Bioconjugates of cyanine dyes

1. A bioconjugate compound of Formula II:

wherein

Q L is a portion of a polymethine bridge selected from the group consisting of:

wherein Q L is the central portion of either a five- or a seven-polymethine-carbon polymethine bridge;

each R 1 is a member independently selected from the group consisting of -L-Y—Z and alkyl that is additionally substituted with from 0 to 1 R 13 and from 0 to 1 R L ; wherein the alkyl is optionally interrupted by at least one heteroatom;

each R 2a and R 2b is a member independently selected from the group consisting of alkyl, alkenyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, amidoalkyl, alkylthioalkyl, carboxyalkyl, alkoxycarbonylalkyl, and sulfonatoalkyl; wherein a carbon of the member is additionally substituted with from 0 to 1 R L ; or, alternatively, a R 2a and R 2b pair, together with the ring carbon to which the R 2a and R 2b are bonded, join to form a spirocycloalkyl ring, wherein the spirocycloalkyl ring is additionally substituted with from 0 to 6 R 14 and from 0 to 1 R L , or an exocyclic alkene, wherein the exocyclic alkene is additionally substituted with from 0 to 2 R 14 and from 0 to 1 R L ;

each R 3 , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b is a member independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, hydroxyl, alkoxy, amino, cyano, carboxyl, alkoxycarbonyl, amido, sulfonato, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, and sulfonatoalkyl; wherein a carbon of the member is additionally substituted with from 0 to 1 R L ; or, alternatively, a pair of said members that is selected from the group consisting of R 3 and R 4a , an R 4a and R 5a , and an R 5a and R 6a , together with the pair of atoms to which the pair of said members is bonded, joins to form an aryl ring, wherein the aryl ring is additionally substituted with from 0 to 2 R 14 and from 0 to 1 R L ;

each R 7 is a member independently selected from the group consisting of hydrogen and alkyl; wherein the alkyl is additionally substituted with from 0 to 3 R 14 and from 0 to 1 R L ; or, alternatively, both R 7 , together with the intervening segment of the polyene to which both R 7 are bonded, join to form a ring, wherein said ring is selected from the group consisting of a cycloalkyl and a heterocyclyl ring; wherein the ring is additionally substituted with from 0 to 3 R 14 and from 0 to 1 R L ;

R 8 , R 9 , R 10 , R 11 , and R 12 are each a member independently selected from the group consisting of hydrogen, alkyl, alkenyl, halo, alkoxy, sulfonato, hydroxyl, amino, carboxyl, alkoxycarbonyl, cyano, amido, thioacetyl, and -L-Y—Z; wherein, if present, at least one member selected from the group consisting of R 8 , R 9 , and R 10 is -L-Y—Z;

each R 13 is a member independently selected from the group consisting of hydroxyl, amino, carboxyl, alkoxycarbonyl, cyano, amido, sulfonato, and thioacetyl;

each R 14 is a member independently selected from the group consisting of alkyl, alkenyl, halo, hydroxyl, alkoxy, amino, cyano, carboxyl, alkoxycarbonyl, amido, sulfonato, alkoxycarbonylalkyl, and alkoxyalkyl; wherein the alkyl or alkenyl is additionally substituted with from 0 to 1 R 13 and from 0 to 1 R L ;

each L is an optional member independently selected from the group consisting of a bond, a C 1 -C 20 alkylene, and a C 1 -C 20 alkenylene; wherein the alkylene or alkenylene is optionally interrupted by at least one heteroatom;

each Y is an optional member independently selected from the group consisting of a bond, —O—, —S—, —NH—, —NHC(O)—, —C(O)NH—, —NR 15 —, —NR 15 C(O)—, —C(O)NR 15 —, —N(Z)—, —N(Z)C(O)—, and —C(O)N(Z)—;

each Z is independently selected from the group consisting of -L-R 13 and -L-R L ;

alternatively, —Y—Z is a member selected from the group consisting of —N(Z) 2 , —N(Z)C(O)Z, and —C(O)N(Z) 2 , and the two Z groups may optionally be linked to form a cycloalkynyl group;

each R 15 is a member independently selected from the group consisting of alkyl and alkoxycarbonylalkyl, wherein the alkyl is optionally interrupted by at least one heteroatom;

each R L comprises a linking group and a biomolecule connected thereby, wherein the compound comprises at least one R L ; wherein the biomolecule is selected from the group consisting of hyaluronan, a tetracycline derivative, avidin, biotin, streptavidin, a peptide, and a protein; and

wherein said compound has a balanced charge.

2. The compound of claim 1 ,

wherein Q is:

wherein each R 1 is an independently selected sulfonatoalkyl or an independently selected alkyl that is additionally substituted with from 0 to 1 R 13 ;

each R 2a and R 2b is a member independently selected from the group consisting of alkyl, carboxyalkyl, and sulfonatoalkyl;

R 3 , R 4a , R 4b , R 5a , R 5b , R 6a , and R 6b each is a member independently selected from the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl, halo, sulfonato, and sulfonatoalkyl;

R 8 , R 9 , R 10 , R 11 , and R 12 are each a member independently selected from the group consisting of hydrogen, alkyl, halo, sulfonato, sulfonatoalkyl, and -L-Y—Z; wherein at least one member selected from the group consisting of R 8 , R 9 , and R 10 is -L-Y—Z;

each R 13 is a member independently selected from the group consisting of hydroxyl, amino, and carboxyl;

each R 14 is a member independently selected from the group consisting of alkyl, alkenyl, carboxyl, alkoxycarbonyl, amido, alkoxycarbonylalkyl, and halo;

each L is a member independently selected from the group consisting of a bond, a C 1 -C 20 alkylene, and a C 1 -C 20 alkenylene; and

each Y is a member independently selected from the group consisting of a bond, —O—, —NHC(O)—, —C(O)NH—, —NR 15 C(O)—, —C(O)NR 15 —, —N(Z)—, —N(Z)C(O)—, and —C(O)N(Z)—;

alternatively, —Y—Z is a member selected from the group consisting of —N(Z) 2 , —N(Z)C(O)Z, and —C(O)N(Z) 2 , and the two Z groups may optionally be linked to form a cycloalkynyl group.

3. The compound of claim 2 , having the formula:

wherein M is an alkali metal ion.

4. The compound of claim 1 , wherein the bioconjugate is hyaluronan.

5. The compound of claim 1 , wherein the bioconjugate is selected from the group consisting of an avidin, streptavidin, and biotin.

6. The compound of claim 1 , wherein the bioconjugate is a tetracycline derivative.

7. The compound of claim 1 , wherein the bioconjugate is a peptide.

8. The compound of claim 7 , wherein the peptide is a cyclic RGD peptide or an acyclic RGD peptide.

9. The compound of claim 1 , wherein the bioconjugate is a protein.

10. The compound of claim 9 , wherein the protein is EGF.

11. The compound of claim 9 , wherein the protein is an antibody or an antibody fragment.

12. The compound of claim 11 , wherein the antibody or antibody fragment is an antibody selected from the group consisting of a goat anti-mouse (GAM) antibody and a goat anti-rabbit (GAR) antibody.

13. The compound of claim 3 , wherein the bioconjugate is hyaluronan.

14. The compound of claim 3 , wherein the bioconjugate is selected from the group consisting of an avidin, streptavidin, and biotin.

15. The compound of claim 3 , wherein the bioconjugate is a tetracycline derivative.

16. The compound of claim 3 , wherein the bioconjugate is a peptide.

17. The compound of claim 16 , wherein the peptide is a cyclic RGD peptide or an acyclic RGD peptide.

18. The compound of claim 3 , wherein the bioconjugate is a protein.

19. The compound of claim 18 , wherein the protein is EGF.

20. The compound of claim 18 , wherein the protein is an antibody or an antibody fragment.

21. The compound of claim 20 , wherein the antibody or antibody fragment is an antibody selected from the group consisting of a goat anti-mouse (GAM) antibody and a goat anti-rabbit (GAR) antibody.