title: 2-Deoxyglucose conjugated platinum (II) complexes for targeted therapy: design, synthesis, and antitumor activity.
abstract: Malignant neoplasms exhibit an elevated rate of glycolysis over normal cells. To target the Warburg effect, we designed a new series of 2-deoxyglucose (2-DG) conjugated platinum (II) complexes for glucose transporter 1 (GLUT1)-mediated anticancer drug delivery. The potential GLUT1 transportability of the complexes was investigated through a comparative molecular docking analysis utilizing the latest GLUT1 protein crystal structure. The key binding site for 2-DG as GLUT1's substrate was identified with molecular dynamics simulation, and the docking study demonstrated that the 2-DG conjugated platinum (II) complexes can be recognized by the same binding site as potential GLUT1 substrate. The conjugates were synthesized and evaluated for in vitro cytotoxicity study with seven human cancer cell lines. The results of this study revealed that 2-DG conjugated platinum (II) complexes are GLUT1 transportable substrates and exhibit improved cytotoxicities in cancer cell lines that over express GLUT1 when compared to the clinical drug, Oxaliplatin. The correlation between GLUT1 expression and antitumor effects are also confirmed. The study provides fundamental information supporting the potential of the 2-DG conjugated platinum (II) complexes as lead compounds for further pharmaceutical R&D.
authors.affiliation: a 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, Nankai District, Tianjin 300072 , P.R. China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Mi
authors.affiliation: a 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, Nankai District, Tianjin 300072 , P.R. China.
authors.forename: Yuru
authors.initials: Y
authors.lastname: Ma
authors.affiliation: a 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, Nankai District, Tianjin 300072 , P.R. China.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Gao
authors.affiliation: a 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, Nankai District, Tianjin 300072 , P.R. China.
authors.forename: Ran
authors.initials: R
authors.lastname: Liu
authors.affiliation: a 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, Nankai District, Tianjin 300072 , P.R. China.
authors.forename: Pengxing
authors.initials: P
authors.lastname: Liu
authors.affiliation: b Central Institute of Pharmaceutical Research, CSPC Pharmaceutical Group , 226 Huanghe Road, Shijiazhuang , Hebei 050035 , P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Mi
authors.affiliation: a 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, Nankai District, Tianjin 300072 , P.R. China.
authors.forename: Xuegang
authors.initials: X
authors.lastname: Fu
authors.affiliation: a 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, Nankai District, Tianjin 300072 , P.R. China.
authors.forename: Qingzhi
authors.initials: Q
authors.lastname: Gao
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003847:Deoxyglucose / Q000737:chemistry*; D015195:Drug Design; D051272:Glucose Transporter Type 1 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry*; D011485:Protein Binding; D066244:Proton Magnetic Resonance Spectroscopy; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D051272:Glucose Transporter Type 1; D008024:Ligands; D009944:Organoplatinum Compounds; D010984:Platinum; D003847:Deoxyglucose
keywords: 2-Deoxyglucose conjugated platinum (II) complex; anticancer agent; glucose transporter; molecular dynamics; tumor targeting