Development of compounds for multiple regulation of intracellular signaling

众所周知，许多疾病是由细胞内信号机制紊乱引起的。这种紊乱可以通过开发一种适当的方法来操纵信号系统来修复。因此，我们试图开发人造分子来保持与获得性免疫缺陷综合征（AIDS）相关的细胞内信号环境的平衡。HIV-1前病毒的表达主要受细胞转录因子NFκB、HIV-EP1和Sp1的调控。抑制这些转录蛋白的功能将导致艾滋病病毒复制受到干扰。在此，我们报告了抑制NFκB、HIV-EP1和Sp1的方法。如果能够获得靶向这些转录因子锌位点的金属螯合剂，则可以抑制锌指蛋白的功能。我们设计了咪唑-吡啶-咪唑体系，发现化合物是高效的锌螯合剂，在300 μM浓度下对HIV-EP1和Sp1的DNA结合有显著的抑制作用。我们进一步设计了含硫配体，半蒸汽-吡啶-半胱胺体系，发现这些配体在30 μM浓度下对HIV-EP1和Sp1均有效。我们也偶然发现一些咪唑-吡啶-咪唑类化合物在300 μM浓度下抑制NFκB的DNA结合。此外，研究表明，在30 μM浓度下，金嘌呤三羧酸是一种有效的NFκB-DNA结合抑制剂。

Many diseases are known to be caused by the disorder of intracellular signaling machinery. The disorder would be repaired by developing an appropriate means of manipulating the signaling system. Thus, we attempted to develop man-made molecules to keep well-balanced intracellular signaling environment related to acquired immune deficiency syndrome (AIDS).Expression of HIV-1 provirus is governed primarily by cellular transcription factors NFκB, HIV-EP1, and Sp1. Inhibition of the function of these transcriptional proteins would lead to the interference of the replication of AIDS virus. Herein we report our approach for the inhibition of NFκB, HIV-EP1, and Sp1.The function of zinc finger protein could be inhibited if we could obtain metal chelators that target the zinc site of these transcription factors. We designed imidazole-pyridine-imidazole systems and found that compounds are efficient zinc chelators exhibiting remarkable inhibitory effect on the DNA binding of HIV-EP1 and Sp1 at 300 μM concentration. We further designed sulfurcontaining ligands, cysteamine-pyridine-cysteamine system, and found those to be uniformly effective at 30 μM concentration against both HIV-EP1 and Sp1.. We have also serendipitously shown that some of imidazole-pyridine-imidazole compounds inhiited the DNA binding of NFκB at 300 μM concentration. Further, it was shown that aurine tricarboxylic acid is a potent inhibitor of NFκB-DNA bindinf effective at 30 μM concentration.