Compositions and methods using platinum compounds for nucleic acid labeling

• US 6,825,330 B2
• Filed: 03/01/2002
• Issued: 11/30/2004
• Est. Priority Date: 03/02/2001
• Status: Expired due to Fees

• Current Assignee: Stratagene California (Agilent Technologies, Inc.)
• Original Assignee: Stratagene California (Agilent Technologies, Inc.)
• Inventors: Braman, Jeffrey, Huang, Haoqiang
• Primary Examiner(s): Riley, Jezia
• Application Number:
  US10/086,515
• Publication Number:
  US 20020165369A1
• Time in Patent Office: 1,005 Days
• Field of Search: 536/23.1, 536/26.6, 536/24.3
• US Class Current: 536/23.1
• CPC Class Codes: C07F 15/0093 without a metal-carbon linkage

Abstract

The invention relates to novel platinum-based compounds for labeling biomolecules. Platinum based labeling compounds according to the invention irreversibly attach to a target biomolecule via coordination of a platinum (II) metal center with N or S atoms on the target biomolecule. The invention relates to the novel compounds themselves, methods of making the platinum-based labeling compounds, probes labeled with such compounds, methods of making such labeled probes, and kits comprising the novel platinum-based labeling compounds and/or probes labeled with them. The invention also relates to methods of using probes labeled with platinum-based labeling compounds of the invention, particularly array and microarray hybridization methods.

Claims

1. A composition comprising the formula:

wherein;

R₁-R₅ may be the same or different and are independently selected from the group consisting of H, alkyl (1 to 10 carbon atoms), benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₆, —

(C═

O)OR₆, or —

OCH₂(C═

O)R₆ and a salt, wherein R₆ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X₁ and X₂ may be the same or different and at least one of X₁ or X₂ is a leaving group; and

linker is a moiety joining a nitrogen to a detectable marker, D.

2. The composition of claim 1, wherein said leaving group is selected from the group consisting of NO₃, halogen CN, OCOR₇, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-demethyl-phenyl-4-sulfate, wherein R₇ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃. halogen, O—

R₆, —

(C═

O)OR₆, —

OCH₂(C═

O)R₆ and a salt.

3. The composition of claim 1 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p. q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNH, NHCSO, wherein

and A, B, D, and B are the same or different and are selected from the group consisting of CH, N, O and S.

4. The composition of claim 1 wherein the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

5. A nucleic acid comprising a composition of claim 1.

6. The nucleic acid of claim 5 wherein said composition forms a non-covalent adduct with said nucleic acid.

7. A probe comprising a composition of claim 1.

8. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 1 with said nucleic acid.

9. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 6 and detecting signal from said detectable marker.

10. A composition comprising the formula:

wherein;

R₁-R₅ may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₆, —

(C═

O)OR₆, or —

OCH₂(C═

O)R₆ and a salt, wherein R₆ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X₁ and X₂ may be the same or different and at least one of X₁ and X₂ is a leaving group; and

linker is a moiety joining a nitrogen to a detectable marker, D.

11. The composition of claim 10, wherein said leaving group is selected from the group consisting of NO₃, halogen, CN, OCOR₇, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₇ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₆, —

(C═

Q)OR₆, —

OCH₂(C═

O)R₆ and a salt.

12. The composition of claim 10 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNH, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

13. The composition of claim 10 wherein the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

14. A nucleic acid comprising a composition of claim 10.

15. The nucleic acid of claim 14 wherein said composition fonus a non-covalent adduct with said nucleic acid.

16. A probe comprising a composition of claim 10.

17. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 10 with said nucleic acid.

18. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 15 and detecting signal from said detectable marker.

19. A composition comprising the formula:

wherein

Y is selected from the group consisting of O, S, and C;

R₁ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₂, —

(C═

O)OR₂, —

OCH₂(C═

O)R₂, and a salt, wherein R₂ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X₁ and X₂ are the same or different and at least one of X₁ or X₂ is a leaving group;

linker is a moiety joining a nitrogen to a detectable marker, D, and u and v are the same or different and are an integer from 1 to 10.

20. The composition of claim 19, wherein said leaving group is selected from the group consisting of NO₃, halogen, CN, OCOR₃, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₃ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₂, —

(C═

O)OR₂, or —

OCH₂(C═

O)R₂ and a salt.

21. The composition of claim 19 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNH, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

22. The composition of claim 19 wherein said detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

23. A nucleic acid comprising a composition of claim 19.

24. The nucleic acid of claim 23 wherein said composition fonns a non-covalent adduct with said nucleic acid.

25. A probe comprising a composition of claim 19.

26. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 19 with said nucleic acid.

27. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 25 and detecting signal from said detectable marker.

28. A composition comprising the formula:

wherein;

—

Y is selected from the group consisting of O, S, and C;

R₁-R₃ may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₄, —

(C═

O)OR₄, or —

OCH₂(C═

O)R₄ and a salt, wherein R₄ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X₁ and X₂ are the same or different and at least one of X₁ or X₂ is a leaving group; and

linker is a moiety joining a nitrogen to a detectable marker, D.

29. The composition of claim 28, wherein said leaving group is selected from the group consisting of NO₃, halogen, CN, OCOR₅, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate wherein R₅ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₄, —

(C═

O)OR₄, —

OCH₂(C═

O)R₄ and a salt.

30. The composition of claim 28 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNH, NEOSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of OH, N, O and S.

31. The composition of claim 28 wherein said detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

32. A nucleic acid comprising a composition of claim 28.

33. The nucleic acid of claim 32 wherein said composition forms a non-covalent adduct with said nucleic acid.

34. A probe comprising a composition of claim 28.

35. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 28 with said nucleic acid.

36. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 34 and detecting signal from said detectable marker.

37. A composition comprising the formula:

wherein;

Y is selected from the group consisting of O, S, and C;

R₁-R₃ may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₄, —

(C═

O)OR₄, or —

OCH₂(C═

O)R₄ and a salt, wherein R₄ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X₁ and X₂ are the same or different and at least one of X₁ or X₂ is a leaving group; and

linker is a moiety joining a nitrogen to a detectable marker, D.

38. The composition of claim 37, wherein said leaving group is selected from the group consisting of No₃, halogen, CN, OCOR₅, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₅ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₄, —

(C═

O)OR₄, —

OCH₂(C═

O)R₄ and a salt.

39. The composition of claim 37 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNH, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

40. The composition of claim 37 wherein said detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

41. A nucleic acid comprising a composition of claim 37.

42. The nucleic acid of claim 41 wherein said composition forms a non-covalent adduct with said nucleic acid.

43. A probe comprising a composition of claim 37.

44. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 37 with said nucleic acid.

45. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 43 and detecting signal from said detectable marker.

46. A composition comprising the formula

wherein

Z is selected from the group consisting of (CH₂)n, and (CH₂)nO(CH₂)m, wherein m and n are integers from 2 to 8, inclusive;

R₁ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₂, —

(C═

O)OR₂, or —

OCH₂(C═

O)R₂ and a salt, wherein R₂ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X₁ and X₂ are the same or different and at least one of X₁ and X₂ is a leaving group; and

linker is a moiety joining a nitrogen to a detectable marker, D.

47. The composition of claim 46, wherein said leaving group is selected from the group consisting of No₃, halogen, CN, OCOR₃, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₃ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₂, —

(C═

O)OR₂, —

OCH₂(C═

O)R₂ and a salt.

48. The composition of claim 46 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNH, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

49. The composition of claim 46 wherein said detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

50. A nucleic acid comprising a composition of claim 46.

51. The nucleic acid of claim 50 wherein said composition forms a non-covalent adduct with said nucleic acid.

52. A probe comprising a composition of claim 46.

53. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 46 with said nucleic acid.

54. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 52 and detecting signal from said detectable marker.

55. A composition comprising the formula

wherein

Z is selected from the group consisting of (CH₂)_n, and (CH₂)_nO(CH₂)_m, wherein m and n are integers from 2 to 8, inclusive;

R₁ and R₂ may be the same or different and are selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₃, —

(C═

O)OR₃, or —

OCH₂(C═

O)R₃ and a salt, wherein R₃ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X is a leaving group; and

linker is a moiety joining a detectable marker, D to the platinum ion.

56. The composition of claim 55, wherein said leaving group is selected from the group consisting of NO₃, halogen, CN, OCOR₄, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₄ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₃, —

(CO)OR₃, —

OCH₂(C═

O)R₃ and a salt.

57. The composition of claim 55 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNH, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

58. The composition of claim 55 wherein said detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

59. A nucleic acid comprising a composition of claim 55.

60. The nucleic acid of claim 59 wherein said composition forms a non-covalent adduct with said nucleic acid.

61. A probe comprising a composition of claim 55.

62. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 55 with said nucleic acid.

63. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 61 and detecting signal from said detectable marker.

64. A composition comprising the formula:

wherein;

R₁-R₆ may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₇, —

(C═

O)OR₇, or —

OCH₂(C═

O)R₇ and a salt, wherein R₇ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X is a leaving group; and

linker is a moiety joining a detectable marker, D to the platinum ion.

65. The composition of claim 64, wherein said leaving group is selected from the group consisting of NO₃, halogen, CN, OCOR₈, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₈ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CE₃, halogen, O—

R₇, —

(C═

O)OR₆, —

OCH₂(C═

O)R₇ and a salt.

66. The composition of claim 64 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NBCSNH, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

67. The composition of claim 64 wherein the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

68. A nucleic acid comprising a composition of claim 64.

69. The nucleic acid of claim 68 wherein said composition forms a non-covalent adduct with said nucleic acid.

70. A probe comprising a composition of claim 64.

71. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 67 with said nucleic acid.

72. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 70 and detecting signal from said detectable marker.

73. A composition comprising the formula

wherein

R₁-R₆ may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₇, —

(C═

O)OR₇, or —

OCH₂(C═

O)R₇ and a salt, wherein R₇ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X is a leaving group; and

linker is a moiety joining a detectable marker, D, to the platinum ion.

74. The composition of claim 73, wherein said leaving group is selected from the group consisting of NO₃, halogen, CN, OCOR₈, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₈ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₇, —

(C═

O)OR₆, —

OCH₂(C═

O)R₇ and a salt.

75. The composition of claim 73 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNB, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

76. The composition of claim 73 wherein the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

77. A nucleic acid comprising a composition of claim 73.

78. The nucleic acid of claim 77 wherein said composition forms a non-covalent adduct with said nucleic acid.

79. A probe comprising a composition of claim 73.

80. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 73 with said nucleic acid.

81. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 79 and detecting signal from said detectable marker.

82. A composition comprising the formula:

wherein

Y is selected from the group consisting of O, S, and C;

R₁-R₄ may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₅, —

(C═

O)OR₅, or —

OCH₂(C═

O)R₅ and a salt, wherein R₅ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X is a leaving group; and

linker is a moiety joining a detectable marker, D, to the platinum ion.

83. The composition of claim 82 wherein said leaving group is selected from the group consisting of NO₃, halogen, CN, OCOR₆, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₆ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₅, —

(C═

O)OR₅, —

OCH₂(C═

O)R₅ and a salt.

84. The composition of claim 82 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NHCO, —

S—

S—

, NHCSNH, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

85. The composition of claim 82 herein the detectable marker, D, is selected from the group consisting of a fluorophore, a chromophore, a radiolabel, an enzyme and an affinity tag.

86. nucleic acid comprising a composition of claim 82.

87. The nucleic acid of claim 86 wherein said composition forms a non-covalent adduct with said nucleic acid.

88. A probe comprising a composition of claim 82.

89. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 82 with said nucleic acid.

90. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 88 and detecting signal from said detectable marker.

91. A composition comprising the formula:

wherein

Y is selected from the group consisting of O, S, and C;

R₁-R₄ may be the same or different and are independently selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₅, —

(C═

O)OR₅, or —

OCH₂(C═

O)R₅ and a salt, wherein R₅ is a straight or branched, saturated or unsaturated, substituted or unsubstituted alkyl having 1-10 carbons;

X is a leaving group; and

linker is a moiety joining a detectable marker, D, to the platinum ion.

92. The composition of claim 91, wherein said leaving group is selected from the group consisting of NO₃, halogen, CN, OCOR₆, OCO-Phenyl, OCOCH₂OC(Phenyl)₃, O-Trityl and 3,5-dimethyl-phenyl-4-sulfate, wherein R₆ is selected from the group consisting of H, methyl, benzyl, sulfonate, phosphonate, NO₂, CF₃, halogen, O—

R₅, —

(C═

O)OR₅, —

OCH₂(C═

O)R₅ and a salt.

93. The composition of claim 91 wherein said linker is selected from the group consisting of:

(CH₂)n, (CH₂)_n(CH═

CH)_mO(CH═

CH)_p(CH₂)_q, CO(CH₂)_n(CH═

CH)_m(CH₂)_p, COAr(CH₂)_n(CH═

CH)_m(CH₂)_p, NH₂(CH₂)_nQ, NH₂((CH₂)_nO)_m(CH₂)_tQ, NH₂(CH₂)_mAr(CH₂)_nQ, wherein m, n, p, q and t are integers from 0 to 8, inclusive, and m, n, p, q and t are the same or different, wherein Q is selected from the group consisting of CONH, NIICO, —

S—

S—

, NHCSNH, NHCSO, wherein

and A, B, D, and E are the same or different and are selected from the group consisting of CH, N, O and S.

94. The composition of claim 91 wherein the detectable marker, D, is selected from the group consisting of a fluorophore, a chrornophore, a radiolabel, an enzyme and an affinity tag.

95. A nucleic acid comprising a composition of claim 91.

96. The nucleic acid of claim 95 wherein said composition forms a non-covalent adduct with said nucleic acid.

97. A probe comprising a composition of claim 91.

98. A method of labeling a nucleic acid, said method comprising the step of contacting a composition of claim 91 with said nucleic acid.

99. A method of probing a nucleic acid array, said method comprising the steps of contacting said array with a probe of claim 97 and detecting signal from said detectable marker.

100. A method of making a platinum labeling compound that comprises a stabilizing bridge, the method comprising the step of contacting potassium tetrachloroplatinate (II) with a cycloaliphatic diamine labeled with a detectable marker, wherein said contacting results in a cis-platinum dichloride labeling compound.

101. The method of claim 100 wherein said cycloaliphatic diamine is a 1,2-cycloaliphatic diamine.

102. The method of claim 100 wherein said cycloaliphatic diamine is a cyclohexyl diamine.

103. The method of claim 102 wherein said cyclohexyl diamine is a 1,2-cyclohexyl diamine.

104. The method of claim 100 wherein said contacting is performed in aqueous solution at a pH of about 1.5 to 5.5 and at a temperature of about 65°

C.