Chemogenomic approach for elucidation and control of intracellular signal transductions

对二萜糖苷（fusicoccane type二萜苷）子叶列宁（cotylenin， CN）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。所得结果总结如下：1。CN分别与干扰素α和雷帕霉素对卵巢癌和乳腺癌细胞有显著的协同作用。通过这些联合治疗，肿瘤的生长在小鼠的异种移植物中得到有效的抑制。3α-羟基fusicoccin J是fusicoccin （FC）的极性同系物，从产生fusicoccin的真菌Phomopsis amygdali中分离得到。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在植物组织中具有相同的活性。然而，只有CN对人髓系白血病细胞株（HL-60）具有较强的诱导分化活性。相反，FC表现出细胞毒性。详细的SAR研究得出了FC的12-OH干扰活性的结论。根据SAR研究的结论，我们成功地合成了12个脱氧梭霉素衍生物，其活性与CN.5一样强。反向化学基因组学研究表明，CN可以与14-3-3 sigma作为一种选择性交联的异构体，并增强了该异构体对其伴侣磷酸化肽的结合能力。

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.