Mechanistic and biological characteristics of different sugar conjugated 2-methyl malonatoplatinum(II) complexes as new tumor targeting agents.
Novel cis-2-methylmalonato(trans-R,R-cyclohexane-1,2-diamine)platinum(II) glycoconjugates derived from different sugar motifs, namely, glucose (Glu-Me-Pt), mannose (Man-Me-Pt) and galactose (Gal-Me-Pt) were designed and synthesized based on the third generation clinical drug oxaliplatin for potential glucose transporters (GLUTs) mediated tumor targeting. All platinum(II) glycoconjugates were characterized by1H NMR,13C NMR, IR, HRMS as well as195Pt-NMR analysis. Despite their substantial improvement in water solubility, the conjugates exhibited comparable or better in vitro cytotoxicities than oxaliplatin determined in six different human cancer cell lines. Glu-Me-Pt has been shown to be more effective than cisplatin and oxaliplatin with improved therapeutic index in leukemia-bearing DBA/2 mice model. The potential GLUT transportability of the complexes was investigated using cell-based fluorescent competition assay and GLUT inhibitor mediated cell viability analysis in GLUT over-expressing HT29 cell line. Each sugar motif was found to be useful to enable the platinum(II) complexes as substrate for GLUT mediated cell uptake. In vitro DNA adduct formation analysis has been investigated for the first time for this class of compounds to reveal the intrinsic differences in antitumor activity between the malonatoplatinum(II) glycoconjugates and oxaliplatin. The intrinsic DNA reactivity of the platinum(II)-sugar conjugates was found as Gal-Me-Pt > Glu-Me-Pt > Man-Me-Pt ≈ oxaliplatin by kinetic study on the formation of platinum(II) adducts with guanosine-5'-monophosphate (5'-GMP). The results from this study demonstrate the usefulness of glucose, mannose and galactose as alternative sugar motif on glycoconjugation for GLUT mediated drug design and pharmaceutical R&D, and the obtained fundamental results also support the potential of the GLUT targeted platinum(II)-sugar conjugates as lead compounds for further pre-clinical evaluation.
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, PR China.
Xiangqian
X
Gao
School of Life Science, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, PR China.
Shengnan
S
Liu
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, PR China.
Yunli
Y
Shi
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, PR China.
Zhenhua
Z
Huang
Central Institute of Pharmaceutical Research, CSPC Pharmaceutical Group, 226 Huanghe Road, Shijiazhuang, Hebei 050035, PR China.
Yi
Y
Mi
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, PR China.
Qian
Q
Mi
Department of Biochemistry, Gudui BioPharma Technology Inc., 5 Lanyuan Road, Huayuan Industrial Park, Tianjin 300384, PR China.
Jinna
J
Yang
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, PR China. Electronic address: qingzhi@tju.edu.cn.
Qingzhi
Q
Gao
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D051246:Glucose Transport Proteins, Facilitative / Q000378:metabolism; D006001:Glycoconjugates / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008745:Methylation; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin
D000970:Antineoplastic Agents; D051246:Glucose Transport Proteins, Facilitative; D006001:Glycoconjugates; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002945:Cisplatin
Glucose transporter; Glycoconjugates; Platinum(II) complexes; Tumor targeting; Warburg effect