Control of hypoxia-inducible gene expression with oligooxopiperazine nonpeptidic helix mimetics

Patent metadata

Field	Value
Publication number	US-9255086-B2
Application number	US-201314379450-A
Country	US
Kind code	B2
Filing date	Feb 19, 2013
Priority date	Feb 16, 2012
Publication date	Feb 9, 2016
Grant date	Feb 9, 2016

Abstract

The present invention relates to oligooxopiperazines that mimic helix αB of the C-terminal transactivation domain of HIF-1α. Also disclosed are pharmaceutical compositions containing these oligooxopiperazines and methods of using these oligooxopiperazines (e.g., to reduce gene transcription, treat or prevent disorders mediated by interaction of HIF-1α with CREB-binding protein and/or p300, reduce or prevent angiogenesis in a tissue, induce apoptosis, and decrease cell survival and/or proliferation).

First claim

What is claimed:

1. A method of reducing transcription of a gene in a cell, wherein transcription of the gene is mediated by interaction of Hypoxia-Inducible Factor 1α with CREB-binding protein and/or p300, said method comprising:
contacting the cell with an oligooxopiperazine under conditions effective to reduce transcription of the gene, wherein the oligooxopiperazine is an oligooxopiperazine of 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′, CONHR′, 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′, CONHR′, 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, 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 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′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;

wherein R 1 and R 2 are hydrophobic and R 4 is a hydrogen bond acceptor or hydrogen bond donor, or A is a moiety of formula

 R 0 and R 3 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor; and
with the proviso that at least one of the following conditions is not met: R 1 is a leucine side chain R 2 is a leucine side chain, and R 4 is a glutamine side chain.

2. The method according to claim 1 , wherein the gene is selected from the group consisting of α 1B -adrenergic receptor, adenylate kinase 3, adrenomedullin, aldolase A, aldolase C, carbonic anhydrase IX, ceruloplasmin, chemokine receptor type 4 (CXCR4, fusin, CD184), c-Met, endothelin-1, enolase 1, erythropoietin, glucose transporter 1, glucose transporter 3, glyceraldehyde-3-phosphate dehydrogenase, heme oxygenase 1, hexokinase 1, hexokinase 2, IGF binding protein 1, IGF binding protein 3, insulin-like growth factor 2, lactate dehydrogenase A, lysyl oxidase, monoamine oxidase isoform A, monoamine oxidase isoform B, nitric oxide synthase 2, p21, p35 srg , phosphofructokinase, phosphoglycerate kinase 1, plasminogen activator inhibitor 1, pyruvate kinase M, stromal-derived factor 1, tranferrin receptor, transferrin, transforming growth factor β 3 , triose phosphate isomerase 1, vascular endothelial growth factor, vascular endothelial growth factor receptor FLT-1, and vascular endothelial growth factor receptor KDR/Flk-1.

3. A method of treating in a subject a disorder mediated by interaction of Hypoxia-Inducible Factor 1α with CREB-binding protein and/or p300, said method comprising:
administering to the subject an oligooxopiperazine under conditions effective to treat the disorder, wherein the oligooxopiperazine is an oligooxopiperazine of 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′, CONHR′, 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′, CONHR′, 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, 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 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′, CONHR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;

wherein R 1 and R 2 are hydrophobic and R 4 is a hydrogen bond acceptor or hydrogen bond donor, or A is a moiety of formula

 R 0 and R 3 are hydrophobic, and R 4 is a hydrogen bond acceptor or hydrogen bond donor; and
with the proviso that at least one of the following conditions is not met: R 1 is a leucine side chain R 2 is a leucine side chain, and R 4 is a glutamine side chain.

4. The method according to claim 3 , wherein the disorder is selected from the group of abnormal organ development, abnormal iron uptake, abnormal iron metabolism, abnormal oxygen transport, abnormal vasoconstriction, abnormal vasomotor tone, aerobic glycolysis, age-related macular degeneration, aggression, angiogenesis, cancer, depression, diabetic macular edema, diabetic retinopathy, Hashimoto's encephalopathy, intrauterine growth retardation, myocardial infarction, pheochromocytoma, pulmonary hypertension, retinal ischemia, and asthma.

5. A method of reducing angiogenesis in a tissue, said method comprising:
contacting the tissue with an oligooxopiperazine under conditions effective to reduce angiogenesis in the tissue, wherein the oligooxopiperazine is an oligooxopiperazine of Formula I:

wherein:
each of R 1 , R 2 , R 3 and R 4 is independently

Assignees

• Arora Paramjit S
• Olenyuk Bogdan
• Lau Brooke Bullock
• Grishagin Ivan
• Univ New York
• Univ Southern California

Inventors

• Arora Paramjit S
• Olenyuk Bogdan
• Lau Brooke Bullock
• Grishagin Ivan

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P43/00

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