Macrocyclic ligands with pendant chelating moieties and complexes thereof
The invention relates to ligands and complexes of metal ions with the ligands useful in various applications, including therapeutic and diagnostic applications.
1. A compound of the structure:
wherein
A b1 and A b2 are members independently selected from:
wherein
each R 7 , and R 8 is independently selected from a bond to L 1 or L 2 , alkanediyl attached to L 1 or L 2 , H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, halogen, CN, —CF 3 , —C(O)R 17 , —SO 2 NR 17 R 18 , —NR 17 R 18 , —OR 17 , —S(O) 2 R 17 , —COOR 17 , —S(O) 2 OR 17 , —OC(O)R 17 , —C(O)NR 17 R 18 , —NR 17 C(O)R 18 , —NR 17 SO 2 R 18 , and —NO 2 ,
wherein
R 17 and R 18 are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; or
R 17 and R 18 , together with the atoms to which they are attached, are optionally joined to form a 5-, 6- or 7-membered ring;
L 1a is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted biaryl, substituted or unsubstituted heteroaryl, and a substituted or unsubstituted polycyclic ring system;
L x6 is independently selected from H, a linker to a reactive functional group, and a linker to a targeting moiety
wherein,
the linker to a reactive functional group, and the linker to a targeting moiety are independently selected from a bond, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, —C(O)NR′—, —C(O)O—, —C(O)S—, and —C(O)CR′R″, wherein R′ and R″ are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
the reactive functional group is selected from olefins, acetylenes, alcohols, phenols, ethers, oxides, halides, aldehydes, ketones, carboxylic acids, esters, amides, cyanates, isocyanates, thiocyanates, isothiocyanates, amines, hydrazines, hydrazones, hydrazides, diazo, diazonium, nitro, nitriles, mercaptans, sulfides, disulfides, sulfoxides, sulfones, sulfonic acids, sulfinic acids, acetals, ketals, anhydrides, sulfates, sulfenic acids isonitriles, amidines, imides, imidates, nitrones, hydroxylamines, oximes, hydroxamic acids thiohydroxamic acids, allenes, ortho esters, sulfites, enamines, ynamines, ureas, pseudoureas, semicarbazides, carbodiimides, carbamates, imines, azides, azo compounds, azoxy compounds, and nitroso compounds; and
the targeting moiety is selected from antibodies, nucleic acids, oligonucleotides, carbohydrates, lipids, hormones, growth factors, lectins, receptors, receptor ligands, and cofactors;
L 2a , L 2b and L 2c are independently selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;
wherein A p1 , and A p2 are independently selected from:
wherein
A and G are independently selected from carbon, nitrogen and oxygen;
J is selected from carbon and nitrogen;
each R 1′ and R 2′ is independently selected from H, and a single negative charge;
each R 6′ , R 7′ , R 8′ , R 9′ , and R 10 ′ moiety is independently selected from a bond linking the moiety to the remainder of the compound, alkanediyl linking the moiety to the remainder of the molecule, H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, halogen, CN, —CF 3 , —C(O)R 17′ , —SO 2 NR 17′ R 18′ , —NR 17′ R 18′ , —OR 17′ , —S(O) 2 R 17′ , —COOR 17′ , —S(O) 2 OR 17′ , —OC(O)R 17′ , —C(O)NR 17′ R 18′ , —NR 17′ SO 2 R 18′ , and —NO 2 ,
wherein
at least two of R 6′ , R 7′ , R 8′ , R 9′ , and R 10′ are optionally joined to form a ring system selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;
R 17′ and R 18′ are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl; or
R 17′ and R 18′ , together with the atoms to which they are attached, are optionally joined to form a 5-, 6- or 7-membered ring;
when A is oxygen, R 9′ is not present; and
when G is oxygen, R 7′ is not present; and
A p1 and A p2 are attached to C1 and C2, respectively, through a member selected from R 6′ , R 7′ , R 8′ , R 9′ and R 10′ .
2. The compound according to claim 1 , wherein L 1a is selected from:
wherein
n is an integer selected from 0, 1, 2, 3, 4, 5, and 6;
each R 1a is independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl; and
X is O, S, or CH 2 .
3. The compound according to claim 1 , wherein L 1a has the structure:
4. The compound according to claim 1 , wherein
when A p1 has a structure according to formula (I), A p1 is attached to L 2 through R 6′ or R 10′ ;
when A p1 has a structure according to formula (II) or (III), A p1 is attached to L 2 through R 6′ or R 9′ ;
when A p2 has a structure according to formula (I), A p2 is attached to L 2 through R 6′ or R 10′ ; and
when A p2 has a structure according to formula (II) or (III), A p2 is attached to L 2 through R 6′ or R 9′ .
5. The compound according to claim 4 , wherein A p1 and A p2 are each independently selected from:
6. The compound according to claim 5 , wherein
when A p1 has a structure according to formula (1), A p1 is attached to L 2 through R 6′ or R 10′ ; and
when A p1 has a structure according to formula (2a), (2b), (3), (4) or (5), A p1 is attached to L 2 through R 6′ or R 9′ ;
when A p2 has a structure according to formula (1), A p2 is attached to L 2 through R 6′ or R 10′ ; and
when A p2 has a structure according to formula (2a), (2b), (3), (4) or (5), A p2 is attached to L 2 through R 6′ or R 9′ .
7. The compound according to claim 1 , wherein A b1 and A b2 are each independently selected from:
8. The compound according to claim 1 , of a structure selected from:
wherein
L x6 is independently selected from H, a linker to a reactive functional group, and a linker to a targeting moiety
wherein,
the linker to a reactive functional group, and the linker to a targeting moiety are independently selected from a bond, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, —C(O)NR′—, —C(O)O—, —C(O)S—, and —C(O)CR′R″, wherein R′ and R″ are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
the reactive functional group is selected from olefins, acetylenes, alcohols, phenols, ethers, oxides, halides, aldehydes, ketones, carboxylic acids, esters, amides, cyanates, isocyanates, thiocyanates, isothiocyanates, amines, hydrazines, hydrazones, hydrazides, diazo, diazonium, nitro, nitriles, mercaptans, sulfides, disulfides, sulfoxides, sulfones, sulfonic acids, sulfinic acids, acetals, ketals, anhydrides, sulfates, sulfenic acids isonitriles, amidines, imides, imidates, nitrones, hydroxylamines, oximes, hydroxamic acids thiohydroxamic acids, allenes, ortho esters, sulfites, enamines, ynamines, ureas, pseudoureas, semicarbazides, carbodiimides, carbamates, imines, azides, azo compounds, azoxy compounds, and nitroso compounds; and
the targeting moiety is selected from antibodies, nucleic acids, oligonucleotides, carbohydrates, lipids, hormones, growth factors, lectins, receptors, receptor ligands, and cofactors; and
L 2a , L 2b and L 2c are independently selected from substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.
9. The compound according to claim 1 , wherein A p1 and A p2 are each independently selected from:
10. The compound according to claim 9 , wherein A p1 and A p2 are each independently selected from:
11. The compound according to claim 1 , wherein at least one of A p1 and A p2 , L 1a , L 2a , L 2b and L 2c is substituted with a linker to a reactive functional group, or a linker to a targeting moiety
wherein,
the linker to a reactive functional group, and the linker to a targeting moiety are independently selected from a bond, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl, —C(O)NR′—, —C(O)O—, —C(O)S—, and —C(O)CR′R″, wherein R′ and R″ are members independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocycloalkyl;
the reactive functional group is selected from olefins, acetylenes, alcohols, phenols, ethers, oxides, halides, aldehydes, ketones, carboxylic acids, esters, amides, cyanates, isocyanates, thiocyanates, isothiocyanates, amines, hydrazines, hydrazones, hydrazides, diazo, diazonium, nitro, nitriles, mercaptans, sulfides, disulfides, sulfoxides, sulfones, sulfonic acids, sulfinic acids, acetals, ketals, anhydrides, sulfates, sulfenic acids isonitriles, amidines, imides, imidates, nitrones, hydroxylamines, oximes, hydroxamic acids thiohydroxamic acids, allenes, ortho esters, sulfites, enamines, ynamines, ureas, pseudoureas, semicarbazides, carbodiimides, carbamates, imines, azides, azo compounds, azoxy compounds, and nitroso compounds; and
the targeting moiety is selected from antibodies, nucleic acids, oligonucleotides, carbohydrates, lipids, hormones, growth factors, lectins, receptors, receptor ligands, and cofactors.
12. The compound according to claim 11 , wherein L 2b is substituted with the linker to a reactive functional group, or the linker to a targeting moiety.
13. The compound according to claim 1 , of a structure selected from:
wherein
L x1 and L x6 are independently selected from H, a linker to a reactive functional group, and a linker to a targeting moiety.
14. The compound according to claim 12 , wherein the linker to the reactive functional group, or the linker to the targeting moiety has the structure:
-L 11 -F x ,
wherein L 11 is selected from a bond, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; and
F x is selected from a reactive functional group selected from olefins, acetylenes, alcohols, phenols, ethers, oxides, halides, aldehydes, ketones, carboxylic acids, esters, amides, cyanates, isocyanates, thiocyanates, isothiocyanates, amines, hydrazines, hydrazones, hydrazides, diazo, diazonium, nitro, nitriles, mercaptans, sulfides, disulfides, sulfoxides, sulfones, sulfonic acids, sulfinic acids, acetals, ketals, anhydrides, sulfates, sulfenic acids isonitriles, amidines, imides, imidates, nitrones, hydroxylamines, oximes, hydroxamic acids thiohydroxamic acids, allenes, ortho esters, sulfites, enamines, ynamines, ureas, pseudoureas, semicarbazides, carbodiimides, carbamates, imines, azides, azo compounds, azoxy compounds, and nitroso compounds, and a targeting moiety selected from antibodies, nucleic acids, oligonucleotides, carbohydrates, lipids, hormones, growth factors, lectins, receptors, receptor ligands, and cofactors.
15. The compound according to claim 14 , wherein the linker to the reactive functional group, or the linker to the targeting moiety has the structure:
wherein
R L is selected from substituted or unsubstituted alkyl, and substituted or unsubstituted heteroalkyl.
16. The compound according to claim 8 , wherein the reactive functional group is a member selected from an amine, carboxylic acid, NHS, sulfo-NHS, maleimide, aldehyde, sulfhydryl, isothiocyanate, and azide.
17. The compound according to claim 8 , wherein the targeting moiety is a member selected from antibodies, peptides, RNA, and DNA.
18. The compound according to claim 16 , wherein the linker with or without the reactive functional group has the structure:
19. A metal ion complex comprising the compound according to claim 1 and a metal ion complexed by the compound.
20. The metal ion complex according to claim 19 , wherein the metal ion is selected from an ion of a lanthanide, and an actinide.
21. The metal ion complex according to claim 19 , wherein the ion is an ion of a metal is selected from zirconium (Zr), iron (Fe), indium (In), europium (Eu), holmium (Ho), lutetium (Lu), yttrium (Y), terbium (Tb), ytterbium (Yb), gadolinium (Gd), samarium (Sm), dysprosium (Dy), erbium (Er), and thorium (Th).
22. The metal ion complex according to claim 19 , wherein the complex is luminescent.
23. The metal ion complex according to claim 19 , wherein the ion is an ion of a metal is selected from Eu, Tb, Sm, and Dy.
24. The metal ion complex according to claim 19 , wherein the ion is an ion of Gd.
25. The metal ion complex according to claim 19 , wherein the metal is a radionuclide.
26. The metal ion complex according to claim 19 , wherein the metal ion is selected from
Zr(IV), Fe(III), Sc(III), In(III), Eu(III), Ho(III), Lu(III), Y(III), Tb(III), Yb(III), Gd(III), Sm(III), Dy(III), Er(III), and Th(IV).
27. The metal ion complex according to claim 19 , wherein the metal ion is selected from 227 Th(IV), 89 Zr(IV), and 177 Lu(III).
28. The compound according to claim 1 , wherein the linker to the reactive functional group has the formula: