Chemogenomic approach for elucidation and control of intracellular signal transductions

阐明和控制细胞内信号转导的化学基因组学方法

基本信息

批准号：
15310150
负责人：
KATO Nobuo
金额：
$ 9.54万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

Forward chemogenomic studies for anti-cancer activity of cotylenin (CN), a fusicoccane type of diterpene glycoside, and reverse chemogenomic investigation on 14-3-3 proteins, regulatory proteins in intracellular signal transductions, have been carried out. Results obtained are summarized below :1. Significant synergistic effects of CN with interferon α or rapamicin are observed on ovary and breast cancer cells, respectively. With these combined treatment, growth of tumors were effectively reduced in xenografts on mice.2. As a polar congener of fusicoccins (FC), 3α-hydroxyfusicoccin J has been isolated from fusicoccin-producing fungus, Phomopsis amygdali. This compound was quite useful for Structure-Activity=Relationship (SAR) studies on anti-cancer activities of CN/FC class of compounds.3. CN and FC have identical activities on plant tissues. However, only CN has a strong differentiation-inducing activity of human myeloid leukemia cell line (HL-60). FC exhibits cytotoxicity instead. Detailed SAR studies lead the conclusion that the 12-OH of FC interferes the activity.4. According to the conclusion of SAR studies, we have succeeded in synthesizing 12-deoxyfusicoccin derivatives of which activities are as potent as that of CN.5. Reverse chemogenomic investigation revealed that CN can cross-link with 14-3-3 sigma as an isoform selective fashion and strength the binding ability of this isoform toward its partner phosphor-peptide.

对子叶素 (CN)（一种二萜糖苷的 Fusicoccane 型）的抗癌活性进行了正向化学基因组研究，并对 14-3-3 蛋白（细胞内信号转导中的调节蛋白）进行了反向化学基因组研究，所得结果总结如下。 :1. CN 与干扰素 α 或雷帕霉素分别对卵巢癌细胞和乳腺癌细胞的生长具有显着的协同作用。小鼠异种移植瘤中的肿瘤得到有效减少。 2. 作为 Fusicoccins (FC) 的极性同系物，3α-羟基 Fusicoccin J 已从产生 Fusicoccin 的真菌 Phomopsis amygdali 中分离出来，该化合物对于结构-活性=关系 (SAR) 非常有用。 ) CN/FC 类化合物的抗癌活性研究。3. CN 和 FC 对植物组织具有相同的活性。 CN对人骨髓性白血病细胞系(HL-60)具有很强的分化诱导活性，而FC却表现出细胞毒性。详细的SAR研究得出FC的12-OH干扰该活性的结论。4．经过研究，我们成功合成了 12-脱氧梭菌素衍生物，其活性与 CN.5 一样有效。反向化学基因组研究表明 CN 可以交联。以 14-3-3 sigma 作为异构体选择性方式，并增强该异构体与其伙伴磷酸肽的结合能力。