IP Library Granted Patent US 7,473,527
Granted Patent B2
US 7,473,527 · App. 10/520,377 · Granted Jan 6, 2009

Compounds promoting delivery of genes

Assignee: The UAB Research Foundation
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Quick Facts
Patent No.
US 7,473,527
App. No.
10/520,377
Granted
Jan 6, 2009
Kind
B2
Abstract

A process is provided for activating gene transfer in a cell by administering a gene transfer activating compound to the cell in conjunction with a gene transfer vector. A kit for activating gene transfer as well as process for identifying a compound that activates gene transfer are described. Use of a gene transfer activator compound enhances gene transfer of a given gene transfer vector.

Claims (91)

1. A kit for activating gene transfer, said kit comprising a gene transfer activating compound packaged in a suitable container together with instructions for use to activate gene transfer wherein said gene transfer compound is selected from the group consisting of:

wherein Q is nitrogen or oxygen, wherein each occurrence of R 1 independently is H, CH 3 , CH 2 CH 3 or a nullity, wherein R 2 is C 1 -C 18 alleyl, C 2 -C 18 ether, C 2 -C 18 thioether, C 2 -C 18 secondary or tertiary amine,

wherein A is

wherein R 3 is H, C 1- C 6 alkyl, or a heteroatom substituted C 1 -C 6 alkyl where the heteroatom is oxygen, nitrogen, or sulfur, wherein R 4 is C 2 -C 6 amide; or ═N—R 5 where R 5 is C 7 -C 12 aryloxyl, C 1 -C 6 hydronyl, carbonyl, carboxyl, or acyl, imidazyl, pyrazyl, thiazyl, or oxazyl, wherein X is H, F, Cl or Br, wherein Z is oxygen or sulfur.

2. The kit of claim 1 wherein said gene transfer compound is bouvardin.

3. The kit of claim 1 wherein said gene transfer compound is that of structure I, wherein A is

and Q is nitrogen in each occurrence.

4. The kit of claim 1 wherein said gene transfer compound is that of structure I, wherein A and each occurrence of Q together are

5. The kit of claim 1 wherein said gene transfer compound is that of structure II wherein Q is nitrogen and R 2 is C 1 -C 18 alkyl.

6. The kit of claim 5 wherein R 4 is ═N—R 5 .

7. The kit of claim 5 wherein X is Cl or Br.

8. The kit of claim 1 wherein said gene transfer compound is that of structure III wherein Q in each occurrence together are

9. The kit of claim 8 wherein said gene transfer compound is that of structure II or VII wherein each occurrence of R 1 is H, or CH 3 .

10. The kit of claim 1 wherein said gene transfer compound is that of structure V wherein Q in each occurrence is oxygen.

11. The kit of claim 1 wherein said gene transfer compound is that of structure VI wherein Q in each occurrence is oxygen.

12. The kit of claim 11 wherein A is

13. The kit of claim 1 wherein said gene transfer compound is that of structure VII wherein Q in each non-aromatic substituent occurrence is oxygen.

14. The kit of claim 13 wherein R 1 in each occurrence is H.

15. The kit of claim 1 wherein said compound is selected from the group consisting of:

1-(5-chloro-2-hydroxyphenyl)-3-(3-pyridinyl)-1,3propanedione;

N-(4-(bis(2-chloroethyl)amino)benzylidene)-1,3-thiazol-2-amine;

2-((4-(bis(2-chloroethyl)amino)benzylidene)amino)benzoic acid;

2-((4-(bis(2-chloroethyl)amino)-2-methylbenzylidene)amino)ethanol;

1-Tetradecylarsonic acid;

4-(4-(bis(2-chloroethyl)amino)phenyl)-N,N-dimethylbutanamide;

N 1 -(2-fluoro-9-acridinyl)-N 3 ,N 3 -dimethyl-1,3-propanediamine;

3-(bromoacetyl)-2-imino-4,5-dimethyl-2,3-dihydro-3-furancarbonitrile;

3,5,12-trihydroxy-3-(N-hydroxyethanimidoyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl 3-amino-2,3,6-trideoxyhexopyranoside;

bouvardin;

5-((3-(dimethylamino)propyl)amino)-3,10-dimethylpyrimido[4,5-b]quinoline-2,4(3H,10H)-diane; and

1-(7-aminoisothiazolo[4,5-d]pyrimidin-3-yl)-1,4-anhydrapentitol.

16. A process for activating gene transfer of a vector to a cell comprising the steps of:

contacting a cell with a recombinant gene transfer vector; and

administering a gene transfer activating compound to the cell, such that transfer of the vector to the cell is activated;

wherein the gene transfer activating compound is selected from the group consisting of:

wherein Q is nitrogen or oxygen, wherein each occurrence of R 1 independently is H, CH 3 CH 2 CH 3 or a nullity, wherein R 2 is C 1 -C 18 alleyl, C 2 -C 18 ether, C 2 -C 18 thioether, C 2 -C 18 secondary or tertiary amine,

wherein A is

wherein R 3 is H, C 1- C 6 alkyl, or a heteroatom substituted C 1 -C 6 alkyl where the heteroatom is oxygen, nitrogen, or sulfur, wherein R 4 is C 2 -C 6 amide, or ═N—R 5 where R 5 is C 7 -C 12 aryloxyl, C 1 -C 6 hydronyl, carbonyl, carboxyl, or acyl, imidazyl, pyrazyl, thiazyl, or oxazyl,

wherein X is H, F, Cl or Br, wherein Z is oxygen or sulfur.

17. A process for activating gene transfer of a vector to a cell comprising the steps of:

contacting a cell with a recombinant gene transfer vector; and

administering a gene transfer activating compound to the cell, such that transfer of the vector to the cell is activated;

wherein the gene transfer activating compound is selected from the group consisting of:

1-(5-chloro-2-hydroxyphenyl)-3-(3-pyridinyl)-1,3-propanedione;

N4(bis(2-chloroethy)amino)benzylidene)1,3-thiazol-2-amine;

2-((4-(bis(2-chloroethyl)amino)benzylidene)amino)benzoic acid;

2-((4-(bis(2-chloroethyl)amino)2-methylbenzylidene)amino)ethanol;

1-Tetradecylarsonic acid;

4-(4-(bis(2-chloroethyl)amino)phenyl)-N,N-dimethylbutananide;

N 1 -(2-fluoro-9-acridinyl)-N 3 N 3 -dimethyl-1,3-propanediamine,

3-(bromoacetyl)-2-imino-4,5-dimethyl-2,3-dihydro-3-furancarbonitrile;

3,5,12-trihydroxy-3-(N-hydroxyethanimidoyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl 3-amino-2,3,6-trideoxyhexopyranoside;

bouvardin:

5-((3-(dimethylamino)propyl)amino)-3,10-dimethylpyrimido[4,5-b]quinoline-2,4(3H,10H)-dione; and

1 -(7-aminoisothiazolo[4,5-d]pyrimidin-3-yl)-1,4-anhydropentitol.

18. A process for determining the efficacy of a putative gene transfer activating compound to activate gene transfer, comprising the steps of:

administering a test compound to a first cell;

contacting the first cell with a first amount of a recombinant vector;

contacting a second cell with a second amount of the recombinant vector, the second amount of the recombinant vector substantially equal to the first amount;

measuring a gene transfer indicator in the first cell to obtain a test measurement;

measuring the gene transfer indicator in the second cell to obtain a control measurement; and

comparing the test measurement and the control measurement to determine the efficacy of the putative gene transfer activating compound to activate gene transfer; wherein said acne transfer compound is selected from the group consisting of:

wherein Q is nitrogen or oxygen, wherein each occurrence of R 1 independently is H, CH 3 , CH 2 CH 3 or a nullity, wherein R 2 is C 1 -C 18 allyl, C 2 -C 18 ether, C 2 -C 18 thioether, C 2 -C 18 secondary or tertiary amine,

wherein A is

wherein R 3 is H, C 1 -C 6 aikyl, or a heteroatom substituted C 1 -C 6 alkyl where the heteroatom is oxygen, nitrogen, or sulfur, wherein R 4 is C 2 -C 6 amide, or ═N—R 5 where R 5 is C 7 -C 12 aryloxyl, C 1 -C 6 hydronyl, carbonyl, carboxyl, or acyl imidazyl, pyrazyl, thiazyl, or oxazyl, wherein X is H, F, Cl or Br, wherein Z is oxygen or sulfur.

19. The process of claim 18 wherein said gene transfer compound is bouvardin.

20. The process of claim 18 wherein said gene transfer compound is that of structure I, wherein A is

and Q is nitrogen in each occurrence.

21. The process of claim 18 wherein said gene transfer compound is that of structure I, wherein A and each occurrence of Q together are

22. The process of claim 18 wherein said gene transfer compound is that of structure II wherein Q is nitrogen and R 2 is C 1 -C 18 alkyl.

23. The process of claim 18 wherein R 4 is ═N—R 5 .

24. The process of claim 18 wherein X is Cl or Br.

25. The process of claim 18 wherein said gene transfer compound is that of structure III wherein Q in each occurrence together are

26. The process of claim 18 wherein said gene transfer compound is that of structure II or VII wherein each occurrence of R 1 is H, or CH 3 .

27. The process of claim 18 wherein said gene transfer compound is that of structure V wherein Q in each occurrence is oxygen.

28. The process of claim 18 wherein said gene transfer compound is that of structure VI wherein Q in each occurrence is oxygen.

29. The process of claim 18 wherein A is

30. The process of claim 18 wherein said gene transfer compound is that of structure VII wherein Q in each non-aromatic substituent occurrence is oxygen.

31. The process of claim 18 wherein R 1 in each occurrence is H.

32. The process of claim 18 wherein said compound is selected from the group consisting of:

1-(5-chloro-2-hydroxyphenyl)-3-(3-pyridinyl)-1,3-propanedione;

N-(4-(bis(2-chloroethyl)amino)benzylidene)-1,3-thiazol-2-amine;

2-((4-(bis(2-chloroethyl)amino)benzylidene)amino)benzoic acid;

2-((4-(bis(2-chloroethyl)amino)-2-methylbenzylidene)amino)ethanol;

1-Tetradecylarsonic acid;

4-(4bis(2-chloroethyl)amino)phenyl)-N,N-dimethylbutanamide;

N 1 -(2-fluoro-9-acridinyl)-N 3 , N 3 -dimethyl-1,3-propanediamine;

3-(bromoacetyl)-2-imino-4,5-dimethyl-2,3-dihydro-3-furancarbonitrile;

3,5,12-trihydroxy-3-(N-hydroxyethanimidoyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydro-1-naphthacenyl 3-amino-2,3,6-trideoxyhexopyranoside;

bouvardin;

5-((3-(dimethylamino)propyl)amino)-3,10-dimethylpyrimido[4,5-b]quinoline-2,4(3H,10H)-dione; and 1-(7-aminoisothiazolo[4,5-d]pyrimidin-3-yl)-1,4-anhyciropentitol.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 6, 2024
From: AHMIC AEROSPACE LLC
To: AVARINT, LLC
Reel/Frame 067641/0507 →
CONFIRMATORY LICENSE Recorded Dec 20, 2018
From: UNIVERSITY OF ALABAMA AT BIRMINGHAM
To: NATIONAL INSTITUTES OF HEALTH-DIRECTOR DEITR
Reel/Frame 047837/0001 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2005
From: SORSCHER, ERIC J.
To: THE UAB RESEARCH FOUNDATION
Reel/Frame 016022/0738 →
Continuity (2)
Provisional Application 6039326600 · Jul 2, 2002
Related Publication 20060233754A1 · Oct 19, 2006