Dna-binding polyamide drug conjugates

Abstract

A conjugate of formula: V—(Y) a -Z-T  (I), T-X—B—(Y) a -Z-T′  (II), V—(Y) a -Z-(Y′) a —V′  (III), T-X—B—(Y) a -Z-(Y′) a —X′—B′-T′  (IV), V—(Y) a -Z-(Y′) a —X—B-T  (V), V—(Y) a -Z-X—B-Z′-(Y′) a —(V′) b   (VI), or (W) a —(Y) b -[(Z) c -(Y′) d —(X—B) e —(Y″) f -(Z′) g ] h -(Y′″) i —(W′) j   (VII), in which W and W′ are independently a DNA intercalator or terminal subunit, V and V′ are independently a DNA intercalator, X and X′ are independently a DNA alkylator, B and B′ are the same or different and each is a heteroaromatic residue that is attached to the N-terminus of an alkylator subunit (X or X′), Y, Y′, Y″ and Y′″ are independently a linker, T and T′ are independently terminal subunits, Z and Z′ are independently a polyamide group that binds to the minor groove of DNA, a, b, c, d, f, g, i, and j are independently 0 to 5, and e and h are independently 1 to 5, a composition comprising a conjugate of any of formulae (I)-(VII) and a carrier, and a method for treating cancer in a mammal comprising administering an effective amount of a conjugate of any of formulae (I)-(VII) or a composition comprising same.

1 . A conjugate of formula:
   V—(Y) a -Z-T  (I)     or     T-X—B—(Y) a -Z-T′  (II),   
     wherein V is a DNA intercalator, X is a DNA alkylator, B is a heteroaromatic residue that is attached to the N-terminus of the alkylator subunit (X), Y is a linker, T and T′ are the same or different and each is a terminal subunit, and Z is a polyamide group that binds to the minor groove of DNA, and a is 0 or 1, provided that when V is naphthalimide, then Z is not lexitropsin, and further provided that when V is doxorubicin, then Z is not netropsin or distamycin. 
   
   
       2 . A conjugate of formula:
   V—(Y) a -Z-(Y′) a —V′  (III),     T-X—B—(Y) a -Z-(Y′) a —X′—B′-T′  (IV)     or     V—(Y) a -Z-(Y′) a —X—B-T  (V),   
     wherein V and V′ are the same or different and each is a DNA intercalator, X and X′ are the same or different and each is a DNA alkylator, B and B′ are the same or different and each is a heteroaromatic residue that is attached to the N-terminus of an alkylator subunit (X or X′), Y and Y′ are the same or different and each is a linker, T and T′ are the same or different and each is a terminal subunit, Z is a polyamide group that binds to the minor groove of DNA, and a is 0 or 1. 
   
   
       3 . A conjugate of formula:
   V—(Y) a -Z-X—B-Z′-(Y′) a —(V′) b   (VI),   
     wherein V and V′ are the same or different and each is a DNA intercalator, X is a DNA alkylator, B is a heteroaromatic residue that is attached to the N-terminus of the alkylator subunit (X), Y and Y′ are the same or different and each is a linker, Z and Z′ are the same or different and each is a polyamide group that binds to the minor groove of DNA, and a and b are independently 0 to 1. 
   
   
       4 . A conjugate of formula:
   (W) a —(Y) b -[(Z) c -(Y′) d —(X—B) e —(Y″) f -(Z′) g ] h -(Y′″) i —(W′) j   (VII),   
     wherein W and W′ are the same or different and each is a DNA intercalator or terminal subunit, V and V′ are the same or different and each is a DNA intercalator, X is a DNA alkylator, B is a heteroaromatic residue that is attached to the N-terminus of the alkylator subunit (X), Y and Y′ are the same or different and each is a linker, Z and Z′ are the same or different and each is a polyamide group that binds to the minor groove of DNA, a, b, c, d, f, g, i, and j are independently 0 to 5, and e and h are independently 1 to 5. 
   
   
       5 . The conjugate of  claim 1 , wherein the DNA intercalator is an anthracycline, doxorubicin, daunorubicin, imidazoacridone, 3-nitrophthalamide or 3-aminophthalamide, any of which can be substituted or unsubstituted. 
   
   
       6 . The conjugate of  claim 1 , wherein the DNA alkylator is selected from the group consisting of a rigid alkylator and flexible alkylator. 
   
   
       7 . The conjugate of  claim 6 , wherein the rigid alkylator is substituted or unsubstituted {1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole-8-carboxylic acid}. 
   
   
       8 . The conjugate of  claim 6 , wherein the flexible alkylator is substituted or unsubstituted 2-{1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indol-8-yl}acetic acid or substituted or unsubstituted 8-(aminomethyl)-1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole. 
   
   
       9 . The conjugate of  claim 1 , wherein the polyamide group that binds to the minor groove of DNA comprises a polypyrrole carboxamide, polyimidazole carboxamide, or a combination thereof, wherein any of the foregoing are optionally substituted. 
   
   
       10 . The conjugate of  claim 1 , wherein the polyamide group that binds to the minor groove of DNA comprises subunits selected from the group consisting of 4-amino-1-methylpyrrole-2-carboxylic acid, 4-amino-1-methylimidazole-2-carboxylic acid, 4-amino-1methyl-3-hydroxypyrrole-2-carboxylic acid, γ-amino-butyric acid, α,γ-diamino-butyric acid, glutamic acid, 8-amino-3,6-dioxanioic acid, β-alanine, 4-amino-benzoic acid, 3-amino-benzoic acid, 2-aminothiazole-5-carboxylic acid, 4-aminothiophene-2-carboxylic acid, 5-aminobenzthiophene-2-carboxylic acid, 5-aminobenzoxazole-2-carboxylic acid, 5-aminobenzimidazole-2-carboxylic acid and combinations thereof. 
   
   
       11 . The conjugate of  claim 1 , wherein the linker comprises N,N′-bis(aminopropyl)piperazine, N,N′-bis(aminopropyl)methylamine, 8-amino-3,6-dioxaoctanoic acid, spermidine and β-alanine. 
   
   
       12 . The conjugate of  claim 1 , wherein the conjugate is optionally terminated with a terminal subunit selected from the group consisting of N,N-dimethylglycine, guanidino acetic acid, 3-aminopropylamidine, glycinol, N,N-dimethylaminopropylamine, N-formyl, N-acetyl, N-propionyl, and N-benzoyl. 
   
   
       13 . The conjugate of  claim 1 , wherein the conjugate binds to at least 5 base pairs in DNA. 
   
   
       14 . The conjugate of  claim 13 , wherein the conjugate binds to at least 7 base pairs in DNA. 
   
   
       15 . The conjugate of  claim 14 , wherein the conjugate binds to at least 9 base pairs in DNA. 
   
   
       16 . The conjugate of  claim 15 , wherein the conjugate binds to at least 10 base pairs in DNA. 
   
   
       17 . The conjugate of  claim 1 , wherein the conjugate binds to a G-C rich DNA sequence. 
   
   
       18 . The conjugate of  claim 1 , wherein the conjugate binds to an A-T rich DNA sequence. 
   
   
       19 . The conjugate of  claim 1 , wherein the DNA alkylator is selected from the group consisting of substituted and unsubstituted: 
     
       
         
         
             
             
         
       
     
   
   
       20 . The conjugate of  claim 1 , wherein the conjugate of formula (I) is: 
     
       
         
         
             
             
         
       
     
     wherein Y is a linker; in each repeat unit, Q is independently N or CH; R 1  and R 2  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; and n and m are independently 1 to 6. 
   
   
       21 . The conjugate of  claim 1 , wherein the conjugate of formula (I) is: 
     
       
         
         
             
             
         
       
     
     wherein R 3  is —NO 2  or —NH 2 , Y is a linker; in each repeat unit, Q is independently N or CH; R 1  and R 2  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; and n and m are independently 1 to 6. 
   
   
       22 . The conjugate of  claim 21 ,  claim 1 , wherein the conjugate of formula (I) is: 
     
       
         
         
             
             
         
       
     
   
   
       23 . The conjugate of  claim 1 , wherein the conjugate of formula (I) is: 
     
       
         
         
             
             
         
       
     
     wherein in each repeat unit, Q is independently N or CH; R 1  and R 2  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; and n and m are independently 1 to 6, provided that, when Q in each repeat unit is CH, R 1  is CH 3 , and R 2  is H, then n is not 1-3. 
   
   
       24 . The conjugate of  claim 23 ,  claim 1 , wherein the conjugate of formula (I) is: 
     
       
         
         
             
             
         
       
     
   
   
       25 . The conjugate of  claim 1 , wherein the conjugate of formula (II) is: 
     
       
         
         
             
             
         
       
     
     wherein B is a heteroaromatic residue that is attached to the N-terminus of the alkylator subunit (X), T is a terminal subunit, Y is a linker; in each repeat unit, Q is independently N or CH; R 1  and R 2  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; n and m are independently 1 to 6; and o is 0 or 1. 
   
   
       26 . The conjugate of  claim 1 , wherein the conjugate of formula (II) is: 
     
       
         
         
             
             
         
       
     
   
   
       27 . The conjugate of  claim 1 , wherein the conjugate of formula (II) is: 
     
       
         
         
             
             
         
       
     
     wherein B is a heteroaromatic residue that is attached to the N-terminus of the alkylator subunit (X), T is a terminal subunit, Y is a linker; in each repeat unit, Q is independently N or CH; R 1  and R 2  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; and n and m are independently 1 to 6. 
   
   
       28 . The conjugate of  claim 2 , wherein the conjugate of formula (III) is: 
     
       
         
         
             
             
         
       
     
     wherein Y and Y′ can be the same or different and each is a linker; in each repeat unit, Q is independently N or CH; R 1  and R 2  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; and n is 1 to 6. 
   
   
       29 . The conjugate of  claim 28 , wherein the conjugate is: 
     
       
         
         
             
             
         
       
     
   
   
       30 . The conjugate of  claim 2 , wherein the conjugate of formula (IV) is: 
     
       
         
         
             
             
         
       
     
     wherein B and B′ are the same or different and each is a heteroaromatic residue that is attached to the N-terminus of an alkylator subunit (X or X′), T is a terminal subunit, Y and Y′ can be the same or different and each is a linker; in each repeat unit, Q is independently N or CH; R 1  and R 2  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; n is 1 to 6; and o and o′ are independently 0 or 1. 
   
   
       31 . The conjugate of  claim 2 , wherein the conjugate of formula (IV) is: 
     
       
         
         
             
             
         
       
     
   
   
       32 . The conjugate of  claim 2 , wherein the conjugate of formula (V) is: 
     
       
         
         
             
             
         
       
     
     wherein B is a heteroaromatic residue that is attached to the N-terminus of an alkylator subunit, T is a terminal subunit, Y and Y′ can be the same or different and each is a linker; in each repeat unit, Q is independently N or CH; R 1  and R 2  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; n is 1 to 6; and o is 0 or 1. 
   
   
       33 . The conjugate of  claim 32 , wherein the conjugate of formula (V) is: 
     
       
         
         
             
             
         
       
     
   
   
       34 . The conjugate of  claim 3 , wherein the conjugate of formula (VI) is: 
     
       
         
         
             
             
         
       
     
     wherein B is a heteroaromatic residue that is attached to the N-terminus of an alkylator subunit, Y, Y′ and Y″ can be the same or different and each is a linker; in each repeat unit, Q is independently N or CH; R 1-4  are selected from the group consisting of hydrogen, C 1 -C 12  alkyl, hydroxy, and halo; n and p independently are 1 to 6; and o is 0 or 1. 
   
   
       35 . (canceled) 
   
   
       36 . The conjugate of  claim 3 , wherein the conjugate of formula (VI) is: 
     
       
         
         
             
             
         
       
     
   
   
       37 . The conjugate of  claim 4 , wherein the conjugate of formula (VII) is: 
     
       
         
         
             
             
         
       
     
     wherein the imidazoacridone moiety can be substituted in position 8 by a C 1 -C 6  alkyl or a C 1 -C 6  alkoxy. 
   
   
       38 . A conjugate of  claim 4 , wherein the conjugate of formula (VII) is: 
     
       
         
         
             
             
         
       
     
   
   
       39 . The conjugate of  claim 4 , wherein the conjugate of formula (VII) is: 
     
       
         
         
             
             
         
       
     
   
   
       40 . The conjugate of  claim 4 , wherein the conjugate of formula (VII) is: 
     
       
         
         
             
             
         
       
     
   
   
       41 . A pharmaceutical composition comprising the conjugate of  claim 1  and a carrier. 
   
   
       42 . A method for treating cancer in a mammal comprising administering to a mammal in need thereof a cancer-treatment effective amount of the conjugate of  claim 1 , whereupon the mammal is treated for cancer. 
   
   
       43 . The conjugate of  claim 2 , wherein the DNA intercalator is an anthracycline, doxorubicin, daunorubicin, imidazoacridone, 3-nitrophthalamide or 3-aminophthalamide, any of which can be substituted or unsubstituted. 
   
   
       44 . The conjugate of  claim 2 , wherein the DNA alkylator is selected from the group consisting of a rigid alkylator and flexible alkylator. 
   
   
       45 . The conjugate of  claim 2 , wherein the polyamide group that binds to the minor groove of DNA comprises a polypyrrole carboxamide, polyimidazole carboxamide, or a combination thereof, wherein any of the foregoing are optionally substituted. 
   
   
       46 . The conjugate of  claim 2 , wherein the polyamide group that binds to the minor groove of DNA comprises subunits selected from the group consisting of 4-amino-1-methylpyrrole-2-carboxylic acid, 4-amino-1-methylimidazole-2-carboxylic acid, 4-amino-1methyl-3-hydroxypyrrole-2-carboxylic acid, γ-amino-butyric acid, α,γ-diamino-butyric acid, glutamic acid, 8-amino-3,6-dioxanioic acid, β-alanine, 4-amino-benzoic acid, 3-amino-benzoic acid, 2-aminothiazole-5-carboxylic acid, 4-aminothiophene-2-carboxylic acid, 5-aminobenzthiophene-2-carboxylic acid, 5-aminobenzoxazole-2-carboxylic acid, 5-aminobenzimidazole-2-carboxylic acid, and combinations thereof. 
   
   
       47 . The conjugate of  claim 2 , wherein the linker comprises N,N′-bis(aminopropyl)piperazine, N,N′-bis(aminopropyl)methylamine, 8-amino-3,6-dioxaoctanoic acid, spermidine and β-alanine. 
   
   
       48 . The conjugate of  claim 2 , wherein the conjugate is optionally terminated with a terminal subunit selected from the group consisting of N,N-dimethylglycine, guanidino acetic acid, 3-aminopropylamidine, glycinol, N,N-dimethylaminopropylamine, N-formyl, N-acetyl, N-propionyl, and N-benzoyl. 
   
   
       49 . The conjugate of  claim 2 , wherein the DNA alkylator is selected from the group consisting of substituted and unsubstituted: 
     
       
         
         
             
             
         
       
     
   
   
       50 . A pharmaceutical composition comprising the conjugate of  claim 2  and a carrier. 
   
   
       51 . A method for treating cancer in a mammal comprising administering to a mammal in need thereof a cancer-treatment effective amount of the conjugate of  claim 2 , whereupon the mammal is treated for cancer. 
   
   
       52 . The conjugate of  claim 3 , wherein the DNA intercalator is an anthracycline, doxorubicin, daunorubicin, imidazoacridone, 3-nitrophthalamide or 3-aminophthalamide, any of which can be substituted or unsubstituted. 
   
   
       53 . The conjugate of  claim 3 , wherein the DNA alkylator is selected from the group consisting of a rigid alkylator and flexible alkylator. 
   
   
       54 . The conjugate of  claim 3 , wherein the polyamide group that binds to the minor groove of DNA comprises a polypyrrole carboxamide, polyimidazole carboxamide, or a combination thereof, wherein any of the foregoing are optionally substituted. 
   
   
       55 . The conjugate of  claim 3 , wherein the polyamide group that binds to the minor groove of DNA comprises subunits selected from the group consisting of 4-amino-1-methylpyrrole-2-carboxylic acid, 4-amino-1-methylimidazole-2-carboxylic acid, 4-amino-1methyl-3-hydroxypyrrole-2-carboxylic acid, γ-amino-butyric acid, α,γ-diamino-butyric acid, glutamic acid, 8-amino-3,6-dioxanioic acid, β-alanine, 4-amino-benzoic acid, 3-amino-benzoic acid, 2-aminothiazole-5-carboxylic acid, 4-aminothiophene-2-carboxylic acid, 5-aminobenzthiophene-2-carboxylic acid, 5-aminobenzoxazole-2-carboxylic acid, 5-aminobenzimidazole-2-carboxylic acid, and combinations thereof. 
   
   
       56 . The conjugate of  claim 3 , wherein the linker comprises N,N′-bis(aminopropyl)piperazine, N,N′-bis(aminopropyl)methylamine, 8-amino-3,6-dioxaoctanoic acid, spermidine and β-alanine. 
   
   
       57 . The conjugate of  claim 3 , wherein the conjugate is optionally terminated with a terminal subunit selected from the group consisting of N,N-dimethylglycine, guanidino acetic acid, 3-aminopropylamidine, glycinol, N,N-dimethylaminopropylamine, N-formyl, N-acetyl, N-propionyl, and N-benzoyl. 
   
   
       58 . The conjugate of  claim 3 , wherein the DNA alkylator is selected from the group consisting of substituted and unsubstituted: 
     
       
         
         
             
             
         
       
     
   
   
       59 . A pharmaceutical composition comprising the conjugate of  claim 3  and a carrier. 
   
   
       60 . A method for treating cancer in a mammal comprising administering to a mammal in need thereof a cancer-treatment effective amount of the conjugate of  claim 3 , whereupon the mammal is treated for cancer. 
   
   
       61 . The conjugate of  claim 4 , wherein the DNA intercalator is an anthracycline, doxorubicin, daunorubicin, imidazoacridone, 3-nitrophthalamide or 3-aminophthalamide, any of which can be substituted or unsubstituted. 
   
   
       62 . The conjugate of  claim 4 , wherein the DNA alkylator is selected from the group consisting of a rigid alkylator and flexible alkylator. 
   
   
       63 . The conjugate of  claim 4 , wherein the polyamide group that binds to the minor groove of DNA comprises a polypyrrole carboxamide, polyimidazole carboxamide, or a combination thereof, wherein any of the foregoing are optionally substituted. 
   
   
       64 . The conjugate of  claim 4 , wherein the polyamide group that binds to the minor groove of DNA comprises subunits selected from the group consisting of 4-amino-1-methylpyrrole-2-carboxylic acid, 4-amino-1-methylimidazole-2-carboxylic acid, 4-amino-1methyl-3-hydroxypyrrole-2-carboxylic acid, γ-amino-butyric acid, α,γ-diamino-butyric acid, glutamic acid, 8-amino-3,6-dioxanioic acid, β-alanine, 4-amino-benzoic acid, 3-amino-benzoic acid, 2-aminothiazole-5-carboxylic acid, 4-aminothiophene-2-carboxylic acid, 5-aminobenzthiophene-2-carboxylic acid, 5-aminobenzoxazole-2-carboxylic acid, 5-aminobenzimidazole-2-carboxylic acid, and combinations thereof. 
   
   
       65 . The conjugate of  claim 4 , wherein the linker comprises N,N′-bis(aminopropyl)piperazine, N,N′-bis(aminopropyl)methylamine, 8-amino-3,6-dioxaoctanoic acid, spermidine and β-alanine. 
   
   
       66 . The conjugate of  claim 4 , wherein the conjugate is optionally terminated with a terminal subunit selected from the group consisting of N,N-dimethylglycine, guanidino acetic acid, 3-aminopropylamidine, glycinol, N,N-dimethylaminopropylamine, N-formyl, N-acetyl, N-propionyl, and N-benzoyl. 
   
   
       67 . The conjugate of  claim 4 , wherein the DNA alkylator is selected from the group consisting of substituted and unsubstituted: 
     
       
         
         
             
             
         
       
     
   
   
       68 . A pharmaceutical composition comprising the conjugate of  claim 4  and a carrier. 
   
   
       69 . A method for treating cancer in a mammal comprising administering to a mammal in need thereof a cancer-treatment effective amount of the conjugate of  claim 4 , whereupon the mammal is treated for cancer.