Metalloinsertor complexes targeted to DNA mismatches
A composition including a Rh or Ru metalloinsertor complex specifically targets mismatch repair (MMR)-deficient cells. Selective cytotoxicity is induced in MMR-deficient cells upon uptake of the inventive metalloinsertor complexes.
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 IV, R 1 and R 2 are each independently 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 and L 3 are both NH 3 , neither of L 4 or L 5 is NH 3 and the second single ligand is not phen, and when L 4 and L 5 are both NH 3 , neither of L 2 or L 3 is NH 3 and the first single ligand is not phen, and
wherein the first single ligand and the second single ligand are different.
2. 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 phen, PPE and PyPrOH.
3. The composition of claim 1 , wherein M is rhodium.
4. The composition of claim 1 , wherein L 2 and L 3 are both NH 3 .
5. The composition of claim 4 , wherein the second single ligand is PPE or PyPrOH.
6. The composition of claim 1 , wherein the complex represented by Formula I comprises a complex selected from the group consisting of M m+ (L 1 )(phen)(PPE) and M m+ (L 1 )(phen)(PyPrO).
7. The composition of claim 1 , wherein the complex represented by Formula I comprises a complex selected from the group consisting of M m+ (chrysi)(phen)(PPE) and M m+ (chrysi)(phen)(PyPrO).
8. The composition of claim 1 , wherein the complex represented by Formula I comprises a complex selected from the group consisting of Rh 3+ (chrysi)(phen)(PPE) and Rh 3+ (chrysi)(phen)(PyPrO).
9. A method of selectively inducing cytotoxicity in mismatch repair (MMR)-deficient cells, comprising:
providing the composition of claim 1 to the MMR-deficient cells.
10. The method of claim 9 , wherein providing the composition of claim 1 comprises providing the composition in vitro.
11. The method of claim 9 , wherein providing the composition of claim 1 comprises providing the composition in vivo.
12. A method of selectively decreasing cell proliferation, comprising:
providing the composition of claim 1 to MMR-deficient cells.
13. A pharmaceutical composition, comprising:
an effective amount of the composition of claim 1 ; and
a pharmaceutically acceptable carrier.
14. 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;
in is 2 or 3;
L 1 is benzo[a]phenazine-5,6-diimine or chrysene-5,6-diimine;
wherein:
L 2 and L 3 combine to form a first single ligand with two coordination sites to M,
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 IV, R 1 and R 2 are each independently 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, and
wherein the first single ligand and the second single ligand are different.