IP Library › Granted Patent US 7,651,997
Granted Patent B2
US 7,651,997 · App. 11/455,937 · Granted Jan 26, 2010

Deoxo-proline-containing tamandarin and didemnin analogs, dehydro-proline-containing tamandarin and didemnin analogs, and methods of making and using them

Assignee: The Trustees of the University of Pennsylvania
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Quick Facts
Patent No.
US 7,651,997
App. No.
11/455,937
Granted
Jan 26, 2010
Kind
B2
Abstract

The present invention relates to tamandarin and didemnin analogs which have a deoxo-proline residue or a dehydro-proline residue in their structure. These analogs are useful as anti-cancer agents and for other purposes. Methods of making these analogs and methods of using them as inhibitors of protein synthesis, cell growth, and tumorigenesis and as enhancers of apoptosis are also provided.

Claims (183)

1. A pharmaceutical composition comprising a tamandarin analog having the structure

wherein:

i) R 1 is selected from the group consisting of

—(N-methyl)leucine-deoxo-proline,

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

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

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

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

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

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

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

—(N-methyl)leucine-dehydro-proline,

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

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

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

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

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

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

—(N-methyl)leucine-dehydro-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 second 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; and

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

a pharmaceutically acceptable carrier.

2. The pharmaceutical composition of claim 1 , wherein

R 1 is selected from the group consisting of

—(N-methyl)leucine-deoxo-(S)proline,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

—(N-methyl)leucine-deoxo-(S)proline,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

4. The pharmaceutical composition of claim 1 , wherein R 2 is

R 3 is methyl, R 4 is an isoleucine side chain, each of R 5 , R 6 , R 8 , and R 9 is a hydride radical, R 7 is methoxy, R 10 is a leucine side chain, X is —O—, and Y is a hydride radical.

5. The pharmaceutical composition of claim 1 , wherein the tamandarin analog is

6. The pharmaceutical composition of claim 1 , wherein R 1 is —(N-methyl)leucine-deoxo(S)proline-lactate.

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

8. The pharmaceutical composition of claim 1 , wherein Y is —H, and wherein R 2 has the structure

9. The pharmaceutical composition of claim 1 , wherein R 2 is a lysine side chain and Y is —H.

10. The pharmaceutical composition of claim 1 , wherein the tamandarin analog has the following structure

wherein FL is a fluorophore.

11. The pharmaceutical composition of claim 1 , wherein X is —NH—.

12. The pharmaceutical composition of claim 1 , wherein the tamandarin analog is present in about 1% to about 10% (w/w) in the form of a topically-administrable formulation.

13. The pharmaceutical composition of claim 1 , wherein the tamandarin analog is:

14. A pharmaceutical composition comprising a compound having a structure selected from the group consisting of

wherein:

i) R 2 and R 3 are one of

(a) R 3 is selected from the group consisting of —CH 3 and —H; and 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 proline side chain, a leucine side chain, a histidine side chain, a tryptophan side chain, an arginine side chain, a lysine side chain, a second fluorophore, and a substituent having the structure

(b) R 2 and R 3 together are a substituent having the structure

ii) 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 ;

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

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

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

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

vii) R 13 is an enzyme-cleavable moiety that is cleavable by an enzyme selected from the group consisting of a carboxypeptidase, a beta-lactamase, a beta galactosidase, a penicillin V-amidase, a cytosine deaminase, a nitroreductase, an alkaline phosphatase, a beta-glucuronidase, and a catalytic antibody; and

a pharmaceutically acceptable earner.

15. The pharmaceutical composition of claim 14 , wherein R 13 has the structure

16. The pharmaceutical composition of claim 14 , wherein R 13 has the structure

17. A pharmaceutical composition comprising a didemnin analog having the structure

wherein:

i) R 1 is selected from the group consisting of

—(N-methyl)leucine-deoxo-proline,

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

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

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

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

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

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

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

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

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

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

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

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

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

ii) R 2 and R 3 are one of

(a) R 3 selected from the group consisting of —CH 3 and —H; and 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 second fluorophore, and a substituent having the structure

(b) R 2 and R 3 together are a substituent having 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; and

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

a pharmaceutically acceptable carrier.

18. The pharmaceutical composition of claim 17 , wherein R 1 is selected from the group consisting of

—(N-methyl)leucine-deoxo-(S)proline,

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

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

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

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

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

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

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

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

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

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

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

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

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

19. The pharmaceutical composition of claim 17 , wherein R 1 is selected from the group consisting of

—(N-methyl)leucine-deoxo-(S)proline,

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

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

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

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

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

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

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

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

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

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

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

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

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

20. The pharmaceutical composition of claim 17 , wherein

R 2 is

R 3 is methyl, R 4 is an isoleucine side chain, each of R 5 , R 6 , R 8 , and R 9 is —H, R 7 is methoxy, R 10 is a leucine side chain, X is —O—, and Y is —H.

21. The pharmaceutical composition of claim 17 , wherein the didemnin analog is

22. The pharmaceutical composition of claim 17 , wherein R 1 is —(N-methyl)leucine-deoxo-(S)proline-lactate.

23. The pharmaceutical composition of claim 17 , wherein Y is —H, and wherein R 2 has the structure

24. The pharmaceutical composition of claim 17 , wherein R 2 is a lysine side chain and Y is —H.

25. The pharmaceutical composition of claim 17 , wherein X is —NH—.

26. The pharmaceutical composition of claim 17 , wherein the didemnin analog is present in about 1% to about 10% (w/w) in the form of a topically-administrable formulation.

27. A compound of formula

wherein:

i) R 1 is selected from the group consisting of

—(N-methyl)leucine-deoxo-(S)proline,

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

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

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

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

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

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

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

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

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

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

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

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

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

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

—(N-methyl)leucine-dehydro-(S)proline-(N-methyl-(S)-alanine)-(S)leucine-(S)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 second 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

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; and

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

Assignments (1)
CONFIRMATORY LICENSE Recorded Dec 8, 2020
From: UNIVERSITY OF PENNSYLVANIA
To: NATIONAL INSTITUTES OF HEALTH - DIRECTOR DEITR
Reel/Frame 054575/0653 →
Continuity (3)
Continuation 0976708000 · Jan 22, 2001
Continuation In Part 0954584800 · Apr 7, 2000
Related Publication 20070129289A1 · Jun 7, 2007