Claims
- 1. A linear polyamine-bridged platinum compound having the general formula [(PtXYZ)-A-(Pt X′Y′Z′)], where X, Y, Z, X′, Y′, and Z′ may be the same or different and are
anionic groups, or neutral groups which may be substituted or unsubstituted; and A is a bridging polyamine having a general formula selected from the group consisting of
H2N(CH2)xNBB′(CH2)yNH2 where x ranges from about 1 to about 10 and y ranges from about 1 to about 10, or H2N(CH2)xNBB′(CH2)yNBB′(CH2)xNH2 where x ranges from about 1 to about 10 and y ranges from about 1 to about 10, where B and B′ are hydrogen or a labile blocking group and may be the same or different, and may be the same or different at each location, and where B′ may be present or absent, and wherein when said anionic groups or neutral groups of said linear polyamine-bridged platinum compound are in a 1,1/t,t configuration with respect to said bridging polyamine, said labile blocking group is not tBOC.
- 2. The compound of claim 1 wherein said anionic groups are selected from the group consisting of halide, pseudohalide, substituted pseudohalide, sulphate, phosphate, phosphonate, nitrate, carboxylate, substituted carboxylate, dicarboxylate, and substituted dicarboxylate.
- 3. The compound of claim 1 wherein said neutral groups are selected from the group consisting of ammonia, primary or secondary amines, a “dangling” diamine H2N(CH2)nNBB′ where only the —NH2 moiety is bound to platinum, sulfoxide, phosphine, pyridine, substituted pyridine, quinoline, imidazole, thiazole, pyrimidine, purine, acridine, pyrazole, benzimidazole, and benzothiazole; and for 1,1/c,c configurations, Y and Z or Y′ and Z′or both Y and Z and Y′ and Z′ may be a chelating bidentate diamine.
- 4. The compound of claim 1 wherein said bridging polyamine portion of said compound is H2N(CH2)xNBB′(CH2)yNH2 and x ranges from about 1 to about 10 and y ranges from about 1 to about 10.
- 5. The compound of claim 4 wherein the values of x and y are selected from the group consisting of: x=4 and y=3, x=6 and y=6; and x=7 and y=8.
- 6. The compound of claim 5 wherein
Y=Y′ and is chloride; and X=X′ and Z=Z′ and are ammonia.
- 7. The compound of claim 5 wherein
X=X′ and is chloride; and Y=Y′ and Z=Z′ and are ammonia.
- 8. The compound of claim 1 wherein said bridging polyamine portion of said compound is H2N(CH2)xNBB′(CH2)yNBB′(CH2)xNH2 and x ranges from about 1 to about 10 and y ranges from about 1 to about 10.
- 9. The compound of claim 8 wherein the values of x and y are selected from the group consisting of: x=4 and y=3; x=6 and y=2; and x=5 and y=4.
- 10. The compound of claim 9 wherein
Y=Y′ and is chloride; and X=X′ and Z=Z′ and are ammonia.
- 11. The compound of claim 1 wherein said labile blocking group is selected from the group consisting of carbamate protection groups and amide protection groups.
- 12. The compound of claim 11 wherein said carbamate protection groups are selected from the group consisting of t-butyl (tBOC), benzyl (CBz), fluorenylmethyl (Fmoc), adamantyl (1-Adoc), piperidinyl (Pipoc), allyl, and vinyl.
- 13. The compound of claim 11 wherein said amide protection groups are selected from the group consisting of 2-(benzoyloxymethyl)benzoyl (BOMB), acetyl, trifluoroacetyl, and monochloroacetyl.
- 14. The compound of claim 1 wherein said blocking group further comprises a targeting element.
- 15. The compound of claim 1 wherein said anionic groups are arranged in a 1,1/t,t configuration with respect to said bridging polyamine.
- 16. The compound of claim 1 wherein said anionic groups are arranged in a 1,1/c,c configuration with respect to said bridging polyamine.
- 17. The compound of claim 1 wherein said anionic groups or neutral groups are arranged in a 2,2/c,c configuration with respect to said bridging polyamine.
- 18. A method for killing cancer cells, comprising the steps of
providing to said cancer cells a linear polyamine-bridged platinum compound having the general formula [(PtXYZ)-A-(Pt X′Y′Z′)], where X, Y, Z, X′, Y′, and Z′ may be the same or different and are
anionic groups, or neutral groups which may be substituted or unsubstituted; and A is a bridging polyamine having a general formula selected from the group consisting of
H2N(CH2)xNH2(CH2)yNH2 where x ranges from about 1 to about 10 and y ranges from about 1 to about 10, or H2N(CH2)xNBB′(CH2)yNBB′(CH2)xNH2 where x ranges from about 1 to about 10 and y ranges from about 1 to about 10, where B and B′ are hydrogen or a labile blocking group and may be the same or different, and may be the same or different at each location, and where B′ may be present or absent, and wherein at least one central amine function of said bridging polyamine portion is blocked with a labile blocking group, wherein said linear polyamine-bridged platinum compound is provided in a quantity sufficient to kill said cancer cells.
- 19. The method of claim 18 wherein said anionic groups are selected from the group consisting of halide, pseudohalide, substituted pseudohalide, sulphate, phosphate, phosphonate, nitrate, carboxylate, substituted carboxylate, dicarboxylate, and substituted dicarboxylate.
- 20. The method of claim 18 wherein said neutral groups are selected from the group consisting of ammonia, primary or secondary amines, a “dangling” diamine H2N(CH2)nNBB′ where only the —NH2 moiety is bound to platinum, sulfoxide, phosphine, pyridine, substituted pyridine, quinoline, imidazole, thiazole, pyrimidine, purine, acridine, pyrazole, benzimidazole, and benzothiazole; and for 1,1/c,c configurations, Y and Z or Y′ and Z′ or both Y and Z and Y′ and Z′ may be a chelating bidentate diamine.
- 21. The method of claim 18 wherein said bridging polyamine portion of said compound is H2N(CH2)xNBB′(CH2)yNH2 and x ranges from about 1 to about 10 and y ranges from about 1 to about 10.
- 22. The method of claim 21 wherein the values of x and y are selected from the group consisting of: x=4 and y=3, x=6 and y=6; and x=7 and y=8.
- 23. The method of claim 22 wherein
Y=Y′ and is chloride; and X=X′ and Z=Z′ and are ammonia.
- 24. The method of claim 22 wherein
X=X′ and is chloride; and Y=Y′ and Z=Z′ and are ammonia.
- 25. The method of claim 18 wherein said bridging polyamine portion of said compound is H2N(CH2)xNBB′(CH2)yNBB′(CH2)xNH2 and x ranges from about 1 to about 10 and y ranges from about 1 to about 10.
- 26. The method of claim 25 wherein the values of x and y are selected from the group consisting of: x=4 and y=3;x=6 and y=2;and x=5 and y=4.
- 27. The method of claim 26 wherein
Y=Y′ and is chloride; and X=X′ and Z=Z′ and are ammonia.
- 28. The method of claim 18 wherein said labile blocking group is selected from the group consisting of carbamate protection groups and amide protection groups.
- 29. The method of claim 28 wherein said carbamate protection groups are selected from the group consisting of t-butyl (tBOC), benzyl (CBz), fluorenylmethyl (Fmoc), adamantyl (1-Adoc), piperidinyl (Pipoc), allyl, and vinyl.
- 30. The method of claim 28 wherein said amide protection groups are selected from the group consisting of 2-(benzoyloxymethyl)benzoyl (BOMB), acetyl, trifluoroacetyl, and monochloroacetyl.
- 31. The method of claim 18 wherein said labile blocking group further comprises a targeting element.
- 32. The method of claim 18 wherein said anionic groups or neutral groups are arranged in a 1,1/t,t configuration with respect to said bridging polyamine.
- 33. The method of claim 18 wherein said anionic groups or neutral groups are arranged in a 1,1/c,c configuration with respect to said bridging polyamine.
- 34. The method of claim 18 wherein said anionic groups or neutral groups are arranged in a 2,2/c,c configuration with respect to said bridging polyamine.
- 35. The method of claim 18 further comprising the step of removing said labile blocking group via an environmental stimulus.
- 36. The method of claim 35 wherein said environmental stimulus is selected from the group consisting of pH and an enzyme.
- 37. A linear polyamine-bridged platinum compound having the general formula [(PtXYZ)-A-(Pt X′Y′Z′)], where X, Y, Z, X′, Y′, and Z′ may be the same or different and are
anionic groups, or neutral groups which may be substituted or unsubstituted; and A is a bridging polyamine having a general formula selected from the group consisting of
H2N(CH2)xNH2(CH2)yNH2 where x ranges from about 1 to about 10 and y ranges from about 1 to about 10, or H2N(CH2)xNBB′(CH2)yNBB′(CH2)xNH2 where x ranges from about 1 to about 10 and y ranges from about 1 to about 10; where B and B′ are hydrogen or a labile blocking group and may be the same or different, and may be the same or different at each location, and where B′ may be present or absent, and wherein said anionic groups or neutral groups are arranged in a 1,1/c,c configuration with respect to said bridging polyamine.
- 38. The compound of claim 37 wherein said anionic groups are selected from the group consisting of halide, pseudohalide, substituted pseudohalide, sulphate, phosphate, phosphonate, nitrate, carboxylate, substituted carboxylate, dicarboxylate, and substituted dicarboxylate.
- 39. The compound of claim 37 wherein said neutral groups are selected from the group consisting of ammonia, primary or secondary amines, a “dangling” diamine H2N(CH2)nNBB′ where only the —NH2 moiety is bound to platinum, sulfoxide, phosphine, pyridine, substituted pyridine, quinoline, imidazole, thiazole, pyrimidine, purine, acridine, pyrazole, benzimidazole, and benzothiazole; and for 1,1/c,c configurations, Y and Z or Y′ and Z′ or both Y and Z and Y′ and Z′ may be a chelating bidentate diamine.
- 40. The compound of claim 37 wherein said bridging polyamine portion of said compound is H2N(CH2)xNBB′(CH2)yNH2 and x ranges from about 1 to about 10 and y ranges from about 1 to about 10.
- 41. The compound of claim 40 wherein the values of x and y are selected from the group consisting of: x=4 and y=3, x=6 and y=6; and x=7 and y=8.
- 42. The compound of claim 41 wherein
Y=Y′ and is chloride; and X=X′ and Z=Z′ and are ammonia.
- 43. The compound of claim 41 wherein
X=X′ and is chloride; and Y=Y′ and Z=Z′ and are ammonia.
- 44. The compound of claim 37 wherein said bridging polyamine portion of said compound is H2N(CH2)xNBB′(CH2)yNBB′(CH2)xNH2 and x ranges from about 1 to about 10 and y ranges from about 1 to about 10.
- 45. The compound of claim 44 wherein the values of x and y are selected from the group consisting of: x=4 and y=3; x=6 and y=2; and x=5 and y=4.
- 46. The compound of claim 45 wherein
Y=Y′ and is chloride; and X=X′ and Z=Z′ and are ammonia.
- 47. The compound of claim 37 wherein said labile blocking group is selected from the group consisting of carbamate protection groups and amide protection groups.
- 48. The compound of claim 47 wherein said carbamate protection groups are selected from the group consisting of t-butyl (tBOC), benzyl (CBz), fluorenylmethyl (Fmoc), adamantyl (1-Adoc), piperidinyl (Pipoc), allyl, and vinyl.
- 49. The compound of claim 47 wherein said amide protection groups are selected from the group consisting of 2-(benzoyloxymethyl)benzoyl (BOMB), acetyl, trifluoroacetyl, and monochloroacetyl.
- 50. The compound of claim 37 wherein said blocking group further comprises a targeting element.
- 51. A method of producing a linear platinum compound with a polyamine bridge in which amine groups of said polyamine bridge are blocked with an amide blocking group, comprising the steps of
substituting anionic leaving groups of said linear platinum compound with acetate to form an acetate derivative of said linear platinum compound; blocking amine groups of said polyamine bridge by reacting said acetate derivative of said linear platinum compound with an acid anhydride of said amide blocking group under anhydrous conditions to form a blocked amide derivative of said linear platinum compound; and forming a blocked anionic derivative of said linear platinum compound by exposing said blocked acetate derivative of said linear platinum compound to anions under conditions which result in the replacement of said acetate by said anions.
- 52. A method of producing a linear platinum compound with a polyamine bridge in which amine groups of said polyamine bridge are blocked with a carbamate blocking group, comprising the step of
reacting said linear platinum compound with a carbamate precursor in an alkaline dioxane/water system under conditions in which a blocked carbamate derivative of said linear platinum compound is formed.
- 53. A method for providing a linear polyamine-bridged platinum compound at a location of interest, comprising the steps of
positioning a blocked linear polyamine-bridged platinum compound formed by attaching a labile blocking group to at least one central amine function of a bridging polyamine portion of said compound at said location of interest, and exposing said blocked linear polyamine-bridged platinum compound to an environmental stimulus which causes removal of said labile blocking group.
- 54. The method of claim 53 wherein said blocked linear polyamine-bridged platinum compound has the general formula [(PtXYZ)-A-(Pt X′Y′Z′)], where X, Y, Z, X′, Y′, and Z′ may be the same or different and are
anionic groups, or neutral groups which may be substituted or unsubstituted; and A is a bridging polyamine having a general formula selected from the group consisting of
H2N(CH2)xNBB′(CH2)yNH2 where x ranges from about 1 to about 10 and y ranges from about 1 to about 10, or H2N(CH2)xNBB′(CH2)yNBB′(CH2)xNH2 where x ranges from about 1 to about 10 and y ranges from about 1 to about 10, where B and B′ are hydrogen or a labile blocking group and may be the same or different, and may be the same of different at each location within the compound, and where B′ may be present or absent, and wherein at least one central amine of said bridging polyamine portion is blocked with a labile blocking group.
- 55. The method of claim 54 wherein said anionic groups are selected from the group consisting of halide, pseudohalide, substituted pseudohalide, sulphate, phosphate, phosphonate, nitrate, carboxylate, substituted carboxylate, dicarboxylate, and substituted dicarboxylate.
- 56. The method of claim 54 wherein said neutral groups are selected from the group consisting of ammonia, primary or secondary amines, a “dangling” diamine H2N(CH2)nNBB′ where only the —NH2 moiety is bound to platinum, sulfoxide, phosphine, pyridine, substituted pyridine, quinoline, imidazole, thiazole, pyrimidine, purine, acridine, pyrazole, benzimidazole, and benzothiazole; and for 1,1/c,c configurations, Y and Z or Y′ and Z′ or both Y and Z and Y′ and Z′ may be a chelating bidentate diamine.
- 57. The method of claim 55 wherein said bridging polyamine portion of said compound is H2N(CH2)xNBB′(CH2)yNH2 and x ranges from about 1 to about 10 and y ranges from about 1 to about 10.
- 58. The method of claim 57 wherein the values of x and y are selected from the group consisting of: x=4 and y=3, x=6 and y=6; and x=7 and y=8.
- 59. The method of claim 58 wherein
Y=Y′ and is chloride; and X=X′ and Z=Z′ and are ammonia.
- 60. The method of claim 58 wherein
X=X′ and is chloride; and Y=Y′ and Z=Z′ and are ammonia.
- 61. The method of claim 54 wherein said bridging polyamine portion of said compound is H2N(CH2)xNBB′(CH2)yNBB′(CH2)xNH2 and x ranges from about 1 to about 10 and y ranges from about 1 to about 10.
- 62. The method of claim 61 wherein the values of x and y are selected from the group consisting of: x=4 and y=3; x=6 and y=2; and x=5 and y=4.
- 63. The method of claim 62 wherein
Y=Y′ and is chloride; and X=X′ and Z=Z′ and are ammonia.
- 64. The method of claim 54 wherein said labile blocking group is selected from the group consisting of carbamate protection groups and amide protection groups.
- 65. The method of claim 64 wherein said carbamate protection groups are selected from the group consisting of t-butyl (tBOC), benzyl (CBz), fluorenylmethyl (Fmoc), adamantyl (1-Adoc), piperidinyl (Pipoc), allyl, and vinyl.
- 66. The method of claim 64 wherein said amide protection groups are selected from the group consisting of 2-(benzoyloxymethyl)benzoyl (BOMB), acetyl, trifluoroacetyl, and monochloroacetyl.
- 67. The method of claim 53 wherein said blocking group further comprises a targeting element.
- 68. The method of claim 53 wherein said environmental stimulus is selected from the group consisting of pH and an enzyme.
- 69. The compound of claim 3 where either Y and Z or Y′ and Z′ or both Y and Z and Y′ and Z′ are a chelating bidentate diamine.
- 70. The method of claim 20 where in the linear polyamine-bridged platinum compound either Y and Z or Y′ and Z′ or both Y and Z and Y′ and Z′ are a chelating bidentate diamine.
- 71. The compound of claim 39 where either Y and Z or Y′ and Z′ or both Y and Z and Y′ and Z′ are a chelating bidentate diamine.
- 72. The method of claim 58 where in the linear polyamine-bridged platinum compound either Y and Z or Y′ and Z′ or both Y and Z and Y′ and Z′ are a chelating bidentate diamine.
Government Interests
[0001] This invention was made in part using funds from grants from the National Institutes of Health having grant number RO1-CA78754. The government may have certain rights in this invention.
Provisional Applications (1)
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Number |
Date |
Country |
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60313818 |
Aug 2001 |
US |