Guanidinium transport reagents and conjugates

1. A compound having the formula:

wherein

the subscript m is an integer of from 6 to 25;

T is a member selected from the group consisting of a protected or unprotected first terminal functional group, a protected or unprotected linking group, and a linking group having an attached therapeutic agent;

W is a member selected from the group consisting of a protected or unprotected second terminal functional group, a protected or unprotected linking group, and a linking group having an attached therapeutic agent, with the proviso that T and W do not simultaneously contain an attached therapeutic agent;

each X i is a backbone subunit independently selected from:

 wherein

each R is a member selected from the group consisting of H and an amino acid sidechain; and

the starred wavy line indicates the point of attachment to Y i and the remaining wavy lines indicate the point of attachment along the backbone;

the superscript i is an integer of from 1 to m and denotes the position downstream of W;

each Y i is selected from the group consisting of H, an amino acid sidechain, aryl, and heteroaryl, when the subscript n is 0; or is selected from the group consisting of C 1 –C 8 )alkylene, (C 2 –C 8 )alkenylene, (C 2 –C 8 )alkynylene, (C 2 –C 8 )heteroalkylene, (C 3 –C 8 )cycloalkylalkylene, (C 2 –C 8 )spirocycloalkylene, arylene, heteroarylene, and combinations thereof, when the subscript n is 1;

each Z i is a guanidinium moiety selected from the group consisting of:

wherein the wavy line denotes the point of attachment to Y i ;

the attached therapeutic agent is different from each Z i ;

and the subscript n is 0, 1 or 2, indicating the absence or presence of one or two Z guanidinium moieties at each i position;

with the proviso that the compound has at least 4 guanidinium moieties that can be the same or different and the portion of the compound joining W and T is not a polypeptide.

2. A compound of claim 1 , wherein each X i is independently selected from the group consisting of:

wherein

each R is a member selected from the group consisting of H and an amino acid sidechain; and

the starred wavy line indicates the point of attachment to Y i and the remaining wavy lines indicate the point of attachment along the backbone.

3. A compound of claim 2 , wherein each Z i is selected from the group consisting of:

4. A compound of claim 3 , wherein each Y i that is attached to a Z i is selected from the group consisting of (C 1 –C 8 )alkylene, (C 2 –C 8 )alkenylene, (C 2 –C 8 )heteroalkylene, (C 3 –C 8 )cycloalkylalkylene, arylene and combinations thereof.

5. A compound of claim 4 , wherein each Y i that is attached to a Z i is an unbranched (C 3 –C 7 )alkylene.

6. A compound of claim 5 , wherein each Y i that is attached to a Z i is a (C 4 –C 6 )alkylene and each Z i is —NH—C(═NH 2 )—NH 2 .

7. A compound of claim 6 , wherein for each odd integer i, n is 0 and for each even integer i, n is 1.

8. A compound of claim 6 , wherein m is an integer of from 12 to 25, and with the proviso that the compound has from 6 to 8 guanidinium moieties that can be the same or different.

9. A compound in accordance with claim 1 , having a carbamate backbone.

10. A compound in accordance with claim 9 , having from 5 to 15 guanidinium head groups.

11. A compound in accordance with claim 9 , having from 5 to 9 guanidinium head groups.

12. A compound in accordance with claim 1 , having a glutaramide backbone.

13. A compound in accordance with claim 12 , having from 5 to 15 guanidinium head groups.

14. A compound in accordance with claim 1 , having a polyamine backbone.

15. A compound in accordance with claim 14 , having from 5 to 15 guanidinium head groups.

16. A compound in accordance with claim 1 , having a γ-peptide backbone.

17. A compound in accordance with claim 16 , having from 5 to 15 guanidinium head groups.

18. A compound of claim 1 , wherein W is a linking group having an attached biologically active agent and has the formula:

wherein:

R 1 the biologically active agent;

X is a linkage between a functional group on the biologically active agent R 1 and the remainder of W;

Y is a functional group attaching W to the remainder of the compound;

A is N or CH;

R 2 is hydrogen, alkyl, aryl, arylaikyl, acyl or allyl;

k and m are independently either 1 or 2; and

n is an integer of from 1 to 10.

19. A compound of claim 18 , wherein Y is selected from the group consisting of O, NH, C(O)O, NHC(O) and C(O)NH.

20. A compound of claim 1 , wherein W is a linking group having an attached biologically active agent and has the formula:

wherein:

R 1 the biologically active agent;

X is a linkage between a functional group on the biologically active agent R 1 and the remainder of W;

Y is a functional group attaching W to the remainder of the compound;

R 4 is S, O, NR 6 or CR 7 R 8 ;

R 5 OH, SH or NHR 6 ;

R 6 is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl;

R 7 and R 8 are independently hydrogen, alkyl or arylalkyl; and

k and m are independently either 1 or 2.

21. A compound of claim 20 , wherein Y is selected from the group consisting of O, NH, C(O)O, NHC(O) and C(O)NH.

22. A compound of claim 1 , wherein W is a linking group having an attached biologically active agent and has the formula:

wherein:

R 1 is the biologically active agent;

X is a linkage between a functional group on the biologically active agent R 1 and the remainder of W;

Y is a functional group attaching W to the remainder of the compound;

R 5 is H, OH, SH or NHR 6 ;

R 6 is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl; and

k is 1 or 2.

23. A compound of claim 22 , wherein Y is selected from the group consisting of O, NH, C(O)O, NHC(O) and C(O)NH.

24. A compound of claim 1 , wherein W is a linking group having an attached biologically active agent and has the formula:

wherein:

R 1 the biologically active agent;

X is a linkage between a functional group on the biologically active agent R 1 and the remainder of W;

Y is a functional group attaching W to the remainder of the compound;

Ar is a substituted or unsubstituted aryl group, wherein the methylene and oxygen substituents are either ortho or para to one another;

R 4 is S, O, NR 6 or CR 7 R 8 ;

R 5 is H, OH, SH, CONHR 6 or NHR 6 ;

R 6 is hydrogen, alkyl, aryl, arylalkyl, acyl or allyl;

R 7 and R 8 are independently hydrogen or alkyl; and,

k and m are independently either 1 or 2.

25. A compound of claim 24 , wherein Y is selected from the group consisting of O, NH, C(O)O, NHC(O) and C(O)NH.

26. A method for enhancing transport of a selected therapeutic agent across a biological membrane, comprising

contacting said biological membrane with a compound of claim 1 wherein one of W or T comprises said therapeutic agent, and said one of W or T is covalently attached to the remainder of said compound of claim 1 , thereby forming a conjugate,

whereby said contacting is effective to promote transport of said conjugate across said biological membrane at a rate that is greater than the trans-membrane transport rate of the therapeutic agent in non-conjugated form.

27. The method of claim 26 , wherein said compound comprises a polymer consisting of from 7 to 25 subunits, at least 4 of which contain a guanidino sidechain moiety.

28. The method of claim 27 , wherein each guanidino sidechain moiety is separated from another such moiety by from one to three non-guanidino or non-amidino subunit.

29. A method of claim 26 , wherein said therapeutic agent is selected from the group consisting of anticancer agents, antibacterial agents, antiinflammation agents and antifungal agents.

30. A method of claim 29 , wherein said agent is an anticancer agent.

31. A method of claim 29 , wherein said agent is an antibacterial agent.

32. A method of claim 29 , wherein said agent is an antiinflammation agent.