Functionalized cyanine dyes (PEG)

1. A compound having the formula:

wherein

Q is:

R m is a substituted or unsubstituted heteroaryl;

R c , and R d are independently selected from alkyl and heteroalkyl, substituted with a member selected from sulfonic acid, carboxylic acid, phosphonic acid, and phosphoric acid;

each R a and each R e , is independently selected from C(O)R 9 , OR 12 , NR 12 R 13 , CR 12 C(O)R 13 , NR 12 C(O) 2 R 13 , SO 3 H, and C(O)NR 12 R 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, and a ring structure formed by joining a member selected from two R a moieties together with the atoms to which they are attached, two R e moieties together with the atoms to which they are attached, and a combination thereof, to form said ring structure, which is a member selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl, said ring substituted with at least one SO 3 H,

wherein

R 9 is a member selected from OR 10 , and NH(CH 2 ) t OR 11

wherein

R 10 is a member selected from H and substituted or unsubstituted alkyl;

t is selected from the integers from 1 to 12;

R 11 is a member selected from H, and

wherein

u is selected from the integers from 1 to 8; and

Y is a nucleobase; and

R 12 and R 13 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;

a and e are integers independently selected from 0, 1, 2, 3 and 4;

R f , R g , R h , and R i are independently selected from unsubstituted alkyl, alkylsulfonic acid, and

wherein

s is selected from the integers from 1 to 12; and

R 9a is a member selected from OH, and

NH(CH 2 ) tt —O—R 10a

wherein

tt is selected from the integers from 1 to 12; and

R 10a is a member selected from H, a moiety comprising poly(ethylene glycol), and

wherein

Y is a nucleobase; and

u is selected from the integers from 1 to 8.

2. The compound according to claim 1 wherein at least two of R f , R g , R h , and R i are alkylsulfonic acid.

3. The compound according to claim 1 wherein neither R c nor R d is unsubstituted alkyl.

4. The compound according to claim 1 wherein when two R a moieties are not joined to form said ring substituted with said at least one SO 3 H moiety, at least one R a is SO 3 H.

5. The compound according to claim 1 wherein when two R e moieties are not joined to form said aryl ring substituted with said at least one SO 3 H moiety, at least one R e is SO 3 H.

6. The compound according to claim 1 wherein two R a moieties are joined, providing said compound with the substructure:

7. The compound according to claim 1 wherein two R e moieties are joined, providing said compound with the substructure:

8. The compound according to claim 1 having the formula:

wherein

each R b and each R j are members independently selected from C(O)R 29 , OR 32 , NR 32 R 33 , CR 32 C(O)R 33 , NR 32 C(O) 2 R 33 , SO 3 H, and C(O)NR 32 R 33 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl

wherein

R 29 is a member selected from OR 31 , and NH(CH 2 ) t′ OR 30

wherein

R 31 is a member selected from H and substituted or unsubstituted alkyl;

t′ is selected from the integers from 1 to 12;

R 30 is a member selected from H, and

wherein

 u′ is selected from the integers from 1 to 8; and

 Y is a nucleobase;

R 32 and R 33 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.

9. The compound according claim 1 having the formula:

10. The compound according to claim 1 having the formula:

11. The compound according to claim 1 having the formula:

12. The compound according to claim 1 having the formula:

13. The compound according to claim 1 wherein R a , and R e are independently selected from:

in which

aa is 0 or 1;

x is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

n is an integer which provides a polyethylene glycol moiety of molecular weight of at least about 100;

R p is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;

R 33 is a member selected from H, COOH,

 and

R 8 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

14. The compound according to claim 1 wherein R m has a formula:

wherein

Z is N;

R 12 is a member selected from OH, and

—NH(CH 2 ) t′ —O—R 10′

wherein

t′ is selected from the integers from 1 to 12;

R 10′ is a member selected from H, a moiety comprising poly(ethylene glycol), and

wherein

u′ is selected from the integers from 1 to 8; and

Y′ is a nucleobase.

15. The compound according to claim 1 wherein R m has the formula:

16. The compound according to claim 1 wherein R m is a member selected from:

in which w is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or greater.

17. The compound according to claim 1 wherein 1, 2, 3 or 4 of R f , R g , R h , R i , R c and R d is:

18. The compound according to claim 1 wherein both R c and R d are:

19. The compound according to claim 1 in which two, three, four, five or six of R a , R e , R c , R d , R f , R g , R h , Ri, and R m in any combination, include an independently selected R 11 moiety which is:

20. The compound according to claim 1 in which two, three, four, five or six of R a , R e , R c , R d , R f , R g , R h , Ri, and R m in any combination, include an independently selected dye moiety or dye linker moiety.

21. The compound according to claim 1 in which two, three, four-, five or six of R a , R e , R j , R c , R d , R f , R g , R h , Ri, and R m ′ in any combination, include an independently selected polyvalent moiety.

22. The compound according to claim 21 wherein said polyvalent moiety has bound thereto one or more member selected from a dye, a dye-linker moiety, and a nucleotide polyphosphate.

23. A method of monitoring an enzyme reaction, said method comprising:

(a) forming a reaction mixture by contacting said enzyme with a fluorescent dye that is a compound having the formula:

wherein

Q is:

R m is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl;

R c , and R d are independently selected from alkyl and heteroalkyl, substituted with a member selected from sulfonic acid, carboxylic acid, phosphonic acid, and phosphoric acid;

each R a and each R e , is independently selected from C(O)R 9 , OR 12 , NR 12 R 13 , CR 12 C(O)R 13 , NR 12 C(O) 2 R 13 , SO 3 H, and C(O)NR 12 R 13 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, and a ring structure formed by joining a member selected from two R a moieties together with the atoms to which they are attached, two R e moieties together with the atoms to which they are attached, and a combination thereof, to form said ring structure, which is a member selected from a substituted or unsubstituted aryl and a substituted or unsubstituted heteroaryl, said ring substituted with at least one SO 3 H

wherein

R 9 is a member selected from OR 10 , and NH(CH 2 ) t OR 11

wherein

R 10 is a member selected from H and substituted or unsubstituted alkyl;

t is selected from the integers from 1 to 12;

R 11 is a member selected from H, and

wherein

u is selected from the integers from 1 to 8; and

Y is a nucleobase; and

R 12 and R 13 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;

a and e are integers independently selected from 0, 1, 2, 3 and 4;

R f , R g , R h , and R i are independently selected from unsubstituted alkyl, alkylsulfonic acid, and

wherein

s is selected from the integers from 1 to 12; and

R 9a is a member selected from OH, and

NH(CH 2 ) tt —O—R 10a

wherein

tt is selected from the integers from 1 to 12; and

R 10a is a member selected from H, a moiety comprising poly(ethylene glycol), and

wherein

Y is a nucleobase; and

u is selected from the integers from 1 to 8;

comprising at least one nucleoside phosphate wherein said dye is a substrate for said enzyme under conditions sufficient for said enzyme and said dye to react; and

(b) monitoring fluorescence of said reaction mixture.

24. The method according to claim 23 wherein said enzyme is a DNA polymerase and said dye comprises a nucleic acid moiety which is said substrate for said enzyme.

25. The method according to claim 23 wherein said enzyme reaction is template directed DNA synthesis.

26. The method according to claim 23 wherein said reaction is a component of a single molecule DNA sequencing analysis.

27. The compound according to claim 8 wherein R b and R j are independently selected from:

in which

aa is 0 or 1;

x is an integer selected from 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;

n is an integer which provides a polyethylene glycol moiety of molecular weight at least about 100;

R p is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl;

R 33 is a member selected from H, COOH,

 and

R 8 is a member selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted heteroalkyl.

28. The compound according to claim 8 in which two, three, four, five or six of R b and R j in any combination, include an independently selected R 11 moiety which is:

29. The compound according to claim 8 in which two, three, four, five or six of R b and R j in any combination, include an independently selected dye moiety or dye linker moiety.

30. The compound according to claim 8 in which two, three, four, five or six of R b and R j in any combination, include an independently selected polyvalent moiety.

31. The compound according to claim 30 wherein said polyvalent moiety has bound thereto one or more member selected from a dye, a dye-linker moiety, and a nucleotide polyphosphate.