title: Design, synthesis and biological evaluation of novel benzimidazole-2-substituted phenyl or pyridine propyl ketene derivatives as antitumour agents.
abstract: 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 IC50 values of compounds A1 and A7 against 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. Compounds A1, A7 and A9 effectively inhibited tumour growth in BALB/c mice with colon carcinoma HCT116 cells. The group administered 200 mg/kg of compound A7 showed 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.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Lin-tao
authors.initials: LT
authors.lastname: Wu
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Jia-jia
authors.initials: JJ
authors.lastname: Shen
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yi
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Yue-chen
authors.initials: YC
authors.lastname: Zhan
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Ming-quan
authors.initials: MQ
authors.lastname: Sha
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China. Electronic address: xuesitubear@sina.com.
authors.forename: Si-tu
authors.initials: ST
authors.lastname: Xue
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China. Electronic address: l-z-r@263.net.
authors.forename: Zhuo-rong
authors.initials: ZR
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005030:Ethylenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D056945:Hep G2 Cells; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D005030:Ethylenes; D007659:Ketones; C031000:benzimidazole; C008223:ketene
keywords: Antiproliferative activities; Benzimidazole; Chalcone; p53-MDM2