1. Mechanistic and biological characteristics of different sugar conjugated 2-methyl malonatoplatinum(II) complexes as new tumor targeting agents.
- Author
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Gao X, Liu S, Shi Y, Huang Z, Mi Y, Mi Q, Yang J, and Gao Q
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cisplatin pharmacology, Drug Screening Assays, Antitumor, Glucose Transport Proteins, Facilitative metabolism, Glycoconjugates pharmacokinetics, Glycoconjugates therapeutic use, Humans, Male, Methylation, Mice, Neoplasms drug therapy, Neoplasms metabolism, Organoplatinum Compounds pharmacokinetics, Organoplatinum Compounds therapeutic use, Oxaliplatin, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Glycoconjugates chemistry, Glycoconjugates pharmacology, Organoplatinum Compounds chemistry, Organoplatinum Compounds pharmacology
- Abstract
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 by
1 H NMR,13 C NMR, IR, HRMS as well as195 Pt-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 โ 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., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)- Published
- 2017
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