A glucose derivative as natural alternative to the cyclohexane-1,2-diamine ligand in the anticancer drug oxaliplatin?
Having oxaliplatin as archetype, several platinum complexes with a carbohydrate moiety resembling the cyclohexane-1,2-diamine ligand of oxaliplatin have been prepared. As leaving groups, the anionic ligands iodide, oxalate, and malonate were utilized, and for comparison purposes the chloro complex was employed. All compounds were characterized by elemental analysis, nuclear magnetic resonance spectroscopy, and electrospray mass spectrometry. The crystal structure of (SP-4-3)-diiodo(2,3-diamino-2,3-dideoxy-D-glucose-kappa(2)N,N')platinum(II) was determined by X-ray diffraction. The affinity toward dGMP was assayed by capillary electrophoresis, revealing that the chloro complex shows the highest reactivity, followed by the iodo complex. In contrast, the binding kinetics of the dicarboxylato complexes are slower, with the malonato complex being the least reactive. Reactivity to dGMP in the cell-free system correlates with cytotoxicity in two of four human cancer cell lines as determined by means of the MTT assay. In three of the four cell lines, the chloro and the malonato complex are the most and the least active of the carbohydrate-Pt complexes, respectively, with IC(50) values differing only by factors of up to 3.2. Cytotoxicity of the chloro complex is one to two orders of magnitude lower than that of oxaliplatin, but still comparable to that of carboplatin in two of the four cell lines.
Berger
Isabella
I
Institute of Inorganic Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Str. 42, 1090 Vienna, Austria.
Nazarov
Alexey A
AA
Hartinger
Christian G
CG
Groessl
Michael
M
Valiahdi
Seied-M
SM
Jakupec
Michael A
MA
Keppler
Bernhard K
BK
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D045744:Cell Line, Tumor; D003514:Cyclohexylamines / Q000737:chemistry*; D005947:Glucose / Q000031:analogs & derivatives* / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D000077150:Oxaliplatin; D013329:Structure-Activity Relationship; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D008024:Ligands; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C030435:1,2-cyclohexanediamine; D005947:Glucose