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

A technology of oligomeric oxopiperazines and pharmaceutical preparations, applied in the direction of using carriers to introduce foreign genetic material, medical preparations containing active ingredients, metabolic diseases, etc., and can solve problems such as leukocytosis

Inactive Publication Date: 2015-02-04
NEW YORK UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although early reports are encouraging, further design of inhibitors of the HIF-1 pathway is still needed because both 1 and 2 have induced coagulative necrosis, anemia, and leukocytosis in experimental animals

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0133] The synthesis of embodiment 1-oligomeric oxypiperazine

[0134] Oligomeric oxopiperazines were synthesized by solid phase synthesis as described in U.S. Patent No. 12 / 917,176 to Arora et al., which is hereby incorporated by reference in its entirety, as shown in the following scheme 1.

[0135]

[0136] plan 1

[0137] Dipeptide 1 was synthesized by standard Fmoc solid-phase peptide synthesis on Knorr resin in a solid-phase reaction vessel. The Fmoc group was removed by treatment with 20% piperidine in dimethylformamide (DMF), and the resin was washed sequentially with DMF, dichloromethane (DCM), methanol (MeOH) and diethyl ether, then dried in vacuo. o-Nitrobenzenesulfonyl chloride (Ns-Cl, 10 equiv) and chloropyridine (10 equiv) were dissolved in anhydrous DCM and added to the reaction vessel. The mixture was shaken at 23°C for 2 hours to give 2. The 2-containing resin was then washed sequentially with DMF, DCM, MeOH and diethyl ether, and dried under vacuum for...

Embodiment 2

[0140] Example 2 - MTT cell viability

[0141] Human breast cancer (MCF7) or human lung cancer (A549) cells were seeded in 96-well plates (Greiner) at a density of 5,000-10,000 cells in 200 μL fresh medium per well; MCF7 cells were seeded in 10% FBS (Irvine Scientific ) in RPMI medium (Gibco), A549 cells (ATCC) were seeded in F-12K medium (ATCC) with 2% FBS (Irvine Scientific). Then place the culture plate in the incubator (37°C, 5%-10% CO 2 ) until the desired confluency (approximately 70%) is reached (approximately 24-72 hours). Thereafter, the medium in all wells was replaced with a solution of BB2-125 or BB2-162 in the appropriate medium (150 μL for the 48 hour study and 200 μL for the 72 hour study, respectively). Then place the culture plate at 37°C, 5%-10% CO 2 maintained in the incubator for 48 or 72 hours. After 48 (or 72) hours of incubation with compounds, MTT (5 mg / ml in PBS, Sigma-Aldrich) (10% v / v) was added to each well and mixed carefully and thoroughly. P...

Embodiment 3

[0142] Example 3 - Luciferase Transcription Assay

[0143] All work was performed in a biohood with sterile supplies. MDA231-VEGF(HRE)-luc cells were seeded in 24-well plates (Greiner BioOne, 65,000 cells per well in 2 ml G418 DMEM medium (Gibco) with 10% FBS (Irvine Scientific)). Place the culture plate in the incubator for 24 hours (37°C and 5%-10% CO 2 ). Thereafter, individual wells were replaced with 10-μM or 20-μM solutions of BB2-125, BB2-162, BB2-164 or vehicle control (1 ml / well each) in medium (G418 DMEM, 10% FBS) Medium in. Incubate the culture plate for 6 hours (37°C, 5%-10% CO 2 ), then an aqueous solution of DFO (Sigma-Aldrich) (19.6 mg / ml, filtered through a 0.2 micron Tuffryn filter (PALL), 10 μL per well) was added to the appropriate wells to induce hypoxia. Incubate the plate for another 3 hours (37°C, 5%-10% CO 2 ), the appropriate culture plate was then placed in a plastic bag containing wet wipes and an anaerobic production pouch (BD GasPak EZ Pouch ...

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Abstract

The present invention relates to oligooxopiperazines that mimic helix alphaB of the C-terminal transactivation domain of HIF-1alpha. 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-1alpha with CREB-binding protein and / or p300, reduce or prevent angiogenesis in a tissue, induce apoptosis, and decrease cell survival and / or proliferation).

Description

[0001] This application claims the benefit of US Provisional Patent Application Serial No. 61 / 599,763, filed February 16, 2012, which is hereby incorporated by reference in its entirety. [0002] This invention was made with US Government support under Grant No. CHE-0848410 awarded by the National Science Foundation. The US Government has certain rights in this invention. field of invention [0003] The present invention relates to oligomeric oxopiperazines comprising a sequence that substantially mimics helix αB of the C-terminal transcriptional activation domain of hypoxia-inducible factor 1α. Background of the invention [0004] Such as figure 1 As exemplified, angiogenesis, the induction of new blood vessels, is central to normal growth as well as the pathogenesis of various disorders. In cancer, angiogenesis accelerates solid tumor growth and provides access for metastasis through newly formed vasculature. In contrast, therapeutic angiogenesis is important to reduce ...

Claims

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Application Information

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IPC IPC(8): C07D401/12C07D401/06C07D403/06C12N15/63A61K31/497A61P35/00
CPCC07D401/12C07D403/06C07D401/06C12N15/63A61K31/496C07D241/08A61P3/10A61P7/06A61P9/00A61P9/10A61P9/12A61P11/06A61P15/00A61P25/00A61P25/24A61P27/02A61P35/00A61P43/00C07D403/14
Inventor P·S·阿罗拉B·奥伦宇克B·B·刘I·格瑞沙晋
Owner NEW YORK UNIV
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