Chemogenomic approach for elucidation and control of intracellular signal transductions

对甘蔗二萜糖苷的抗癌活性进行了正向化学基因组学研究，对细胞内信号转导调节蛋白14-3-3蛋白进行了反向化学基因组学研究。结果如下：1.CN与干扰素α或雷帕米星分别对卵巢癌细胞和乳腺癌细胞有显著的协同作用。结论：1.通过这些联合治疗，小鼠移植瘤的生长得到了有效的抑制。3-羟基褐孢菌素J是褐霉素类化合物(Fc)的一种极性异构体，是从褐霉素产生菌杏仁拟南星中分离得到的。3-α-羟基fusicocin J是从产生褐霉素的真菌中分离得到的。该化合物可用于CN/FC类化合物抗癌活性的构效关系(SAR)研究。CN和FC在植物组织上具有相同的活性。然而，只有CN具有较强的人髓系白血病细胞系(HL-60)的诱导分化活性。相反，FC表现出细胞毒性。详细的合成孔径雷达研究表明，FC的12-羟基干扰了活性。根据构效关系研究的结论，我们成功地合成了活性与CN.5相当的12-脱氧褐霉素衍生物。反向化学基因组学研究表明，CN可以与14-3-3西格玛以一种异构体选择性的方式进行交联，并增强该异构体与其配对的荧光肽的结合能力。

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.