Diphenyl urea-benzylidene acetohydrazide hybrids as fibroblast growth factor receptor 1 inhibitors and anticancer agents

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL
Heba T. Abdel-Mohsen, Amira M. Nageeb, Iman A. Y. Ghannam
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Abstract

Molecular hybridization between diphenyl urea and benzylidene acetohydrazide was adopted for the design of a new series of FGFR-1 targeting cancer. The designed series was synthesized and submitted to NCI-USA to be screened for their growth inhibitory activity on NCI cancer cell lines. Some of the synthesized hybrids displayed promising growth inhibitory activity on NCI cancer cell lines with a mean GI% between 70.39% and a lethal effect. Compounds 9a, 9i, 9j, and 9n-p were further selected for a five-dose assay and all the tested candidates showed promising antiproliferative activity with GI50 reaching the submicromolar range. Encouraged by the potent activity of 9a on colon cancer on the one hand and the well-known overexpression of FGFR-1 in it on the other hand, it was further selected as a representative example to be evaluated for its mechanism on the cell cycle and apoptosis of HCT116 cell line. Interestingly, 9a was found to pause the cell cycle of the HCT116 cell line at the G1 phase and induced late apoptosis. In parallel, all the synthesized hybrids 9a-p were examined for their potential to inhibit FGFR-1 at 10 µM. Compounds 9a, 9g, 9h, and 9p were found to have potent inhibitory activity with % inhibition = 63.04%, 58.31%, 60.87% and 79.84%, respectively. Molecular docking simulation of 9a in the binding pocket of FGFR-1 confirms its capability to achieve the characteristic interactions of the type II FGFR-1 inhibitors. Exploration of the ADME properties of 9a-p by SwissADME web tool proved their satisfactory physicochemical properties for the discovery of new anticancer hits.

作为成纤维细胞生长因子受体 1 抑制剂和抗癌剂的二苯基脲-亚苄基乙酰肼混合物。
采用二苯基脲和苯亚甲基乙酰肼之间的分子杂交技术,设计了一系列新的 FGFR-1 癌症靶向药物。所设计的系列已合成并提交给美国国家癌症研究中心(NCI-USA),以筛选其对 NCI 癌细胞系的生长抑制活性。合成的一些杂交化合物对 NCI 癌细胞株显示出良好的生长抑制活性,平均 GI% 在 70.39% 之间,并具有致死效应。化合物 9a、9i、9j 和 9n-p 进一步被选中进行五剂量试验,所有候选化合物都显示出良好的抗增殖活性,GI50 达到亚摩尔范围。一方面,9a 对结肠癌具有强效活性,另一方面,众所周知结肠癌中 FGFR-1 过度表达,因此,我们进一步选择了 9a 作为代表,评估其对 HCT116 细胞系细胞周期和凋亡的作用机制。有趣的是,研究发现 9a 能使 HCT116 细胞株的细胞周期暂停在 G1 期,并诱导细胞晚期凋亡。与此同时,研究人员还检测了所有合成的混合物 9a-p 在 10 µM 的浓度下抑制表皮生长因子受体-1 的潜力。结果发现,化合物 9a、9g、9h 和 9p 具有很强的抑制活性,抑制率分别为 63.04%、58.31%、60.87% 和 79.84%。9a 在 FGFR-1 结合袋中的分子对接模拟证实了它能够实现 II 型 FGFR-1 抑制剂特有的相互作用。利用 SwissADME 网络工具对 9a-p 的 ADME 特性进行的探索证明了它们令人满意的理化特性,有助于发现新的抗癌药物。
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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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