Metalloinsertor complexes targeted to DNA mismatches

1. A composition comprising a complex represented by Formula I:

M m+ (L 1 )(L 2 )(L 3 )(L 4 )(L 5 )  Formula I

wherein M is rhodium or ruthenium;

m is 2 or 3;

L 1 is benzo[a]phenazine-5,6-diimine or chrysene-5,6-diimine;

wherein:

L 2 and L 3 are adjacent each other, and either L 2 and L 3 are both NH 3 , or L 2 and L 3 combine to form a first single ligand with two coordination sites to M,

L 4 and L 5 are adjacent each other, and either L 4 and L 5 are both NH 3 , or L 4 and L 5 combine to form a second single ligand with two coordination sites to M, and

each of the first and second single ligands is independently selected from the group consisting of:

wherein, in Formula II and Formula III, R 1 is selected from the group consisting of:

alkyl groups terminating in one selected from the group consisting of CH 3 , OH, SH, NH 2 , COOH, N 3 , and alkynyl-linked peptide moieties, and

PEGylated groups terminating in one selected from the group consisting of CH 3 , OH, SH, NH 2 , COOH, N 3 , and alkynyl-linked peptide moieties,

wherein:

when L 2 , L 3 , L 4 , and L 5 are each NH 3 , L 1 is phzi and/or M is ruthenium,

when M is rhodium and the first single ligand is bpy or HDAP, L 4 and L 5 are both NH 3 ,

when the first single ligand and the second single ligand are both the same and are bpy, phen, or HDAP, L 1 is phzi and/or M is ruthenium, or

when M is rhodium and the first single ligand is phen, L 4 and L 5 combine to form the second single ligand, and the second single ligand is selected from the group consisting of bpy, DPE, HDPA, DPK, 2-(pyridin-2-ylmethyl)pyridine, Formula II, and Formula III.

2. The composition of claim 1 , wherein the first single ligand and/or the second single ligand is represented by Formula II(a):

wherein R 2 is selected from the group consisting of CH 3 , OH, SH, NH 2 , COOH, N 3 , and alkynyl-linked peptide moieties; and n is any number from 1 to 10.

3. The composition of claim 1 , wherein the first single ligand and/or the second single ligand is represented by Formula II(b):

wherein X is O or NH; R 3 is selected from the group consisting of CH 3 , OH, SH, NH 2 , COOH, N 3 , and alkynyl-linked peptide moieties; and n is any number from 1 to 10.

4. The composition of claim 1 , wherein the first single ligand and/or the second single ligand is a ligand selected from the group consisting of DPE, HDPA, N-methyl-(pyridin-2-yl)pyridin-2-amine (MeDPA), N-ethyl-N-(pyridin-2-yl)(pyridin-2-amine) (EtDPA), phen, N-propyl-N-(pyridin-2-yl)pyridin-2-amine (PrDPA), N-hexyl-N-(pyridin-2-yl)pyridin-2-amine (HexDPA), and 2-(di(pyridin-2-yl)amino)ethanol (DPAE).

5. The composition of claim 1 , wherein L 4 and L 5 combine to form the second single ligand having two coordination sites to M, and each of the first and second single ligands having two coordination sites to M is independently selected from the group consisting of DPE, HDPA, MeDPA, EtDPA, phen, PrDPA, HexDPA, and DPAE.

6. The composition of claim 1 , wherein M is rhodium.

7. The composition of claim 1 , wherein the first single ligand and/or the second single ligand is represented by Formula II in which R 1 is selected from the group consisting of:

alkyl groups terminating in an alkynyl-linked peptide moiety having an antibody or a carbohydrate, and

PEGylated groups terminating in an alkynyl-linked peptide moiety having an antibody or a carbohydrate.

8. The composition of claim 1 wherein L 4 and L 5 are both NH 3 .

9. The composition of claim 1 , wherein L 4 and L 5 combine to form the second single ligand having two coordination sites to M, and the second single ligand having two coordination sites to M is selected from the group consisting of DPE, HDPA, MeDPA, EtDPA, phen, PrDPA, HexDPA, and DPAE.

10. The composition of claim 1 , wherein all of L 2 through L 5 are NH 3 .

11. The composition of claim 1 , wherein the complex represented by Formula I is a complex selected from the group consisting of M m+ (L 1 )(DPE)(NH 3 ) 2 , M m+ (L 1 )(NH 3 ) 4 , M m+ (L 1 )(HDPA) 2 , M m+ (L 1 )(MeDPA) 2 , M m+ (L 1 )(MDPA) 2 (phen), M m+ (L 1 )(PrDPA) 2 (phen), M m+ (L 1 )(HexDPA) 2 (phen), M m+ (L 1 )(PrDPA) 2 , M m+ (L 1 )(DPAE) 2 , M m+ (L 1 )(HDPA)(phen), and M m+ (L 1 )(DPE)(phen).

12. The composition of claim 1 , wherein the complex represented by Formula I is a complex selected from the group consisting of M m+ (DPK)(NH 3 ) 2 (chrysi), M m+ (DPE)(NH 3 ) 2 (chrysi), M m+ (NH 3 ) 4 (phzi), M m+ (HDPA) 2 (phzi), M m+ (MeDPA) 2 (phzi), M m+ (MeDPA) 2 (chrysi), M m+ (MeDPA)(phen)(chrysi), M m+ (EtDPA)(phen)(chrysi), M m+ (PrDPA)(phen)(chrysi), M m+ (HexDPA)(phen)(chrysi), M m+ (PrDPA) 2 (chrysi), M m+ (DPAE) 2 (chrysi), M m+ (HDPA)(phen)(chrysi), and M m+ (DPE)(phen)(chrysi).

13. The composition of claim 1 , wherein the complex represented by Formula I is a complex selected from the group consisting of Rh 3+ (DPK)(NH 3 ) 2 (chrysi), Rh 2+ (DPE)(NH 3 ) 2 (chrysi), Rh 3+ (NH 3 ) 4 (phzi), Rh 3+ (HDPA) 2 (phzi), Rh 3+ (MeDPA) 2 (phzi), Rh 3+ (MeDPA) 2 (chrysi), Rh 3+ (MeDPA)(phen)(chrysi), Rh 3+ (EtDPA)(phen)(chrysi), Rh 3+ (PrDPA)(phen)(chrysi), Rh 3+ (HexDPA)(phen)(chrysi), Rh 3+ (PrDPA) 2 (chrysi), Rh 3+ (DPAE) 2 (chrysi), Rh 3+ (HDPA)(phen)(chrysi), and Rh 2+ (DPE)(phen)(chrysi).

14. A method of selectively inducing cytotoxicity in mismatch repair (MMR)-deficient cells, comprising:

providing the composition of claim 1 to the MMR-deficient cells.

15. The method of claim 14 , wherein providing the composition of claim 1 comprises providing the composition in vitro.

16. The method of claim 14 , wherein providing the composition of claim 1 comprises providing the composition in vivo.

17. A method of selectively decreasing cell proliferation, comprising:

providing the composition of claim 1 to MMR-deficient cells.

18. A pharmaceutical composition, comprising:

an effective amount of the composition of claim 1 ; and

a pharmaceutically acceptable carrier.