Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents.
Design, synthesis and bioevaluation of dihydropyrazolo[3,4-b]pyridine and benzo[4,5]imidazo[1,2-a]pyrimidine compounds as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents.
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DOI：
10.1016/j.bmc.2010.09.020
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发表时间：
2010-11
影响因子：
3.5
通讯作者：
Rong-Geng Fu;Q. You;Lei Yang;Wu-tong Wu-Wu-tong-Wu-12237523;Cheng Jiang;Xiaoli Xu
中科院分区：
文献类型：
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作者：
Rong-Geng Fu;Q. You;Lei Yang;Wu-tong Wu-Wu-tong-Wu-12237523;Cheng Jiang;Xiaoli Xu
通过在我们的KSP抑制剂CPUYL064中引入一些Aurora-A激酶抑制剂片段，设计并合成了四个系列的二氢吡唑并[3，4-b]吡啶和苯并[4，5]咪唑并[1，2-a]嘧啶作为双重KSP和Aurora-A激酶抑制剂。通过两种相关的酶抑制试验和体外细胞毒性试验对19个目标化合物进行了评价。结果表明，部分目标化合物对两种酶均有抑制作用，其中几个化合物对HCT116细胞有明显的抑制作用。尽管先导化合物6a和6e表现出中等程度的KSP和Aurora-A激酶抑制作用，但它们在微摩尔范围内表现出显著的细胞毒活性，特别是对HCT116细胞和HepG2细胞株。这些结果可能有助于开发一类具有双重功能的新的抑制剂，即KSP抑制和Aurora-A激酶抑制，用于癌症的治疗。
Four series of dihydropyrazolo[3,4-b]pyridines and benzo[4,5]imidazo[1,2-a]pyrimidines were designed and synthesized as dual KSP and Aurora-A kinase inhibitors for anti-cancer agents by introducing some fragments of Aurora-A kinase inhibitors into our KSP inhibitor CPUYL064. A total of 19 target compounds were evaluated by two related enzyme inhibition assays and a cytotoxicity assay in vitro. The results showed that some target compounds could inhibit both enzymes, and several of them showed significant inhibition activity against HCT116 cell line. Despite showing moderate KSP and Aurora-A kinase inhibition, the lead compounds 6a and 6e displayed significant cytotoxic activity in the micromolar range, especially against the HCT116 cell line and HepG2 cell line. The results may be useful for developing a new class of inhibitors having a dual function, KSP inhibition and Aurora-A kinase inhibition, for the treatment of cancer.