Negatively charged minor groove binders

1. A negatively charged minor groove binding compound comprising a binding moiety that binds preferentially into a minor groove of a double stranded oligonucleotide, wherein said binding moiety comprises:

at least one aryl moiety, and

a plurality of acidic moieties capable of ionizing under physiological conditions, wherein each acidic moiety is covalently attached to a phenyl moiety of said at least one aryl moiety or a heteroatom of a heteroaryl portion of said at least one aryl moiety, wherein said acidic moiety optionally comprises an acidic moiety linker.

2. The negatively charged minor groove binding compound according to claim 1 , wherein said aryl moiety is selected from the group consisting of phenyl, a heteroaryl, a fused phenyl-heteroaryl, a fused heteroaryl-phenyl-heterocyclyl and a combination thereof.

3. The negatively charged minor groove binding compound according to claim 1 , wherein said acid moiety has pKa of about 6 or less.

4. The negatively charged minor groove binding compound according to claim 1 , wherein said binding moiety comprises a plurality of aryl moieties.

5. The negatively charged minor groove binding compound according to claim 4 , wherein said binding moiety comprises at least three aryl moieties.

6. The negatively charged minor groove binding compound according to claim 4 , wherein each of said aryl moiety is independently selected from the group consisting of indole, benzofuran, pyrroloindole, hydropyrroloindole, phenyl, pyrrole, benzimidazole, imidazole, pyridine, 6-phenylimidazo[4,5-b]pyridine, furan, thiazole and oxazole.

7. The negatively charged minor groove binding compound according to claim 6 of the formula:

wherein

n is an integer from 2 to 10;

R 3 is selected from the group consisting of:

(a) alkoxy,

(b) aryloxy,

(c) R a —O-L 3 -NR b —, where R a is hydrogen or a hydroxyl protecting group; R b is hydrogen, alkyl, cycloalkyl or a nitrogen protecting group, and L 3 is a linker comprising a chain of from 3 to 20 atoms selected from the group consisting of C, N, O, S, P and combinations thereof, and

(d) a moiety of the formula:

each R 4 is independently hydrogen, alkyl or said acidic moiety, optionally comprising said acidic moiety linker;

each X 3 is independently selected from the group consisting of:

(a) hydrogen,

(b) alkyl,

(c) alkoxy,

(d) halide,

(e) cyano,

(f) nitro,

(g) —NR b1 —C(═O)—R e , where R b1 is hydrogen, alkyl, cycloalkyl or a nitrogen protecting group and R e is hydrogen, alkyl or cycloalkyl, and

(h) said acidic moiety, optionally comprising said acidic moiety linker;

each R 5 is independently selected from the group consisting of

(a) hydrogen,

(b) alkyl,

(c) alkoxy,

(d) cycloalkyl,

(e) halide,

(d) cyano,

(g) nitro,

(h) —[X 4 ] m1 —C(═O)—[O] m2 —R 8 , where each m1 and m2 is independently 0 or 1, X 4 is O or NR b1 , where R b1 is hydrogen, alkyl, cycloalkyl or a nitrogen protecting group, and R 8 is hydrogen, alkyl or cycloalkyl, provided when m2 is 1, R 8 is alkyl or cycloalkyl,

(i) —C(═O)—NR e R f , where each of R e and R f is independently hydrogen, alkyl, cycloalkyl or a nitrogen protecting group, and

(j) said acidic moiety, optionally comprising said acidic moiety linker;

each of R 6 and R 7 is independently selected from the group consisting of:

(a) hydrogen,

(b) alkyl,

(c) cycloalkyl,

(d) -L x Z x , where L x is a linker comprising from 3 to 20 atoms selected from the group consisting of C, N, O, S, P and combinations thereof, and Z x is selected from the group consisting of hydrogen, a protecting group and a solid support,

(e) a moiety of the formula —(Z 1 ) j —C(═O)—(R 10 ) k —[C(═O)] l —R 11 ,

where

each of j, k and l is independently 0 or 1;

each Z 1 is independently selected from the group consisting of O, NR 12 and alkylene;

each R 10 is independently selected from the group consisting of alkylene and cycloalkylene;

each R 11 is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —NR 13 R 14 , —NR 15 —NR 16 R 17 , hydroxyalkyl and thioalkyl; and

each of R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and a nitrogen protecting group; and

(f) said acidic moiety, optionally comprising said acidic moiety linker;

provided at least one of X 3 , R 4 , R 6 and R 7 is said acidic moiety optionally comprising said acidic moiety linker.

8. The negatively charged minor groove binding compound according to claim 7 , wherein n is 2 to 8.

9. The negatively charged minor groove binding compound according to claim 6 of the formula:

wherein

W 1 is N or CR x30 , where R x30 is hydrogen, alkyl, or hydroxy;

W 2 is NR 19 , S or O;

p is an integer from 2 to 12;

each R 19 is independently selected from the group consisting of:

(a) hydrogen,

(b) alkyl,

(c) a nitrogen protecting group, and

(d) said acidic moiety optionally comprising an acidic moiety linker;

each of R 18 and R 20 is independently selected from the group consisting of:

(a) hydrogen,

(b) alkyl,

(c) cycloalkyl,

(d) said acidic moiety; and

(e) —(Z 1 ) j —C(═O)—(R 10 ) k —[C(═O)] l —R 11 ,

where

each of j, k and l is independently 0 or 1;

each Z 1 is independently selected from the group consisting of O, NR 12 and alkylene;

each R 10 is independently selected from the group consisting of alkylene and cycloalkylene;

each R 11 is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —NR 13 R 14 , —NR 15 —NR 16 R 17 , hydroxyalkyl and thioalkyl; and

each R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and a nitrogen protecting group;

provided at least one of R 18 , R 19 , or R 20 is said acidic moiety, optionally comprising said acidic moiety linker.

10. The negatively charged minor groove binding compound according to claim 9 of the formula:

wherein

p, R 18 , R 19 and R 20 are those defined in claim 9 .

11. The negatively charged minor groove binding compound according to claim 6 of the formula:

wherein

R 21 is an optionally substituted aryl-heterocyclyl;

each of R 22 and R 24 is independently selected from the group consisting of hydrogen, alkyl, and a nitrogen protecting group;

Ar 1 is optionally substituted aryl moiety; and

R 23 is selected from the group consisting of hydrogen and said acidic moiety, optionally comprising said acidic moiety linker;

provided when R 23 is hydrogen at least one of Ar 1 or R 21 is substituted with said acidic moiety, optionally comprising said acidic moiety linker.

12. The negatively charged minor groove binding compound according to claim 11 , wherein R 22 and R 24 are hydrogen.

13. The negatively charged minor groove binding compound according to claim 12 , wherein R 21 is of the formula:

wherein

R 26 is selected from the group consisting of hydrogen, alkyl, and a nitrogen protecting group;

R 27 is selected from the group consisting of:

(a) hydrogen,

(b) alkyl,

(c) cycloalkyl,

(d) said acidic moiety, optionally comprising said acidic moiety linker,

(e) —(Z 1 ) j —C(═O)—(R 10 ) k —[C(═O)] l —R 11 ,

where

each of j, k and l is independently 0 or 1;

each Z 1 is independently selected from the group consisting of O, NR 12 and alkylene;

each R 10 is independently selected from the group consisting of alkylene and cycloalkylene;

each R 11 is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —NR 13 R 14 , —NR 15 —NR 16 R 17 , hydroxyalkyl and thioalkyl; and

each R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl and a nitrogen protecting group; and

(f) -L x Z x , where L x is a linker comprising from 3 to 20 atoms selected from the group consisting of C, N, O, S, P and combinations thereof, and Z x is selected from the group consisting of hydrogen, a protecting group and a solid support,

R 28 is selected from the group consisting of hydrogen and said acidic moiety optionally comprising said acidic moiety linker.

14. The negatively charged minor groove binding compound according to claim 12 , wherein Ar 1 is selected from the group consisting of:

wherein

each of R 29 , R 30 and R 32 is independently selected from the group consisting of hydrogen and said acidic moiety, optionally comprising said acidic moiety linker;

R 34 is selected from the group consisting of:

(a) hydrogen,

(b) alkyl,

(c) cycloalkyl,

(d) said acidic moiety, optionally comprising said acidic moiety linker,

(e) —(Z 1 ) j —C(═O)—(R 10 ) k —[C(═O)] l —R 11 ,

where

each of j, k and l is independently 0 or 1;

each Z 1 is independently selected from the group consisting of O, NR 12 and alkylene;

each R 10 is independently selected from the group consisting of alkylene and cycloalkylene;

each R 11 is independently selected from the group consisting of alkyl, alkoxy, aryloxy, —NR 13 R 14 , —NR 15 —NR 16 R 17 , hydroxyalkyl and thioalkyl; and

each of R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 is independently selected from the group consisting of hydrogen, alkyl, cylcoalkyl, and a nitrogen protecting group; and

(f) -L x Z x , where L x is a linker comprising from 3 to 20 atoms selected from the group consisting of C, N, O, S, P and combinations thereof, and Z x is selected from the group consisting of hydrogen, a protecting group or a solid support;

each of R 31 and R 33 is independently selected from the group consisting of hydrogen, alkyl, a nitrogen protecting group and said acidic moiety optionally comprising an acidic moiety linker;

each of R 40 , R 43 and R 44 is independently selected from the group consisting of hydrogen, alkyl, and a moiety of the formula -L x Z x , —(Z 1 ) j —C(═O)—(R 10 ) k —[C(═O)] l —R 11 ;

each of R 41 and R 42 is independently selected from the group consisting of hydrogen, alkyl, and said acidic moiety which optionally comprises said acidic moiety linker; and

R 45 is selected from the group consisting of hydrogen, alkyl, alkoxy, cycloalkyl, halide, cyano, nitro, and a moiety of the formula —[X 4 ] m1 —C(═O)—[O] m2 —R 8 , wherein each of m1 and m2 is independently 0 or 1, X 4 is O or NR b1 , where R b1 is hydrogen, alkyl, cycloalkyl or a nitrogen protecting group, and R 8 is hydrogen, alkyl or cycloalkyl, provided when m2 is 1, R 8 is alkyl or cycloalkyl.

15. The negatively charged minor groove binding compound according to claim 1 comprising at least three of said acidic moieties.

16. The negatively charged minor groove binding compound according to claim 1 , wherein each of said acidic moiety is independently selected from the group consisting of:

(i) —(O) d S(O) e OH, wherein d is 0 or 1 and e is 1 or 2, and

(ii) —(O) f P(O) g (OR a1 ) h (OH) i , wherein each R a1 is independently selected from the group consisting of alkyl, aralkyl and aryl; f is 0 or 1; each of g and h is independently 0, 1, or 2, and i is 1, 2 or 3, provided the sum of g+h+i is 2 or 3;

(iii) —CO 2 H; and

(iv) salts thereof.

17. The negatively charged minor groove binding compound according to claim 16 further comprising said acidic moiety linker, wherein said acidic moiety linker comprises from 1 to about 20 atoms selected from the group consisting of C, N, O, S, P and combinations thereof.

18. The negatively charged minor groove binding compound according to claim 17 , wherein the combination of said acidic moiety and said acidic moiety linker is of the formula:

—(X 1 ) a —[C(═O)] b —(R 1 ) c X 2

wherein

each of a, b and c is independently 0 or 1, provided at least one of b and c is 1;

each X 1 is independently selected from the group consisting of:

(i) O,

(ii) NR 2 , where each R 2 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and a nitrogen atom protecting group, and

(iii) alkylene;

each R 1 is independently selected from the group consisting of alkylene, cycloalkylene, arylene and a combination thereof; and

X 2 is said acid moiety.

19. The negatively charged minor groove binding compound according to claim 16 , wherein X 2 is selected from the group consisting of —SO 2 OH, —OPO 2 (OH), —CO 2 H, and salts thereof.

20. The negatively charged minor groove binding compound according to claim 1 , wherein said negatively charged minor groove binding compound is covalently attached to a solid support.

21. The negatively charged minor groove binding compound according to claim 20 , wherein said negatively charged minor groove binding compound is attached to said solid support through a solid support linker.