Novel derivatives of aclacinomycin A block cancer cell migration through inhibition of farnesyl transferase
Novel derivatives of aclacinomycin A block cancer cell migration through inhibition of farnesyl transferase
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阿克拉霉素 A 的新型衍生物通过抑制法尼基转移酶来阻止癌细胞迁移
DOI：
10.1038/ja.2012.108
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Masaya Imoto
中科院分区：
文献类型：
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作者：
Shigeyuki Magi;Tetsuo Shitara;Yasushi Takemoto;Masato Sawada;Mitsuhiro Kitagawa;Etsu Tashiro;Yoshikazu Takahashi;Masaya Imoto
在筛选法尼基转移酶（FTase）抑制剂的过程中，我们鉴定了两个化合物，N-苄基阿克拉霉素A（ACM）和N-烯丙基ACM，这是ACM的新衍生物。N-苄基-ACM和N-烯丙基-ACM抑制FTase活性，IC 50值分别为0.86和2.93 μ M。不仅ACM，而且每个ACM衍生物的C-10差向异构体也不能抑制FTase。N-苄基-ACM和N-烯丙基-ACM对FTase的抑制似乎是特异性的，因为这两种化合物在高达100 μ M的浓度下不会抑制香叶基香叶基转移酶或香叶基香叶基焦磷酸（GGPP）合酶。在培养的A431细胞中，N-苄基-ACM和N-烯丙基-ACM也阻断H-Ras的膜定位和H-Ras依赖的PI 3 K/Akt通路的激活。此外，它们还抑制表皮生长因子（EGF）诱导的A431细胞迁移。因此，N-苄基-ACM和N-烯丙基-ACM通过抑制H-Ras的法尼基化和随后的H-Ras依赖的PI 3 K/Akt通路的激活来抑制EGF诱导的A431细胞迁移。
In the course of screening for an inhibitor of farnesyl transferase (FTase), we identified two compounds, N-benzyl-aclacinomycin A (ACM) and N-allyl-ACM, which are new derivatives of ACM. N-benzyl-ACM and N-allyl-ACM inhibited FTase activity with IC 50 values of 0.86 and 2.93 μ M, respectively. Not only ACM but also C-10 epimers of each ACM derivative failed to inhibit FTase. The inhibition of FTase by N-benzyl-ACM and N-allyl-ACM seems to be specific, because these two compounds did not inhibit geranylgeranyltransferase or geranylgeranyl pyrophosphate (GGPP) synthase up to 100 μ M. In cultured A431 cells, N-benzyl-ACM and N-allyl-ACM also blocked both the membrane localization of H-Ras and activation of the H-Ras-dependent PI3K/Akt pathway. In addition, they inhibited epidermal growth factor (EGF)-induced migration of A431 cells. Thus, N-benzyl-ACM and N-allyl-ACM inhibited EGF-induced migration of A431 cells by inhibiting the farnesylation of H-Ras and subsequent H-Ras-dependent activation of the PI3K/Akt pathway.