Didemnin analogs and fragments and methods of making and using them

1. A compound having the structure

wherein:

i) R 1 is selected from the group consisting of

—H,

-(tert-butyloxycarbonyl),

-leucine,

—(N-methyl)leucine,

—(N-methyl)leucine-proline,

—(N-methyl)leucine-proline-lactate,

—(N-methyl)leucine-proline-pyruvate,

—(N-methyl)leucine-proline-lactate-(a fluorophore),

—(N-methyl)leucine-proline-lactate-glutamine-pyroglutamate,

—(N-methyl)leucine-proline-lactate-glutamine-cyclopentanoate,

—(N-methyl)leucine-proline-alanine-leucine-pyroglutamate, and

—(N-methyl)leucine-proline-(N-methyl-alanine)-leucine-pyroglutamate;

ii) R 2 and R 3 are one of

(a) R 2 is selected from the group consisting of an isoleucine side chain, a valine side chain, an alanine side chain, a norleucine side chain, a norvaline side chain, a leucine side chain, a histidine side chain, a tryptophan side chain, an arginine side chain, a lysine side chain, a fluorophore, and a substituent having the structure

and R 3 is selected from the group consisting of —CH 3 and —H; or

(b) R 2 and R 3 form the structure

iii) each of R 5 , R 6 , R 7 , R 8 , and R 9 , when present, is independently selected from the group consisting of —H, —OH, —OCH 3 , —CO(C 6 H 5 ), —Br, —I, —F, —Cl, —CH 3 , and —C 2 H 5 ;

iv) R 4 is selected from the group consisting of an isoleucine side chain and a valine side chain;

v) X is selected from the group consisting of —O— and —(NH)—;

vi) Y is selected from the group consisting of —H and a hydroxyl protecting group;

vii) R 10 is selected from the group consisting of a leucine side chain and a lysine side chain; and

viii) the compound is not tamandarin A and is not tamandarin B.

2. The compound of claim 1 , wherein R 1 is selected from the group consisting of

—H,

-(tert-butyloxycarbonyl),

-leucine,

—(N-methyl)leucine,

—(N-methyl)leucine-(S)proline,

—(N-methyl)leucine-(S)proline-(S)lactate,

—(N-methyl)leucine-(S)proline-pyruvate,

—(N-methyl)leucine-(S)proline-(S)lactate-(a fluorophore),

—(N-methyl)leucine-(S)proline-(S)lactate-glutamine-pyroglutamate,

—(N-methyl)leucine-(S)proline-(S)lactate-glutamine-cyclopentanoate,

—(N-methyl)leucine-(S)proline-alanine-leucine-pyroglutamate, and

—(N-methyl)leucine-(S)proline-(N-methyl-alanine)-leucine-pyroglutamate.

3. The compound of claim 1 , wherein R 1 is selected from the group consisting of

—H,

-(tert-butyloxycarbonyl),

-leucine,

—(N-methyl)leucine,

—(N-methyl)leucine-(S)proline,

—(N-methyl)leucine-(S)proline-(S)lactate,

—(N-methyl)leucine-(S)proline-pyruvate,

—(N-methyl)leucine-(S)proline-(S)lactate-(a fluorophore),

—(N-methyl)leucine-(S)proline-(S)lactate-(S)glutamine-(S)pyroglutamate,

—(N-methyl)leucine-(S)proline-(S)lactate-(S)glutamine-(S)cyclopentanoate,

—(N-methyl)leucine-(S)proline-(S)alanine-(S)leucine-(S)pyroglutamate, and

—(N-methyl)leucine-(S)proline-(N-methyl-(S)-alanine)-(S)leucine-(S)pyroglutamate.

4. The compound of claim 1 , wherein R 1 is selected from the group consisting of

—H,

-(tert-butyloxycarbonyl),

-leucine,

—(N-methyl)leucine,

—(N-methyl)leucine-(S)proline,

—(N-methyl)leucine-(S)proline-pyruvate,

—(N-methyl)leucine-(S)proline-(S)lactate-(a fluorophore),

—(N-methyl)leucine-(S)proline-(S)lactate-glutamine-pyroglutamate,

—(N-methyl)leucine-(S)proline-(S)lactate-glutamine-cyclopentanoate,

—(N-methyl)leucine-(S)proline-alanine-leucine-pyroglutamate, and

—(N-methyl)leucine-(S)proline-(N-methyl-alanine)-leucine-pyroglutamate.

5. The compound of claim 1 , wherein R 1 is —(N-methyl-R-leucine).

6. The compound of claim 1 , wherein Y is —H, and wherein R 2 is a lysine side chain.

7. The compound of claim 1 , wherein R 4 is an allo-isoleucine side chain.

8. The compound of claim 1 , wherein R 2 is a fluorophore and wherein Y is —H.

9. The compound of claim 1 , wherein X is O.

10. The compound of claim 4 , wherein X is O and Y is H.

11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a compound according to claim 4 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising a compound according to claim 6 and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a compound according to claim 10 and a pharmaceutically acceptable carrier.

19. The compound of claim 1 , wherein R 1 is —(N-methyl)leucine-(S)proline-pyruvate.

20. The compound of claim 19 , wherein the compound is represented by a structure selected from the group consisting of:

21. The compound of claim 19 , wherein the compound is represented by the structure consisting of:

22. The compound of claim 19 , wherein the compound is represented by the structure consisting of:

23. The compound of claim 1 , wherein Y is —H, and wherein R 2 has the structure

24. The compound of claim 1 , wherein the compound is represented by a structure selected from the group consisting of

25. The compound of claim 1 , wherein the compound is represented by a structure selected from the group consisting of:

26. The compound of claim 1 , wherein the compound is represented by a structure selected from the group consisting of:

27. The compound of claim 1 , wherein the compound is represented by a structure selected from the group consisting of:

28. The compound of claim 1 , wherein the compound is represented by a structure selected from the group consisting of:

29. The compound of claim 1 , wherein R 1 is —(N-methyl-R-leucine)-(S)proline-(S)lactate-(S)glutamine-(S)pyroglutamate, Y is —H, and X is —O—.

30. The compound of claim 29 , wherein the compound is represented by a structure selected from the group consisting of:

31. The compound of claim 29 , wherein the compound is represented by the structure consisting of:

32. The compound of claim 29 , wherein the compound is represented by the structure consisting of:

33. The compound of claim 1 , wherein R 4 is a valine side chain, Y is —H, and X is —O—.

34. The compound of claim 33 , wherein the compound is represented by the structure selected from the group consisting of

35. The compound of claim 33 , wherein the compound is represented by the structure consisting of:

36. The compound of claim 33 , wherein the compound is represented by the structure consisting of:

37. The compound of claim 33 , wherein the compound is represented by the structure consisting of:

38. The compound of claim 33 , wherein the compound is represented by the structure consisting of:

39. The compound of claim 1 , wherein R 1 is —(N-methyl)leucine-(S)proline-(S)lactate-(a fluorophore).

40. The compound of claim 1 , wherein the compound is represented by a structure selected from the group consisting of:

41. The compound of claim 1 , wherein the compound is represented by the structure consisting of:

42. The compound of claim 39 , wherein the compound is represented by the structure consisting of:

43. The compound of claim 39 , wherein the compound is represented by the structure consisting of

44. The compound of claim 39 , wherein the compound is represented by the structure consisting of:

45. The compound of claim 1 , wherein X is —(NH)—.

46. The compound of claim 45 , wherein the compound is represented by a structure selected from the group consisting of:

47. The compound of claim 45 , wherein the compound is represented by the structure consisting of:

48. The compound of claim 45 , wherein the compound is represented by the structure consisting of:

49. The compound of claim 45 , wherein the compound is represented by the structure consisting of:

50. The compound of claim 45 , wherein the compound is represented by the structure consisting of: