Design of hypoxic cell radiosensitizer utilized for hypoxia orientation of macrophage

我们设计了一种新型的低氧细胞放射增敏剂TX-2068，用于巨噬细胞的低氧定位。TX-2068的N-乙酰半乳糖胺部分为巨噬细胞识别基团，TX-1877部分为放射增敏基团。以N-乙酰氨基半乳糖和TX-1877为原料，以BF3为催化剂，经脱保护反应合成了TX-2068，总收率35%。TX-2068的水-辛醇分配系数(POCT)为0.0010，与TX-1877的POCT=0.056相比，具有很高的水溶解度。TX-2068的放射增敏活性与EMT6/KU细胞的增敏比(ER)=1.88(1 MM)，与TX-1877的ER=1.75(1 MM)相比略有提高。通过巨噬细胞吞噬实验评价TX-2068对巨噬细胞的激活程度。结果表明，当TX-2068浓度达到1 mM时，吞噬活性增加，5 mM时，吞噬活性降低。我们认为这种行为是免疫反应中常见的钟尖型激活曲线，而TX-2068是巨噬细胞的激活。此外，用四甲基偶氮唑蓝比色法对TX-2068巨噬细胞在5 mM以下未观察到细胞毒作用。综合以上结果，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。最终完成了用于巨噬细胞低氧定位的低氧细胞放射增敏剂的设计。

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".