Molecular design and synthesis of anti-cancer compounds that cause apoptosis

引起细胞凋亡的抗癌化合物的分子设计和合成

• 批准号: 09672280
• 负责人: OTSUKA Masami
• 金额: $ 2.3万
• 依托单位: Kumamoto University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672280/
• 关键词: apoptosis; apoptosis resistant cell; active oxygen; anti-cancer agent

Apoptosis is a programmed cell death induced through the intracellular signalling pathway caused by the binding of TNF or Fas ligand with receptors of cell surface. Involvement of active oxygen species has been postdated in the signal transduction pathway leading to apoptosis. The objective of the present research is to synthesize man-made molecules that supply active oxygen into the signalling pathway to induce apoptosis in the tumor cells.The head investigators are successful in the synthesis of highly efficient oxygen activating molecules by introducing various functional groups such as imidazole into dimethylaminopyridine. The synthesitic molecule induced apoptosis in mouse leukaemia L1210 cells, human leukaemia K562/ADM cells, human carcinoma KB-C4 cells, and human pancreatic carcinoma AsPC-1 cells depending on time and concentration. The cell death was found to be apoptosisbased on the morphological change of the cells and intranucleosomal degradation of DNA.The apoptosis was inhibited by an antioxidant ascorbic acid suggesting the involvement of active oxygen species. It was found that caspase-1, caspase-3, Bcl-2, Bax, p53, and p21 do not participate in the apoptosis caused by the synthetic molecule.Thus the head investigators are successful in the molecular design and synthesis of an artificial molecule that generates active oxygen species to induce apoptosis in carcinoma cells.

细胞凋亡是由TNF或Fas配体与细胞表面受体结合引起的细胞内信号通路诱导的程序性细胞死亡。活性氧的参与已被推迟到导致细胞凋亡的信号转导途径中。本研究的目的是合成人造分子，向信号通路提供活性氧以诱导肿瘤细胞凋亡。主要研究人员通过引入多种功能基团，如咪唑转化为二甲氨基吡啶。合成分子根据时间和浓度诱导小鼠白血病 L1210 细胞、人白血病 K562/ADM 细胞、人癌 KB-C4 细胞和人胰腺癌 AsPC-1 细胞凋亡。根据细胞的形态变化和核小体内DNA的降解，发现细胞死亡是凋亡。抗氧化剂抗坏血酸抑制了细胞凋亡，表明活性氧的参与。发现caspase-1、caspase-3、Bcl-2、Bax、p53和p21不参与合成分子引起的细胞凋亡。由此，首席研究员成功地进行了人工分子的分子设计和合成。产生活性氧以诱导癌细胞凋亡。

项目成果

Takumi Watanabe et al.: "Total synthesis of * -aglaiastatin, a novel bioactive alkaloid" J.Chem.Soc., Chem.Commun.1998. 1097-1098 (1998)

Takumi Watanabe 等人：“* -aglaistatin（一种新型生物活性生物碱）的全合成”J.Chem.Soc.，Chem.Commun.1998。

Masami Otsuka et al.: "Cloning and Characterization of a cDNA Encoding the Human Homolog of Tumor Necrosis Factor Receptor-Associated Factor 5 (TRAF 5)" Gene. 207. 135-140 (1998)

Masami Otsuka 等人：“编码肿瘤坏死因子受体相关因子 5 (TRAF 5) 人类同源物的 cDNA 的克隆和表征”基因。

Rei Suginaka et al.: "Induction of Apoptosis in Human Pancreatic Carcinoma Cells by a Synthetic Bleomycin-like Ligand" Jpn.J.Cancer Res.89. 947-953 (1998)

Rei Suginaka 等人：“通过合成博莱霉素样配体诱导人胰腺癌细胞凋亡”Jpn.J.Cancer Res.89。

大塚雅巳: "ブレオマイシンをモデルにしたアポトーシス誘導剤の分子設計" 癌と化学療法. 24・4. 412-417 (1997)

大冢正美：“以博莱霉素为模型的细胞凋亡诱导剂的分子设计”《癌症与化疗》24・4（1997）。

大塚雅巳: "Cloning and Characterization of a cDNA Encoding the Human Homolog of Tumor Necrosis Factor Receptor-Associated Factor 5(TRAF5)" Gene. (印刷中). (1998)

Masami Otsuka：“编码肿瘤坏死因子受体相关因子 5 (TRAF5) 人类同源物的 cDNA 的克隆和表征”（正在出版）。