title: Glycosylated platinum(iv) prodrugs demonstrated significant therapeutic efficacy in cancer cells and minimized side-effects.
abstract: Conjugates (A1-A5) of the Pt(iv) derivative (A6) with amino groups from peracetyl glucose, rhamnose and mannose with a propyl amino or ethyl amino linker at the reducing end were synthesized and exhibited significant therapeutic efficacy in tumour cells, especially for prostate cancer (PCa). The antitumor activities are greatly affected by glycosyl groups. Cytotoxic experiments in vitro indicated that the antitumor activities were increased by 5-fold when its Pt(iv) derivative was conjugated to S18 (IC50 = 4.82 ± 0.45 μM) and by 12-fold when conjugated to S21 (IC50 = 1.9 ± 0.67 μM). The mannose substituted Pt(iv) complexes A4 and A5 were also over an order of magnitude more potent towards HeLa, A549, MCF-7 and PC3 than cisplatin and oxaliplatin. Importantly, the glycosylated Pt(iv) derivatives A4 and A5 displayed potential safety for clinical therapeutic exposure with IC50 of 84 μM and 169 μM compared with cisplatin (IC50 = 8 μM) to 3T3. Cellular uptake and DNA platination are higher than cisplatin and oxaliplatin. ESI-MS analysis of A5 binding to 5'-dGMP revealed that bifunctional DNA lesions were formed. The antitumor activities in vivo showed that the MTD and LD50 for A4 and A5 are nearly 4-fold higher than that of oxaliplatin indicating the potential safety for the glycosylated Pt(iv) complexes.
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. wangxinnk@nankai.edu.cn pwang@nankai.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. wangxinnk@nankai.edu.cn pwang@nankai.edu.cn.
authors.forename: Qingpeng
authors.initials: Q
authors.lastname: Wang
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. wangxinnk@nankai.edu.cn pwang@nankai.edu.cn.
authors.forename: Xiande
authors.initials: X
authors.lastname: Yang
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. wangxinnk@nankai.edu.cn pwang@nankai.edu.cn.
authors.forename: Wenpei
authors.initials: W
authors.lastname: Hao
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. wangxinnk@nankai.edu.cn pwang@nankai.edu.cn.
authors.forename: Zhonglv
authors.initials: Z
authors.lastname: Huang
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. wangxinnk@nankai.edu.cn pwang@nankai.edu.cn.
authors.forename: Jiabao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. wangxinnk@nankai.edu.cn pwang@nankai.edu.cn and Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: College of Pharmacy, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China. wangxinnk@nankai.edu.cn pwang@nankai.edu.cn and Tianjin Key Laboratory of Molecular Drug Research, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, P. R. China.
authors.forename: Peng George
authors.initials: PG
authors.lastname: Wang
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007928:Lethal Dose 50; D020714:Maximum Tolerated Dose; D051379:Mice; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D011355:Prodrugs; D010984:Platinum; D004247:DNA