A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. However, its clinical potential has been limited by toxicity and water solubility. To address those limitations of triptolide, we designed and synthesized glucose-triptolide conjugates (glutriptolides) and demonstrated their antitumor activity in vitro and in vivo. Herein, we identified a lead, glutriptolide-2 with an altered linker structure. Glutriptolide-2 possessed improved stability in human serum, greater selectivity toward cancer over normal cells, and increased potency against cancer cells. Glutriptolide-2 exhibits sustained antitumor activity, prolonging survival in a prostate cancer metastasis animal model. Importantly, we found that glutriptolide-2 was more potent against cancer cells under hypoxia than normoxia. Together, this work provides an attractive glutriptolide drug lead and suggests a viable strategy to overcome chemoresistance through conjugation of cytotoxic agents to glucose.

癌症治疗中的主要障碍是在缺氧下诱导的化学抗性，这是肿瘤微环境的特征。雷公藤内酯醇是一种有效的真核转录抑制剂，具有强大的抗肿瘤活性。但是，其临床潜力受到毒性和水溶性的限制。为了解决雷公藤甲素的这些局限性，我们设计和合成了葡萄糖-雷公藤内酯共轭物（glutriptolides），并证明了它们在体外和体内的抗肿瘤活性。在这里，我们确定了铅，ripriptolide-2具有改变的接头结构。Glutriptolide-2在人血清中具有改善的稳定性，相对于正常细胞对癌症的选择性更高，并且对癌细胞的效力增强。Glutriptolide-2在前列腺癌转移动物模型中表现出持续的抗肿瘤活性，延长了其生存期。重要的是，我们发现在低氧条件下，glutriptolide-2对癌细胞的作用要比常氧作用更强。总之，这项工作提供了有吸引力的谷氨酰胺内酯药物前导，并提出了一种可行的策略，即通过将细胞毒剂与葡萄糖结合来克服化学抗性。