Zhang Qiumeng, Jin Chen, Yu Jiahui, Lu Wei
Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China.
ACS Omega. 2018 Aug 8;3(8):8813-8818. doi: 10.1021/acsomega.8b01208. eCollection 2018 Aug 31.
Because of the low selectivity and efficiency of normal antitumor agents, the strategy of ligand-targeted drugs was put forward. In this paper, we designed and synthesized a new bioreductive linker based on 2-nitroimidazole, which was used in three paclitaxel (PTX) prodrugs. The drug release mechanism via six-membered ring was demonstrated by chemical reduction and nitroreductase assay. Glucose and acetazolamide, which have been reported widely as ligands, were attached to compound to afford Glu-PTX and AZO-PTX. The prodrugs were considerably stable in phosphate-buffered saline (pH 7.4) and plasma. What is more, PTX releasing could be triggered by nitroreductase rapidly. In in vitro cytotoxicity assay, the prodrugs exhibited moderate selectivity toward hypoxic tumor cells. We considered that the 2-nitroimidazole linker could accelerate the release of prodrugs under hypoxic condition. It was promising in the development of ligand-targeted drugs.
由于普通抗肿瘤药物的选择性和效率较低，因此提出了配体靶向药物的策略。在本文中，我们设计并合成了一种基于2-硝基咪唑的新型生物还原连接子，并将其应用于三种紫杉醇（PTX）前药中。通过化学还原和硝基还原酶测定证明了经由六元环的药物释放机制。已被广泛报道为配体的葡萄糖和乙酰唑胺连接到化合物上，得到Glu-PTX和AZO-PTX。前药在磷酸盐缓冲盐水（pH 7.4）和血浆中相当稳定。此外，硝基还原酶可快速触发PTX释放。在体外细胞毒性试验中，前药对缺氧肿瘤细胞表现出适度的选择性。我们认为2-硝基咪唑连接子可在缺氧条件下加速前药的释放。它在配体靶向药物的开发中很有前景。
