Oligooxopiperazines for p53 reactivation

Patent metadata

Field	Value
Publication number	US-9695153-B2
Application number	US-201414160037-A
Country	US
Kind code	B2
Filing date	Jan 21, 2014
Priority date	Jan 19, 2013
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

Abstract

The present invention relates to oligooxopiperazines for reactivating p53. The oligooxopiperazines comprise two or three oxopiperazine rings and substantially mimic helix αB of the C-terminal transactivation domain of Hypoxia-Inducible Factor 1α. Methods of using the oligooxopiperazines are also disclosed. Exemplary oligooxopiperazines include those of Formula I below (wherein A, R 1 , R 2 , R 3 , R 4 , and B are as defined herein).

First claim

What is claimed is:

1. A method of treating in a subject a disorder mediated by interaction of E6 with CREB-binding protein and/or p300, said method comprising:
administering to the subject an oligooxopiperazine that substantially mimics helix αB of the C-terminal transactivation domain of Hypoxia-Inducible Factor 1α under conditions effective to treat the disorder, wherein the oligooxopiperazine is Formula I:

wherein:
each of R 1 , R 2 , R 3 , and R 4 is independently an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
each R 6 is independently H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
A is X 1 or C, wherein:
X 1 is H, COR′, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag; wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
C is a moiety of the formula

wherein:
each X′ is independently H, COR′, CO 2 R′, N(R″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; wherein:
R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
each R″ is independently H, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;

R 0 is an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl; and
R 6 is H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl; and

B is Y or D, wherein:
Y is OR′, COR′, N(R′″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag;
wherein:
R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
each R′″ is independently H, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and

D is a moiety of the formula

wherein:
R 5 is an amino acid side chain, H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
R 6 is H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl; and
E is X 2 or F, wherein:
X 2 is H, COR′, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of an amine, a targeting moiety, or a tag; wherein R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
F is a moiety of the formula

wherein:
R 6 is H, N(R) 2 , OR, halogen, an alkyl, or an aryl; wherein each R is independently H, an alkyl, or an aryl;
R 7 is an amino acid side chain; and
Y is OR′, COR′, N(R′″) 2 , an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a protecting group for protection of a carboxylic acid, a targeting moiety, or a tag; wherein:
 R′ is H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
 each R′″ is independently H, CO 2 R′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag.

2. The method according to claim 1 , wherein the oligooxopiperazine is BB2-125:

BB2-125: R 1 =CH 2 CH(CH 3 ) 2 , R 2 =CH 2 CH(CH 3 ) 2 , R 3 =CH 3 , R 4 =CH 3 .

3. The method according to claim 1 , wherein:
(i) (a) A is X 1 , R 1 and R 2 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor; or (b) A is C, R 0 and R 3 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor;
(ii) each R″ is independently H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; and
(iii) B is not D.

4. The method according to claim 3 , wherein A is X 1 , R 1 and R 2 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor.

5. The method according to claim 4 , wherein the oligooxopiperazine is BB2-162:

BB2-162: R 1 =CH 2 CH(CH 3 ) 2 , R 2 =CH 2 CH(CH 3 ) 2 , R 3 =CH 3 , R 4 =CH 2 CH 2 CONH 2 .

6. The method according to claim 1 , wherein the oligooxopiperazine has a formula of Formula IB:

7. The method according to claim 6 , wherein R 1 , R 2 , and R 4 of the oligooxopiperazine of Formula D3 mimic the amino acid side chain of, respectively, residues i, i+4, and i+7, of the α-helix.

Assignees

• Univ New York
• Univ Ohio State Res Found
• Univ Michigan Regents

Inventors

• Arora Paramjit S
• Pan Quintin
• Mapp Anna

Classifications

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61P35/00

  Antineoplastic agents · CPC title