Ruthenium-based photolinkers and methods of use
The present invention provides ruthenium-based photolinker compounds, caged molecules comprising the ruthenium-based photolinker compounds, and methods of use. In certain aspects, the compositions disclosed herein comprise an active domain conjugated to a ruthenium-based photolinker, such that irradiation of the photolinker exposes the active domain.
1. A composition comprising at least one ruthenium-based photolinker compound of formula (II):
wherein in formula (II):
L 1 , L 2 , L 3 , and L 4 are each independently a ligand; and
X 1 and X 2 are each independently a monodentate photolabile ligand having a reactive moiety,
wherein the reactive moiety is selected from the group consisting of an alkyne group, azide group, alkyl bromide group, aryl bromide group, a maleimide group, and a carbonyl group.
2. The composition of claim 1 , wherein X 1 and X 2 are each independently selected from the group consisting of 3-ethynylpyridine, 3-(bromomethyl)pyridine, maleimide, nicotinaldehyde, 1-(4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethanone, 4-pentynenitrile, and 4-aminobutyne.
3. The composition of claim 1 , wherein L 1 and L 2 are joined to form a first bidentate ligand and L 3 and L 4 are joined to form a second bidentate ligand, further wherein the first bidentate ligand and the second bidentate ligand are selected from the group consisting of 2,2′-bipyridyl (bpy) and biquinoline.
4. The composition of claim 1 , wherein L 1 , L 2 , and L 3 are joined to form a tridentate ligand, further wherein the tridentate ligand is 2,2′:6′,2″-terpyridine.
5. The composition of claim 4 , wherein L 4 is a fluorophore.
6. The composition of claim 1 , wherein the compound of formula (II) is selected from the group consisting of [Ru(bipyridine) 2 (3-ethynyl-pyridine) 2 ] 2+ , Ru(bipyridine) 2 (3-ethynylpyridine) 2 Cl 2 , Ru(bipyridine) 2 (3-ethynylpyridine) 2 (PF 6 ) 2 , [Ru(biquinoline) 2 (4-pentynenitrile) 2 ] 2+ , Ru(biquinoline) 2 (4-pentynenitrile) 2 Cl 2 , Ru(biquinoline) 2 (4-pentynenitrile) 2 (PF 6 ) 2 , [Ru(bipyridine) 2 (4-aminobutyne) 2 ] 2+ , [Ru(bipyridine) 2 (4-pentynenitrile) 2 ] 2+ , [Ru(bipyridine) 2 (nicotinaldehyde) 2 ] 2+ , [Ru(bipyridine) 2 (1-(4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethanone) 2 ] 2+ , [Ru(bipyridine) 2 (3-(bromomethyl)pyridine) 2 ] 2+ , [Ru(bipyridine) 2 (maleimide) 2 ] 2+ , a salt thereof, and any combinations thereof.
7. The composition of claim 1 , wherein the compound of formula (II) is a compound of formula (III):
wherein in formula (III):
X 1 and X 2 are each independently a monodentate photolabile ligand having a reactive moiety,
wherein the reactive moiety is selected from the group consisting of an alkyne group, azide group, alkyl bromide group, aryl bromide group, a maleimide group, and a carbonyl group.
8. A composition comprising at least one ruthenium-based photolinker compound of formula (II):
wherein in formula (II):
L 1 , L 2 , L 3 , and L 4 are each independently a ligand; and
X 1 and X 2 are each independently a monodentate photolabile ligand having a reactive moiety;
wherein the reactive moiety is selected from the group consisting of an alkyne group, azide group, alkyl bromide group, aryl bromide group, a maleimide group, and a carbonyl group; and
wherein the composition comprises a caged molecule, wherein the caged molecule comprises at least one active domain conjugated to the at least one ruthenium-based photolinker compound.
9. The composition of claim 8 , wherein the active domain is at least one selected from the group consisting of a peptide, protein, antibody, oligonucleotide, polynucleotide, morpholino, antisense polynucleotide, probe, oligosaccharide, polysaccharide, and a small molecule.
10. The composition of claim 8 , wherein the composition comprises a circular caged molecule comprising the at least one ruthenium-based photolinker compound and the active domain, wherein a first end of the active domain is conjugated to a first photolabile ligand of the compound and wherein a second end of the active domain is conjugated elsewhere on the compound.
11. The composition of claim 10 , wherein the second end of the active domain is conjugated to a second photolabile ligand of the compound.
12. The composition of claim 9 , wherein the active domain is an oligonucleotide comprising a nucleic acid sequence that is substantially complementary to a target molecule.
13. The composition of claim 12 , wherein the oligonucleotide comprises at least one intramolecular base pair.
14. The composition of claim 9 , wherein the active domain is a morpholino comprising a nucleobase sequence substantially complementary to a target nucleic acid.
15. The composition of claim 8 , wherein the caged molecule further comprises a cell penetrating domain.
16. The composition of claim 8 , wherein the caged molecule further comprises a label.
17. A method of manipulating the expression of a gene in a cell comprising administering to the cell a composition comprising a caged molecule comprising an active domain conjugated to the at least one ruthenium-based photolinker compound of formula (II)
wherein in formula (II):
L 1 , L 2 , L 3 , and L 4 are each independently a ligand; and
X 1 and X 2 are each independently a photolabile ligand having a reactive moiety;
wherein the reactive moiety is selected from the group consisting of an alkyne group, azide group, alkyl bromide group, aryl bromide group, a maleimide group, and a carbonyl group;
wherein the active domain manipulates the expression of the gene.
18. The method of claim 17 , wherein the method further comprises irradiating the cell thereby cleaving the ruthenium-based photolinker compound and exposing the active domain.
19. The method of claim 17 , wherein the active domain is at least one selected from the group consisting of a peptide, protein, antibody, oligonucleotide, polynucleotide, morpholino, antisense polynucleotide, probe, oligosaccharide, polysaccharide, and a small molecule.
20. The method of claim 18 , wherein the active domain is an oligonucleotide comprising a nucleic acid sequence that is substantially complementary to a target molecule.
21. The method of claim 19 , wherein the oligonucleotide comprises at least one intramolecular base pair.
22. The method of claim 18 , wherein the active domain is a morpholino comprising a nucleobase sequence substantially complementary to a target nucleic acid.
23. The composition of claim 1 , wherein the X 1 reactive moiety binds to a first end of an active domain and the X 2 reactive moiety binds to a second end of the active domain to form a circular caged molecule.
24. The method of claim 17 , wherein X 1 and X 2 are each independently selected from the group consisting of 3-ethynylpyridine, 3-(bromomethyl)pyridine, maleimide, nicotinaldehyde, 1-(4-(pyridin-3-yl)-1H-1,2,3-triazol-1-yl)ethanone, 4-pentynenitrile, and 4-aminobutyne.