Ma Jing, Yang Xiande, Hao Wenpei, Huang Zhonglv, Wang Xin, Wang Peng George
College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, PR China.
College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, PR China; Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, PR China.
Eur J Med Chem. 2017 Mar 10;128:45-55. doi: 10.1016/j.ejmech.2017.01.032. Epub 2017 Jan 23.
A serious of carbohydrate-conjugated platinum(IV) complexes in the form Pt(L2)(A2)(OH)R based on the clinical drug cisplatin and oxaliplatin were designed, synthesized and evaluated as antitumor agents in vitro and in vivo. The conjugates possessing both pH and redox dual-responsive properties exhibited more potent cytotoxicity in seven different human cancer cell lines and lower toxicity to the normal 3T3 cells than cisplatin, oxaliplatin and even the reported bis-functionalized glycosylated platinum(IV) complexes indicating the enhanced safety of the sugar conjugates. Cellular drug uptake and DNA platination were also superior to cisplatin, oxaliplatin and the reported bis-functionalized ones. Peak current of B7 and B8 with the scan rate of 200mv/s at the concentration of 0.08 mM was 5-fold higher at pH 6.4 than the pH 7.4, indicating that carbohydrate-conjugated mono-functionalized platinum(IV) complexes possessed both pH and redox dual-responsive properties in the cancer cells. The in vivo assays demonstrated that the Pt(IV) compounds could inhibit the growth of MCF-7 tumour and exert more safety than oxaliplatin.
基于临床药物顺铂和奥沙利铂，设计、合成了一系列Pt(L2)(A2)(OH)R形式的碳水化合物共轭铂(IV)配合物，并在体外和体内作为抗肿瘤剂进行了评估。具有pH和氧化还原双重响应特性的共轭物在七种不同的人类癌细胞系中表现出更强的细胞毒性，对正常3T3细胞的毒性低于顺铂、奥沙利铂，甚至低于已报道的双功能糖基化铂(IV)配合物，表明糖共轭物的安全性有所提高。细胞药物摄取和DNA铂化也优于顺铂、奥沙利铂和已报道的双功能化化合物。在0.08 mM浓度下，扫描速率为200mv/s时，B7和B8在pH 6.4时的峰值电流比pH 7.4时高5倍，表明碳水化合物共轭单功能铂(IV)配合物在癌细胞中具有pH和氧化还原双重响应特性。体内试验表明，Pt(IV)化合物可以抑制MCF-7肿瘤的生长，并且比奥沙利铂更安全。
