title: Design, Synthesis of Novel Platinum(II) Glycoconjugates, and Evaluation of Their Antitumor Effects.
abstract: 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 (GLUTs). 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 GLUT1 transportability of the complexes was investigated through a molecular docking study and was confirmed with GLUT1 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 GLUT1 and their cell killing effect depends highly on the GLUT1 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.
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Tianjin, Nankai District, 300072, China.
authors.forename: Jianbin
authors.initials: J
authors.lastname: Han
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Tianjin, Nankai District, 300072, China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Gao
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Tianjin, Nankai District, 300072, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Biochemistry, Gudui BioPharma Technology Inc., 5 Lanyuan Road, Huayuan Industrial Park, Tianjin, 300384, China.
authors.forename: Jinna
authors.initials: J
authors.lastname: Yang
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Tianjin, Nankai District, 300072, China.
authors.forename: Menghua
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Central Institute of Pharmaceutical Research, CSPC Pharmaceutical Group, 226 Huanghe Road, Shijiazhuang, Hebei, 050035, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Mi
authors.affiliation: Central Institute of Pharmaceutical Research, CSPC Pharmaceutical Group, 226 Huanghe Road, Shijiazhuang, Hebei, 050035, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, Collaborative Innovation Center of Chemical Science and Engineering, School of Pharmaceutical Science and Technology, Tianjin University, 92 Weijin Road, Tianjin, Nankai District, 300072, China.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006001:Glycoconjugates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D006001:Glycoconjugates; D009944:Organoplatinum Compounds; D010984:Platinum
keywords: antitumor activity; glucose transporter; molecular docking; platinum(II) glycoconjugates; water solubility