Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents
Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents
复制标题
新型苯并咪唑-2-取代苯基或吡啶丙基烯酮衍生物作为抗肿瘤药物的设计、合成和生物学评价
DOI：
10.1016/j.ejmech.2016.03.029
复制
发表时间：
2016
影响因子：
6.7
通讯作者：
Li Zhuo-rong
中科院分区：
文献类型：
--
作者：
Wu Lin-tao;Jiang Zhi;Shen Jia-jia;Yi Hong;Zhan Yue-chen;Sha Ming-quan;Wang Zhen;Xue Si-tu;Li Zhuo-rong
设计并合成了一系列新型苯并咪唑-2-取代苯基或吡啶丙基烯酮衍生物。这些衍生物的生物活性，然后评价作为潜在的抗肿瘤剂。这些化合物在体外测定对HCT 116、MCF-7和HepG 2细胞系的生长抑制活性。化合物A1和A7对癌细胞的IC_（50）值分别为0.06-3.64 μM和0.04-9.80 μM。它们的抗增殖活性明显优于5-氟尿嘧啶（IC_（50）：56.96-174.50 μM），接近紫杉醇（IC_（50）：0.026-1.53 μM）。这些衍生物的活性比其他已报道的查尔酮类似物（甘草查尔酮A）的活性高100倍以上。初步机制研究表明，这些化合物抑制p53-MDM 2结合。化合物A1、A7和A9有效抑制BALB/c小鼠结肠癌HCT 116细胞的肿瘤生长。施用200 mg/kg化合物A7的组显示74.6%的肿瘤生长抑制，在高剂量下没有毒性迹象，这与用12.5 mg/kg伊立替康阳性对照实现的抑制（70.2%）相似。因此，这类苯并咪唑-2-取代的苯基或吡啶丙基烯酮衍生物代表了一个有前途的铅结构的发展可能的p53-MDM 2抑制剂作为新的抗肿瘤药物。
A series of novel benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives were designed and synthesized. The biological activities of these derivatives were then evaluated as potential antitumour agents. These compounds were assayed for growth-inhibitory activity against HCT116, MCF-7 and HepG2 cell lines in vitro. The IC50values of compoundsA1andA7against the cancer cells were 0.06–3.64 μM and 0.04–9.80 μM, respectively. Their antiproliferative activities were significantly better than that of 5-Fluorouracil (IC50: 56.96–174.50 μM) and were close to that of Paclitaxel (IC50: 0.026–1.53 μM). The activity of these derivatives was over 100 times more effective than other reported structures of chalcone analogues (licochalcone A). A preliminary mechanistic study suggested that these compounds inhibit p53-MDM2 binding. CompoundsA1,A7andA9effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compoundA7showed a 74.6% tumour growth inhibition with no signs of toxicity at high doses that was similar to the inhibition achieved with the 12.5 mg/kg irinotecan positive control (70.2%). Therefore, this class of benzimidazole-2-subsituted phenyl or pyridine propyl ketene derivatives represents a promising lead structure for the development of possible p53-MDM2 inhibitors as new antitumour agents.