Design of hypoxic cell radiosensitizer utilized for hypoxia orientation of macrophage

我们设计了一种新的缺氧细胞放射增敏剂TX-2068，用于巨噬细胞的缺氧定向。TX-2068有一个n -乙酰半乳糖胺片段作为巨噬细胞识别组，TX-1877片段作为放射致敏组。以乙酰化n -乙酰半乳胺和TX-1877为原料，以BF3为催化剂，脱保护o -乙酰基，缩合合成了TX-2068，总收率为35%。TX-2068的水-辛醇分配系数（Poct）为Poct = 0.0010，水溶性较TX-1877的Poct = 0.056高。与EMT6/KU细胞的增强比（ER）为1.88 (1 mM)，与TX-1877的ER = 1.75 （1 mM）相比，TX-2068的放射增敏活性略高。通过巨噬细胞吞噬活化实验评价TX-2068对巨噬细胞的活化程度。结果表明，当使用TX-2068时，吞噬活性增加至1mm，在5mm时下降。我们认为这种行为是在免疫反应中常见的钟形激活曲线，TX-2068被巨噬细胞激活。此外，MTT法在5 mM内未观察到TX-2068巨噬细胞的细胞毒性。综上所述，我们认为TX-2068是一种具有放射增敏活性和巨噬细胞吞噬活性的双功能药物，无细胞毒性。最后完成了“用于巨噬细胞缺氧定向的缺氧细胞放射增敏剂的设计”的科研工作。

We designed a novel hypoxic cell radiosensitizer TX-2068 that utilize for hypoxia orientation of macrophage. TX-2068 has a N-acetylgalactosamine moiety as a macrophage recognition group and TX-1877 moiety as a radiosensitizing group. We synthesized TX-2068 at condensation reaction with acetylated N-acetylgalactosamine and TX-1877 using BF3 as a catalyst followed by deprotection of O-acetyl group, TX-2068 was obtained by the total yield 35%. Water-octanol distribution coefficient (Poct) of TX-2068 was Poct = 0.0010, and a very high water solubility was shown compared with Poct = 0.056 of TX-1877. Radiosensitizing activity of TX-2068 was indicated as a enhancement ratio (ER) = 1.88 (1 mM) with EMT6/KU cell, and a little high sensitization revitalization was shown compared with ER = 1.75 (1 mM) of TX-1877. The degree of macrophage activation of TX-2068 was evaluated by macrophage phagocytic activation experiment. As a result, phagocytic activity was increased by the use of TX-2068 up to 1 mM and decreased at 5 mM. We suggested that this behavior is the bell-sharp type activation curve as a generally seen in immune reaction, and TX-2068 be activated of the macrophage. Besides, cytotoxicity for the macrophage cell of TX-2068 was not observed up to 5 mM at MTT method. From the all above-mentioned results, we concluded that TX-2068 is a bifunctional drug having radiosensitizing activity and macrophage phagocytic activity without cytotoxicity. Finally we finish the scientific research titled "Design of hypoxic cell radiosensitizer utilized for hypoxia orientation of macrophage".