ELECTROCHEMICALLY ACTIVE AGENTS FOR PH MODULATION IN BIOLOGICAL BUFFERS

• US 20170008825A1
• Filed: 07/06/2015
• Published: 01/12/2017
• 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
• Granted Patent: US 10,011,549 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 electrochemically active composition comprising 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

the composition is configured such that the pH of the composition is electrochemically modulated via the quinone derivative.

2. The composition of claim 1, wherein the quinone derivative is defined by a chemical formula selected from the group consisting of:

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

4. The composition of claim 2, wherein two or more of the R groups of the quinone derivative are the same.

5. The composition of claim 1, wherein the composition is an aqueous solution.

6. The composition of claim 1, further comprising 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 combinations thereof.

7. The composition of claim 1, wherein the one or more nucleophiles are selected from the group consisting of:

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

8. The composition of claim 2, 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).

9. The composition of claim 2, wherein the quinone derivative has the chemical formula:

11. The composition of claim 2, wherein the quinone derivative has the chemical formula:

13. The composition of claim 2, wherein the quinone derivative has the chemical formula:

15. The composition of claim 2, wherein the quinone derivative has the chemical formula:

17. The composition of claim 2, wherein the quinone derivative has the chemical formula:

19. The composition of claim 2, wherein the quinone derivative has the chemical formula:

10. (canceled)

12. (canceled)

14. (canceled)

16. (canceled)

18. (canceled)

20. (canceled)

21. A method comprising modifying a quinone having one or more R groups by substituting one or more of the R groups with a substituent to provide a quinone derivative, wherein:

the quinone derivative has a reduced reactivity with a nucleophile compared to a reactivity between the quinone and the nucleophile; and

the substituent is independently 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)COOH, S(C_nH₂O)_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+, 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.

22. The method of claim 21, 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).

23. The method of claim 21, wherein the quinone derivative has a chemical formula:

25. The method of claim 21, wherein the quinone derivative has a chemical formula:

27. The method of claim 21, wherein the quinone derivative has a chemical formula:

29. The method of claim 21, wherein the quinone derivative has a chemical formula:

31. The method of claim 21, wherein the quinone derivative has a chemical formula:

33. The method of claim 21, wherein the quinone derivative has a chemical formula:

35. The method of claim 21, wherein the one or more R groups are substituted with a polar group.

36. The method of claim 35, wherein the polar group has atoms containing lone pair electrons and/or is capable of forming hydrogen bonds with water.

38. The method of claim 35, wherein the polar group contains at least one of oxygen, nitrogen, and sulfur atoms.

39. The method of claim 35, 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.

24. (canceled)

26. (canceled)

28. (canceled)

30. (canceled)

32. (canceled)

34. (canceled)

37. (canceled)

40. A method of synthesizing substituted methyl quinone comprising:

(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,

wherein;

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, OCH_2nSH, O(C_nH_2nO)SH, O(C_nH_2nO)_ySCH_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+1NCnH_2n+1 COC_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;

y is an integer from 1 to 10⁹; and

X is either OH, NH₂, NHR, SH, O⁻

, or S.

41. The method of claim 40, wherein the starting material is dialkoxybenzene.

42. The method of claim 41, wherein the result of the halide substitution step is an ortho-quinon, para-quinone, or a combination thereof.

43. The method of claim 41, wherein a number of halide groups per molecule of the ortho-quinone or para-quinone is 1, 2, 3, or 4.

44. The method of claim 40, wherein the starting material is dialkoxynaphthalene.

45. The method of claim 44, wherein the result of the halide substitution step is an ortho-naphthoquinone, para-naphthoquinone, or a combination thereof.

46. The method of claim 44, wherein a number of halide groups per molecule of the ortho-naphthoquinone or para-naphthoquinone is 1 or 2.

47. The method of claim 40, wherein the hydrogen halide is selected from the group consisting of:

HCl, HBr, HI, and combinations thereof.

48. The method of claim 40, 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.

49. The method of claim 40, wherein the reducing agent is selected from the group consisting of:

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

50. A method comprising:

a. providing a biosensor comprising a support in an solution,

i. the support comprising one or more electrodes, and a biomolecule interface layer having one or more immobilized probes thereon;

ii. the solution comprising a quinone derivative;

b. adding a biomolecule analyte to the solution;

c. electrochemically reacting the quinone derivative using the one or more electrodes to produce an amount of H⁺ ions and/or an amount of Off 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 Off ions produced;

d. collecting signals from the biosensor,

e. 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.

51. The method of claim 50, wherein the quinone derivative is defined by a chemical formula selected from the group consisting of:

54. The method of claim 50, wherein the solution contains one or more nucleophiles.

56. The method of claim 50, 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.

57. The method of claim 56, wherein the concentration of the reduced quinone derivative is 0 to 1M.

58. The method of claim 50, 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.

59. The method of claim 58, wherein the concentration of the oxidized quinone derivative is 0 to 1M.

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

61. The method of claim 60, wherein the one or more buffer components are selected from the group consisting of:

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

62. The method of claim 50, further comprising measuring the pH of the solution and optionally continuously measuring the pH.

64. The method of claim 50, wherein the quinone derivative is electrochemically reacted by providing an amount of electric current.

65. The method of claim 64, wherein the pH is measured before providing the amount of electric current.

66. The method of claim 65, wherein the amount of electric current is selected based on the measured pH.

52. (canceled)

53. (canceled)

55. The method of claim 53, wherein the one or more nucleophiles are selected from the group consisting of:

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

63. (canceled)