School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Bioorg Med Chem. 2018 Jul 23;26(12):3217-3226. doi: 10.1016/j.bmc.2018.04.048. Epub 2018 Apr 23.
A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1-methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC values in range of 2.2-4.6 μM, while the IC value of reference compound VX-680 was 8.5-15.3 μM. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC values were 118 ± 8.1 and 80 ± 4.2 nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer.
一系列 2,4-二取代的酞嗪酮被合成，并评估了它们的生物活性，包括抗增殖、抑制 Aurora 激酶和细胞周期效应。其中，N-环己基-4-((4-(1-甲基-1H-吡唑-4-基)-1-氧代酞嗪-2(1H)-基)甲基)苯甲酰胺（12c）对五种癌细胞系（HeLa、A549、HepG2、LoVo 和 HCT116 细胞）表现出最强的抗增殖活性，IC 值在 2.2-4.6 μM 范围内，而参考化合物 VX-680 的 IC 值为 8.5-15.3 μM。此外，Aurora 激酶测定表明，化合物 12c 是 AurA 和 AurB 激酶的有效抑制剂，IC 值分别为 118±8.1 和 80±4.2 nM。分子对接研究表明，化合物 12c 与 AurA 和 AurB 均形成更好的相互作用。此外，化合物 12c 通过调节细胞周期蛋白 B1 和 cdc2 的蛋白水平诱导 HeLa 细胞 G2/M 细胞周期阻滞。这些结果表明，12c 是一种有前途的泛 Aurora 激酶抑制剂，可用于癌症的潜在治疗。
