Eight mono- or disaccharide analogues derived from BLM disaccharide, along with the corresponding carbohydate-dye conjugates have been designed and synthesized in this study, aiming at exploring the effect of a gulose residue on the cellular binding/uptake of BLM disaccharide and it possible uptake mechanism. Our evidence is presented indicating that, for the cellular binding/uptake of BLM disaccharide, a gulose residue is an essential subunit but unrelated to its chemical nature. Interestingly, d-gulose-dye conjugate is able to selectively target A549 cancer cells, but l-gulose-dye conjugate fails. Further uptake mechanism studies demonstrate d-gulose-dye derivatives similar to BLM disaccharide-dye ones behave in a temperature- and ATP-dependent manner, and are partly directed by the GLUT1 receptor. Moreover, d-gulose modifying gemcitabine 53a exhibits more potent antitumor activity compared to derivatives 53b-c in which gemcitabine is decorated with other monosaccharides. Taken together, the monosacharide d-gulose conjugate offers a new strategy for solving cytotoxic drugs via the increased tumor targeting in the therapy of lung cancer.

本研究设计并合成了八种源自 BLM 二糖的单糖或二糖类似物以及相应的碳水化合物-染料偶联物，旨在探索古洛糖残基对 BLM 二糖细胞结合/摄取的影响及其可能的摄取机制。我们的证据表明，对于 BLM 二糖的细胞结合/摄取，古洛糖残基是必需的亚基，但与其化学性质无关。有趣的是，d -gulose-dye conjugate 能够选择性地靶向 A549 癌细胞，但l -gulose-dye conjugate 失败。进一步的摄取机制研究表明d与 BLM 二糖染料类似的-古洛糖染料衍生物以温度和 ATP 依赖性方式表现，并且部分受 GLUT1 受体指导。此外，与吉西他滨被其他单糖修饰的衍生物53b-c相比，修饰d-古洛糖的吉西他滨53a表现出更强的抗肿瘤活性。总之，单糖d-古洛糖缀合物提供了一种通过增加肺癌治疗中的肿瘤靶向来解决细胞毒性药物的新策略。