OC_nH_2nOH, O(C_nH_2nO)_yOH, O(C_nH_2nO)_yOC_nH_2n+1, O(C_nH_2nO)_yCOOH, O(C_nH_2nO)_yCOOM, COOH, COOM, COOC_nH_2n+1, CONHC_nH_2n+1, CON(C_nH_2n+1)₂, SO₃H, SO₃M, NH₂, NHC_nH_2n+1, N(C_nH_2n+1)₂, NHC_nH_2nOH, NHC_nH_2nNH₂, N(C_nH_2nOH)₂, N(C_nH_2nNH)₂, NHCOC_nH_2n+1, NC_nH_2n+1COC_nH_2n+1, NC_nH_2n+1COC_nH_2nOH, NC_nH_2n+1COC_nH_2nNH₂, NC_nH_2n+1COC_nH_2nSH, SH, SC_nH_2n, SC_nH_2nOH, S(C_nH_2nO)_yOH, S(C_nH_2nO)_yOC_nH_2n+1, S(C_nH_2nO)_yCOOH, S(C_nH_2nO)_yCOOM, OC_nH_2nSH, O(C_nH_2nO)_ySH, O(C_nH_2nO)_ySC_nH_2n+1, C_nH_2n, C_nH_2nOC_nH_2n, C_nH_2nSC_nH_2n, C_nH_2nNHC_nH_2n, C_nH_2nN(C_nH_2n+1)C_nH_2n, C_nH_2n+1, C_nH_2n+1OH, C_nH_2n+1OC_nH_2n, C_nH_2n+1OC_nH_2nOH, C_nH_2n+1O(C_nH_2nO)_yCOOH, C_nH_2n+1O(C_nH_2nO)_yCOOM, C_nH_2n+1COOH, C_nH_2n+1COOM, C_nH_2n+1COOC_nH_2n+1, C_nH_2n+1CONHC_nH_2n+1, C_nH_2n+1CONH(C_nH_2n+1)₂, C_nH_2n+1SO₃H, C_nH_2n+1SO₃M, C_nH_2n+1NH₂, C_nH_2n+1NHC_nH_2n+1, C_nH_2n+1N(C_nH_2n+1)₂, C_nH_2n+1NHC_nH_2nOH, C_nH_2n+1NHC_nH_2nNH₂, C_nH_2n+1N(C_nH_2nOH)₂, C_nH_2n+1N(C_nH_2nNH₂)₂, C_nH_2n+1NHCOC_nH_2n+1, C_nH_2n+1NC_nH_2n+1COC_nH_2nOH, C_nH_2n+1NC_nH_2n+1COC_nH_2nNH₂, C_nH_2n+1NC_nH_2n+1COC_nH_2nSH, C_nH_2n+1SH, C_nH_2n+1SC_nH_2n, C_nH_2n+1SC_nH_2nOH, C_nH_2n+1S(C_nH_2n+1O)_yOH, C_nH_2n+1S(C_nH_2nO)_yOC_nH_2n+1, C_nH_2n+1S(C_nH_2nO)_yCOOH, C_nH_2n+1S(C_nH_2nO)_yCOOM, sugars, peptides, and amino acids;

M is any metal cation or NH₄⁺;

n is an integer from 1 to 10⁹; and

y is an integer from 1 to 10⁹.

21. The apparatus of claim 20, wherein the reactivity between the quinone derivative and the nucleophile is less than the reactivity between the quinone and the nucleophile due to at least one of:

(i) elimination of a nucleophile binding site in the quinone derivative by covalent bonding between the substituent and the nucleophile binding site;

(ii) steric hindrance of the nucleophile binding site by the substituent;

or

(iii) both (i) and (ii).

22. The apparatus of claim 20, wherein the quinone derivative has a chemical formula:

23. The apparatus of claim 20, wherein the quinone derivative has a chemical formula:

24. The apparatus of claim 20, wherein the quinone derivative has a chemical formula:

25. The apparatus of claim 20, wherein the quinone derivative has a chemical formula:

26. The apparatus of claim 20, wherein the quinone derivative has a chemical formula:

27. The apparatus of claim 20, wherein the quinone derivative has a chemical formula:

28. The apparatus of claim 20, wherein the one or more R groups are substituted with a polar group.

29. The apparatus of claim 28, wherein the polar group has atoms containing lone pair electrons and/or is capable of forming hydrogen bonds with water.

30. The apparatus of claim 28, wherein the polar group contains at least one of oxygen, nitrogen, and sulfur atoms.

31. The apparatus of claim 28, wherein the polar group is selected from the group consisting of:

OH, CH₂OH, OCH₃, COOH, SO₃H, NH₂, NH₃Cl, ONa, a sugar, an amino acid, and a peptide.

32. The apparatus of claim 19, wherein:

the quinone derivative is a substituted methyl quinone synthesizable by;

(i) a halide substitution step of reacting a starting material with a hydrogen halide in the presence of acetic acid and an aldehyde;

(ii) reacting a material produced by step (i) with a nucleophile of structure R—

X;

(iii) reacting a material produced by step (ii) with an oxidizing agent; and

(iv) reacting a material produced by step (iii) with a reducing agent;

R is selected from the group consisting of;

H, C_nH_2n+1, Cl, F, I, Br, OM, NO₂, OH, OC_nH_2n, OC_nH_2nOH, O(C_nH_2nO)_yOH, O(C_nH_2nO)_yOC_nH_2n+1, O(C_nH_2nO)_yCOOH, O(C_nH_2nO)_yCOOM, COOH, COOM, COOC_nH_2n+1, CONHC_nH_2n+1, CON(C_nH_2n+1)₂, SO₃H, SO₃M, NH₂, NHC_nH_2n+1, N(C_nH_2n+1)₂, NHC_nH_2nOH, NHC_nH_2nNH₂, N(C_nH_2nOH)₂, N(C_nH_2nNH)₂, NHCOC_nH_2n+1, NC_nH_2n+1COC_nH_2n+1, NC_nH_2n+1COC_nH_2nOH, NC_nH_2n+1COC_nH_2nNH₂, NC_nH_2n+1COC_nH_2nSH, SH, SC_nH_2n, SC_nH_2nOH, S(C_nH_2nO)_yOH, S(C_nH_2nO)_yOC_nH_2n+1, S(C_nH_2nO)_yCOOH, S(C_nH_2nO)_yCOOM, OC_nH_2nSH, O(C_nH_2nO)_ySH, O(C_nH_2nO)_ySC_nH_2n+1, C_nH_2n, C_nH_2nOC_nH_2n, C_nH₂SC_nH_2n, C_nH_2nNHC_nH_2n, C_nH_2nN(C_nH_2n+1)C_nH_2n, C_nH_2n+1, C_nH_2n+1OH, C_nH_2n+1OC_nH_2n, C_nH_2n+1OC_nH_2nOH, C_nH_2n+1O(C_nH_2nO)_yCOOH, C_nH_2n+1O(C_nH_2nO)_yCOOM, C_nH_2n+1COOH, C_nH_2n+1COOM, C_nH_2n+1COOC_nH_2n+1, C_nH_2n+1CONHC_nH_2n+1, C_nH_2n+1CONH(C_nH_2n+1)₂, C_nH_2n+1SO₃H, C_nH_2n+1SO₃M, C_nH_2n+1NH₂, C_nH_2n+1NHC_nH_2n+1, C_nH_2n+1N(C_nH_2n+1)₂, C_nH_2n+1NHC_nH_2nOH, C_nH_2n+1NHC_nH_2nNH₂, C_nH_2n+1N(C_nH_2nOH)₂, C_nH_2n+1N(C_nH_2nNH₂)₂, C_nH_2n+1NHCOC_nH_2n+1, C_nH_2n+1NC_nH_2n+1COC_nH_2nOH, C_nH_2n+1NC_nH_2n+1COC_nH_2nNH₂, C_nH_2n+1NC_nH_2n+1COC_nH_2nSH, C_nH_2n+1SH, C_nH_2n+1SC_nH_2n, C_nH_2n+1SC_nH_2nOH, C_nH_2n+1S(C_nH_2n+1O)_yOH, C_nH_2n+1S(C_nH_2nO)_yC_nH_2n+1, C_nH_2n+1S(C_nH_2nO)_yCOOH, C_nH_2n+1S(C_nH_2nO)_yCOOM, sugars, peptides, and amino acids;

M is any metal cation or NH₄⁺;

n is an integer from 1 to 10⁹;

y is an integer from 1 to 10⁹; and

X is either OH, NH₂, NHR, SH, O⁻

, or S⁻

.

33. The apparatus of claim 32, wherein the starting material is dialkoxybenzene.

34. The apparatus of claim 33, wherein the result of the halide substitution step is an ortho-quinon, para-quinone, or a combination thereof.

35. The apparatus of claim 33, wherein a number of halide groups per molecule of the ortho-quinone or para-quinone is 1, 2, 3, or 4.

36. The apparatus of claim 32, wherein the starting material is dialkoxynaphthalene.

37. The apparatus of claim 36, wherein the result of the halide substitution step is an ortho-naphthoquinone, para-naphthoquinone, or a combination thereof.

38. The apparatus of claim 36, wherein a number of halide groups per molecule of the ortho-naphthoquinone or para-naphthoquinone is 1 or 2.

39. The apparatus of claim 32, wherein the hydrogen halide is selected from the group consisting of:

HCl, HBr, HI, and combinations thereof.

40. The apparatus of claim 32, wherein the oxidizing agent is selected from the group consisting of:

cerium ammonium nitrate, iodine, hydrogen peroxide, hypervalent iodine, iodobenzene diacetate, bromine compounds, and combinations thereof.

41. The apparatus of claim 32, wherein the reducing agent is selected from the group consisting of:

sodium borohydrate, potassium borohydrate, sodium hydrosulfite, trichlorosilane, and combinations thereof.

42. A method using an apparatus, the apparatus comprising (a) an electrochemically active composition that includes a quinone derivative and an additive selected from the group consisting of:

an aqueous buffer, an organic solvent, an electrolyte, a buffer salt, a bioreagent, a biomolecule, a surfactant, a preservative, a cryoprotectant, and a combination of two or more thereof and (b) at least one electrode, which the apparatus is configured to control to modulate a pH of at least a portion of the composition to predefined levels by the control of the at least one electrode electrochemically reacting the quinone derivative in a targeted manner to thereby produce H⁺ ions or OH⁻

ions, the method comprising;

electrochemically reacting the quinone derivative using the one or more electrodes to produce an amount of H⁺ ions and/or an amount of OH⁻

ions, wherein the pH of the solution close to the one or more electrodes is controlled by the amount of H⁺ ions and/or the amount of OH⁻

ions produced; and

collecting signals from the apparatus, wherein a reactivity between a nucleophile and the quinone derivative is reduced compared to a reactivity between the nucleophile and an unsubstituted quinone from which the quinone derivative is derived.

43. The method of claim 42, wherein:

the quinone derivative is defined by a chemical formula selected from the group consisting of;

44. The method of claim 42, wherein the solution contains one or more nucleophiles.

45. The method of claim 44, wherein the one or more nucleophiles are selected from the group consisting of:

amines, thiols, amino acids, peptides, proteins, and combinations thereof.

46. The method of claim 42, wherein the solution contains a reduced quinone derivative and electrochemically reacting the quinone derivative results in an electrochemical oxidation reaction of the reduced quinone derivative to make the pH of the solution more acidic.

47. The method of claim 46, wherein the concentration of the reduced quinone derivative is 0 to 1M.

48. The method of claim 42, wherein the solution contains an oxidized quinone derivative and electrochemically reacting the quinone derivative results in an electrochemical reduction reaction of the oxidized quinone derivative to make the pH of the solution more basic.

49. The method of claim 48, wherein the concentration of the oxidized quinone derivative is 0 to 1M.

50. The method of claim 42, wherein the solution contains one or more buffer components provided in a concentration that is 0 to 1M.

51. The method of claim 50, wherein the one or more buffer components are selected from the group consisting of:

organic solvents, electrolytes, bioreagents, biomolecules, surfactants, and combinations thereof.

52. The method of claim 42, further comprising measuring the pH of the solution.

53. The method of claim 42, wherein the quinone derivative is electrochemically reacted by providing an amount of electric current.

54. The method of claim 53, further comprising measuring the pH before providing the amount of electric current.

55. The method of claim 54, wherein the amount of electric current is selected based on the measured pH.