Development of compounds for multiple regulation of intracellular signaling

开发用于细胞内信号传导多重调节的化合物

• 批准号: 11470496
• 负责人: OTSUKA Masami
• 金额: $ 4.22万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470496/
• 关键词: Man-made ligand; AIDS virus; NFκB; HIV-EP1; Sp1; HIV-EPl; Spl; NFkB

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.

已知许多疾病是由细胞内信号传导机制的紊乱引起的，这种紊乱可以通过开发适当的操纵信号传导系统的方法来修复，因此，我们试图开发人造分子来保持相关的细胞内信号传导环境的良好平衡。 HIV-1原病毒的表达主要受细胞转录因子NFκB、HIV-EP1和Sp1的控制，抑制这些转录蛋白的功能将导致艾滋病复制的干扰。在此，我们报告了抑制 NFκB、HIV-EP1 和 Sp1 的方法。如果我们能够获得针对这些转录因子的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，发现该化合物是高效的锌螯合剂，在300 μM浓度下对HIV-EP1和Sp1的DNA结合表现出显着的抑制作用。我们进一步设计了含硫化合物。配体，半胱胺-吡啶-半胱胺系统，并发现这些化合物在 30 μM 浓度下对 HIV-EP1 和 Sp1 均有效。我们还偶然发现，一些咪唑-吡啶-咪唑化合物在300 μM 浓度此外，金三羧酸是 NFκB-DNA 结合的有效抑制剂。 30 μM 浓度有效。

项目成果

Rakesh Kumar Sharma, Bhagwan Singh Garg, Hiromasa Kurosaki, Masafumi Goto, Masami Otsuka, Tadashi Yamamoto, Jun-ichiro Inoue: "Aurine Tricarboxylic Acid, a Potent Metal-Chelating Inhibitor of NF_B-DNA Binding"Bioorg.Med.Chem.. 8(7). 1819-1823 (2000)

Rakesh Kumar Sharma、Bhagwan Singh Garg、Hiromasa Kurosaki、Masafumi Goto、Masami Otsuka、Tadashi Yamamoto、Jun-ichiro Inoue：“金三羧酸，NF_B-DNA 结合的有效金属螯合抑制剂”Bioorg.Med.Chem.. 8

Teruhiko Inoue: "Fluorescence property of oxazole yellow-linked oligonucleotide. Triple helix formation and photocleavage of double-stranded DNA"Bioorg.Med.Chem.. 7. 1207-1211 (1999)

Teruhiko Inoue：“恶唑黄连接寡核苷酸的荧光特性。双链 DNA 的三螺旋形成和光裂解”Bioorg.Med.Chem.. 7. 1207-1211 (1999)

Masami Otsuka, Akiyuki Hamasaki, Hiromasa Kurosaki, Masafumi Goto: "Synthesis, Structure of Copper (II) Complexes of S-containing Pentadentate Ligands"J.Organomet.Chem.. 611. 577-585 (2000)

Masami Otsuka、Akiyuki Hamasaki、Hiromasa Kurosaki、Masafumi Goto：“含 S 五齿配体的铜 (II) 配合物的合成、结构”J.Organomet.Chem.. 611. 577-585 (2000)

Rakesh Kumar Sharma: "Aurine tricarboxylic acid, a potential metal-chelating inhibitor of NFκB-DNA binding"Bioorg.Med.Chem.. 8. 1819-1823 (2000)

Rakesh Kumar Sharma：“金三羧酸，NFκB-DNA 结合的潜在金属螯合抑制剂”Bioorg.Med.Chem.. 8. 1819-1823 (2000)

Kazuo Umezawa, Kumi Nakazawa, Yuki Uchihata, Masami Otsuka: "Screening for Inducers of Apoptosis in Apoptosis-Resistant Human Carcinoma Cells"Adv.Enz.Regul.. Vol.39.. 145-156 (1999)

Kazuo Umezawa、Kumi Nakazawa、Yuki Uchihata、Masami Otsuka：“筛选抗凋亡人类癌细胞中的凋亡诱导物”Adv.Enz.Regul.. Vol.39.. 145-156 (1999)