5,10-二氢-11H-二苯并[b,e][1,4]二氮杂䓬-11-酮结构衍生物作为抗癌和诱导凋亡剂的合成及生物学评价
Synthesis and biological evaluation of 5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one structural derivatives as anti-cancer and apoptosis inducing agents.
作者信息
Praveen Kumar Chintakunta, Reddy T Srinivasa, Mainkar Prathama S, Bansal Vipul, Shukla Ravi, Chandrasekhar Srivari, Hügel Helmut M
机构信息
School of Applied Sciences, RMIT University, Melbourne 3001, Australia; IICT-RMIT Research Centre SIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Division of Natural Products Chemistry, CSIR-IICT, Hyderabad 500 007, India.
School of Applied Sciences, RMIT University, Melbourne 3001, Australia; Health Innovations Research Institute, RMIT University, Melbourne 3083, Australia; Ian Potter NanoBioSensing Facility, NanoBiotechnology Research Laboratory, School of Applied Sciences, RMIT University, Melbourne 3000, Australia; Centre for Advanced Materials and Industrial Chemistry, RMIT University, Melbourne 3000, Australia.
出版信息
Eur J Med Chem. 2016 Jan 27;108:674-686. doi: 10.1016/j.ejmech.2015.12.007. Epub 2015 Dec 10.
A series of thirteen 5H-dibenzo [b,e][1,4]diazepin-11(10H)-one structural derivatives has been synthesized and evaluated for anti-proliferative activity against five human cancer cell lines. Compound 9a exhibited potent tumour growth inhibition in all cell lines with IC50 values in the range of 0.71-7.29 μM. Experiments on lung (A549) and breast (MDAMB-231) cancer cell lines to investigate the mechanisms of growth inhibition and apoptosis inducing effects of 9a showed that it arrested both cancer cell lines in the G2/M phase of cell cycle in a dose dependent manner. Hoechst staining analysis revealed that 9a inhibited tumour cell proliferation through apoptosis induction. Additionally, the mitochondrial membrane potential (ΔΨm) was affected and the levels of reactive oxygen species (ROS) were raised. The simple synthetic preparation and their biological properties make these dibenzodiazepinone-triazole scaffolds promising new entities for the development of cancer therapeutics.
已经合成了一系列十三种5H-二苯并[b,e][1,4]二氮杂䓬-11(10H)-酮结构衍生物，并评估了它们对五种人类癌细胞系的抗增殖活性。化合物9a在所有细胞系中均表现出强大的肿瘤生长抑制作用，IC50值在0.71 - 7.29 μM范围内。对肺癌(A549)和乳腺癌(MDAMB - 231)细胞系进行的实验，以研究9a的生长抑制和凋亡诱导作用机制，结果表明它以剂量依赖的方式使两种癌细胞系停滞在细胞周期的G2/M期。Hoechst染色分析显示，9a通过诱导凋亡抑制肿瘤细胞增殖。此外，线粒体膜电位(ΔΨm)受到影响，活性氧(ROS)水平升高。这些二苯并二氮杂䓬酮 - 三唑支架简单的合成制备方法及其生物学特性使其成为癌症治疗开发中有前景的新实体。
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