CONTROL OF HYPOXIA-INDUCIBLE GENE EXPRESSION WITH OLIGOOXOPIPERAZINE NONPEPTIDIC HELIX MIMETICS

摘要

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).

主权项

1. An oligooxopiperazine of Formula I: wherein: each of R1, R2, R3, and R4 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 R6 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 X1 or C, wherein:
X1 is H, COR′, CO2R′, CONR′, 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; andC is a moiety of the formula  wherein:
each X′ is independently H, COR′, CO2R′, CONR′, 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; andeach R″ is independently H, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag;R0 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; andR6 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; andeach R′″ is independently H, CO2R′, CONR′, an alkyl, an aryl, an arylalkyl, a cycloalkyl, a heteroaryl, a targeting moiety, or a tag; wherein R1 and R2 are hydrophobic and R4 is a hydrogen bond acceptor or hydrogen bond donor, or A is a moiety of formula  R0 and R3 are hydrophobic, and R4 is a hydrogen bond acceptor or hydrogen bond donor; and with the proviso that at least one of the following conditions is not met: R1 is a leucine side chain, R2 is a leucine side chain, and R4 is a glutamine side chain.