Targeted bisplatinum polyamines as pro-drugs: selective release of platinum
AssigneeVirginia Commonwealth University
InventorsNicholas Farrell, Alexander Hegmans, John D. Roberts
Life of this patent
Estimating the term…
Abstract
Pro-drug forms of linear polyamine-bridged platinum compounds and methods for their production and use are provided. The polyamine-bridge portion of the compounds is based on spermine or spermidine, and the central amines of the polyamine-bridge are chemically bonded to labile blocking groups. The presence of the blocking groups serves to minimize the toxicity of the Pt compounds upon administration. Selective removal of the blocking groups and release of the active, unblocked species occurs upon exposure to suitable environmental conditions.
Claims72
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.
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.
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.
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.
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.
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.
Dependencies are inferred from the claim text.