Nandy Promita, Mukherjee Alivia, Pradhan Chiranjit, Das Saurabh
Department of Chemistry, Inorganic Chemistry Section, Jadavpur University, Kolkata 700032, India.
ACS Omega. 2020 Oct 1;5(40):25668-25676. doi: 10.1021/acsomega.0c02811. eCollection 2020 Oct 13.
The treatment of malignant cells that are deficient in oxygen due to the insufficient flow of blood is often seen as a major hindrance in radiotherapy. Such cells become radio-resistant because molecular oxygen, the natural and best radio-sensitizer, is depleted. Hence, to compensate this deficiency in oxygen, there is a need for agents that enhance radiation-induced damage of cells (radio-sensitizers) in a manner that normal cells are least affected. Simultaneously, agents capable of showing activity under hypoxic conditions are known as hypoxic cytotoxins that selectively and preferably destroy cells under hypoxic environments. 5-Nitroimidazoles fit both definitions. Their efficiency is based on their ability to generate the nitro radical anion that interacts with the strands of DNA within cells, either damaging or modifying them, leading to cell death. 5-Nitroimidazoles are important radio-pharmaceuticals (radio-sensitizers) in cancer-related treatments where the nitro radical anion has an important role. Since its generation leads to neurotoxic side effects that may be controlled through metal complex formation, this study looks at the possibility of two monomeric complexes of Ornidazole [1-chloro-3-(2-methyl-5-nitro-1-imidazole-1-yl)propan-2-ol] with Cu and Zn to be better radio-sensitizers and/or hypoxic cytotoxins than Ornidazole. The study reveals that although there is a decrease in nitro radical anion formation by complexes, such a decrease does not hamper their radio-sensitizing ability. Nucleic acid bases (thymine, cytosine, and adenine) or calf thymus DNA used as targets were irradiated with Co γ rays either in the absence or presence of Ornidazole and its monomeric complexes. Radiation-induced damage of nucleic acid bases was followed by high-performance liquid chromatography (HPLC), and modification of calf thymus DNA was followed by ethidium bromide fluorescence. Studies indicate that the complexes were better in performance than Ornidazole. Cu-ornidazole was significantly better than either Ornidazole or Zn-ornidazole, which is attributed to certain special features of the Cu complex; aspects like having a stable lower oxidation state enable it to participate in Fenton reactions that actively influence radio-sensitization and the ability of the complex to bind effectively to DNA.
由于血液流动不足而导致缺氧的恶性细胞的治疗，常常被视为放射治疗中的一个主要障碍。这类细胞会产生抗辐射性，因为作为天然且最佳放射增敏剂的分子氧被耗尽了。因此，为了弥补这种氧气不足的情况，需要一些能够以对正常细胞影响最小的方式增强辐射诱导的细胞损伤的药物（放射增敏剂）。同时，能够在缺氧条件下表现出活性的药物被称为缺氧细胞毒素，它们能在缺氧环境中选择性且优先地破坏细胞。5-硝基咪唑符合这两种定义。它们的功效基于其产生硝基自由基阴离子的能力，该阴离子会与细胞内的DNA链相互作用，对其造成损伤或进行修饰，从而导致细胞死亡。在癌症相关治疗中，5-硝基咪唑是重要的放射性药物（放射增敏剂），其中硝基自由基阴离子起着重要作用。由于其产生会导致可能通过形成金属络合物来控制的神经毒性副作用，本研究探讨了奥硝唑[1-氯-3-(2-甲基-5-硝基-1-咪唑-1-基)丙-2-醇]与铜和锌形成的两种单体络合物比奥硝唑成为更好的放射增敏剂和/或缺氧细胞毒素的可能性。研究表明，尽管络合物形成的硝基自由基阴离子有所减少，但这种减少并不妨碍它们的放射增敏能力。以核酸碱基（胸腺嘧啶、胞嘧啶和腺嘌呤）或小牛胸腺DNA作为靶标，在不存在或存在奥硝唑及其单体络合物的情况下，用钴γ射线进行照射。通过高效液相色谱法（HPLC）跟踪核酸碱基的辐射诱导损伤，并用溴化乙锭荧光法跟踪小牛胸腺DNA的修饰情况。研究表明，这些络合物的性能优于奥硝唑。铜-奥硝唑明显优于奥硝唑或锌-奥硝唑，这归因于铜络合物的某些特殊特性；比如具有稳定的较低氧化态使其能够参与对放射增敏有积极影响的芬顿反应，以及该络合物与DNA有效结合的能力。
