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Design, Synthesis of Novel Platinum(II) Glycoconjugates, and Evaluation of Their Antitumor Effects
Author(s) -
Han Jianbin,
Gao Xiangqian,
Liu Ran,
Yang Jinna,
Zhang Menghua,
Mi Yi,
Shi Ying,
Gao Qingzhi
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12718
Subject(s) - oxaliplatin , chemistry , glycoconjugate , carboplatin , cytotoxicity , platinum , solubility , cisplatin , glut1 , combinatorial chemistry , lipophilicity , biochemistry , stereochemistry , glucose transporter , cancer , in vitro , organic chemistry , chemotherapy , medicine , colorectal cancer , insulin , catalysis
A new series of sugar‐conjugated (trans‐ R , R ‐cyclohexane‐1, 2‐diamine)‐2‐halo‐malonato‐platinum( II ) complexes were designed and synthesized to target tumor‐specific glucose transporters ( GLUT s). The water solubility of the sugar‐conjugated platinum ( II ) complexes was greatly improved by average of 570‐fold, 33‐fold, and 94‐fold, respectively, compared to cisplatin (1.0 mg/ mL ), carboplatin (17.1 mg/ mL ), and the newest generation of clinical drug oxaliplatin (6.0 mg/ mL ). Despite the high water solubility, the platinum( II ) glycoconjugates exhibited a notable increase in cytotoxicity by a margin of 1.5‐ to 6.0‐fold in six different human cancer cell lines with respect to oxaliplatin. The potential GLUT 1 transportability of the complexes was investigated through a molecular docking study and was confirmed with GLUT 1 inhibitor‐mediated cytotoxicity dependency evaluation. The results showed that the sugar‐conjugated platinum( II ) complexes can be recognized by the glucose recognition binding site of GLUT 1 and their cell killing effect depends highly on the GLUT 1 inhibitor, quercetin. The research presenting a prospective concept for targeted therapy anticancer drug design, and with the analysis of the synthesis, water solubility, antitumor activity, and the transportability of the platinum( II ) glycoconjugates, this study provides fundamental data supporting the inherent potential of these designed conjugates as lead compounds for GLUT ‐mediated tumor targeting.