Chemogenomic approach for elucidation and control of intracellular signal transductions

本文对一种镰刀菌型二萜苷类化合物Cotylenin（CN）的抗癌活性进行了正向化学基因组学研究，并对细胞内信号转导调节蛋白14-3-3进行了反向化学基因组学研究。所获得的结果总结如下：1. CN与干扰素α或雷帕霉素分别在卵巢癌和乳腺癌细胞上观察到显著的协同效应。通过这些联合治疗，有效地减少了小鼠异种移植瘤的生长。3α-hydroxyfusicoccin J是从产梭孢菌素（fusicoccin，FC）的真菌扁桃拟茎点霉（Phomopsis amygdali）中分离得到的一种极性同系物。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对植物组织的活性相当。然而，只有CN对人髓系白血病细胞系（HL-60）具有较强的诱导分化活性。FC表现出细胞毒性。详细的SAR研究得出结论，FC的12-OH干扰活性.根据构效关系研究的结论，我们成功地合成了12-脱氧梭孢菌素衍生物，其活性与CN.5的活性相当。反向化学基因组学研究表明，CN可以与14-3-3 sigma交联作为异构体选择性方式，并加强该异构体与其伴侣磷肽的结合能力。

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.