Glycosylated Platinum(IV) Complexes as Substrates for Glucose Transporters (GLUTs) and Organic Cation Transporters (OCTs) Exhibited Cancer Targeting and Human Serum Albumin Binding Properties for Drug Delivery

被引：88

作者：

Ma, Jing ^{[1
,2
]}

Wang, Qingpeng ^{[1
,3
]}

Huang, Zhonglv ^{[1
]}

Yang, Xiande ^{[1
]}

Nie, Quandeng ^{[1
]}

Hao, Wenpei ^{[1
]}

Wang, Peng George ^{[1
,3
]}

Wang, Xin ^{[1
,3
]}

机构：

[1] Nankai Univ, State Key Lab Elementoorgan Chem, Tianjin Key Lab Mol Drug Res, Coll Pharm, Tianjin 300071, Peoples R China

[2] Henan Univ, Pharmaceut Coll, Kaifeng 475004, Henan, Peoples R China

[3] Liaocheng Univ, Inst Biopharmaceut Res, Liaocheng 252059, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2017年 / 60卷 / 13期

基金：

中国国家自然科学基金;

关键词：

ANTITUMOR-ACTIVITY; CRYSTAL-STRUCTURE; CISPLATIN; PRODRUG; OXALIPLATIN; CONJUGATION; MECHANISMS; EFFICACY; DESIGN; SERIES;

D O I：

10.1021/acs.jmedchem.7b00433

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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(W) were highly cytotoxic and showed specific cancer-targeting properties in vitro and in vivo. Glycosylated platinum(W) complexes 5, 6, 7, and 8 (IC50 0.24-3.97 mu M) 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.

引用

页码：5736 / 5748

页数：13

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[1] Rational design of platinum(IV) compounds to overcome glutathione-S-transferase mediated drug resistance [J].