Protected and De-protected Platinum(IV) Glycoconjugates With GLUT1 and OCT2-Mediated Selective Cancer Targeting: Demonstrated Enhanced Transporter-Mediated Cytotoxic Properties in vitro and in vivo

Jing Ma; Hanfang Liu; Zhuoqing Xi; Jiuzhou Hou; Yingguang Li; Jie Niu; Tong Liu; Shuning Bi; Xin Wang; Chaojie Wang; Jiajia Wang; Songqiang Xie; Peng G Wang

doi:10.3389/fchem.2018.00386

Protected and De-protected Platinum(IV) Glycoconjugates With GLUT1 and OCT2-Mediated Selective Cancer Targeting: Demonstrated Enhanced Transporter-Mediated Cytotoxic Properties in vitro and in vivo

Front Chem. 2018 Sep 21:6:386. doi: 10.3389/fchem.2018.00386. eCollection 2018.

Authors

Jing Ma¹, Hanfang Liu¹, Zhuoqing Xi¹, Jiuzhou Hou¹, Yingguang Li¹, Jie Niu¹, Tong Liu¹, Shuning Bi¹, Xin Wang², Chaojie Wang³, Jiajia Wang⁴, Songqiang Xie¹, Peng G Wang²

Affiliations

¹ Institute of Chemical Biology, College of Pharmacy, Henan University, Kaifeng, China.
² Tianjin Key Laboratory of Molecular Drug Research, State Key Laboratory of Elemento-organic Chemistry, College of Pharmacy, Nankai University, Tianjin, China.
³ The Key Laboratory of Natural Medicine and Immuno-Engineering, Henan University, Kaifeng, China.
⁴ Henan University Joint National Laboratory for Antibody Drug Engineering, School of Basic Medicine Science, Henan University, Kaifeng, China.

Abstract

Physiological characteristics of human malignancies are increased glycolysis and overexpression of glucose transporters (GLUTs). ¹⁸Flurodeoxyglucose-positron emission tomography (FDG-PET) has successfully developed as clinical modality for the diagnosis and staging of many cancers based on the Warburg effect. To leverage this glucose transporter mediated metabolic disparity between normal and malignant cells, in the current report, protected, and de-protected glucose, mannose, galactose, rhamnose, maltose, and lactose-conjugated platinum(IV) complexes were designed and synthesized. The suggested potential of facilitated intravenous to oral switching of glycosylated platinum(IV) prodrugs with cancer-targeting properties were evaluated for glucose transporter 1 (GLUT1) and organic cation transporter 2 (OCT2)-mediated selective properties in vitro and in vivo. The cytotoxicity of 2d, 5d, and 6d were ~23-fold greater than that of the positive controls cisplatin, oxaliplatin, and satraplatin, respectively. The leading compound 6d, the IC₅₀ of which with the GLUT1 inhibitor 4,6-oethylidene-α-D-glucose (EDG) and phloretin (31.80 and 38.71 μM) are 36- and 44-folds higher, respectively, than the 48 h IC₅₀ (0.89 μM), is superior to the reported 5-8, exhibiting enhanced cancer targeting. The compounds also showed reduced toxicity to normal cells (293T IC₅₀ = 12.06 μM and 3T3 cells IC₅₀ > 100 μM) and exhibited no cross-resistance to cisplatin. Moreover, the encouraging selectivity of 6d for MCF-7 cells in vivo indicated that the pyranoside performs an important function in cancer targeting.

Keywords: cancer targeting; glucose transporter 1; organic cation transporter 2; platinum(IV) glycoconjugates; transporter-mediated cytotoxic properties.