College of Pharmacy, Tianjin Key Laboratory of Molecular Drug Research, State Key Laboratory of Elemento-organic Chemistry, Nankai University , Tianjin 300071 P. R. China.
Pharmaceutical College, Henan University , Kaifeng 475004, Henan P. R. China.
J Med Chem. 2017 Jul 13;60(13):5736-5748. doi: 10.1021/acs.jmedchem.7b00433. Epub 2017 Jun 27.
Glycosylated platinum(IV) complexes were synthesized as substrates for GLUTs and OCTs for the first time, and the cytotoxicity and detailed mechanism were determined in vitro and in vivo. Galactoside Pt(IV), glucoside Pt(IV), and mannoside Pt(IV) were highly cytotoxic and showed specific cancer-targeting properties in vitro and in vivo. Glycosylated platinum(IV) complexes 5, 6, 7, and 8 (IC 0.24-3.97 μM) had better antitumor activity of nearly 166-fold higher than the positive controls cisplatin (1a), oxaliplatin (3a), and satraplatin (5a). The presence of a hexadecanoic chain allowed binding with human serum albumin (HSA) for drug delivery, which not only enhanced the stability of the inert platinum(IV) prodrugs but also decreased their reduction by reductants present in human whole blood. Their preferential accumulation in cancer cells compared to noncancerous cells (293T and 3T3 cells) suggested that they were potentially safe for clinical therapeutic use.
首次将糖基化的铂（IV）配合物作为 GLUTs 和 OCTs 的底物进行合成，并在体外和体内确定了其细胞毒性和详细的作用机制。半乳糖基铂（IV）、葡萄糖基铂（IV）和甘露糖基铂（IV）具有高细胞毒性，并在体外和体内表现出特异性的癌症靶向特性。糖基化的铂（IV）配合物 5、6、7 和 8（IC0.24-3.97 μM）具有比阳性对照顺铂（1a）、奥沙利铂（3a）和沙铂（5a）高近 166 倍的更好的抗肿瘤活性。十六烷酸链的存在允许与人血清白蛋白（HSA）结合进行药物递送，这不仅增强了惰性铂（IV）前药的稳定性，而且还降低了它们在人全血中存在的还原剂的还原。与非癌细胞（293T 和 3T3 细胞）相比，它们在癌细胞中的优先积累表明它们可能对临床治疗用途是安全的。
