A glucose derivative as natural alternative to the cyclohexane-1,2-diamine ligand in the anticancer drug oxaliplatin?

Abstract

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.

• Authors: Isabella Berger, Alexey A Nazarov, Christian G Hartinger, Michael Groessl, Seied-M Valiahdi, Michael A Jakupec, Bernhard K Keppler
• Journal: ChemMedChem (ChemMedChem) Vol. 2 Issue 4 Pg. 505-14 (Apr 2007) ISSN: 1860-7187 [Electronic] Germany
• PMID: 17340670 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Cyclohexylamines
• Ligands
• Organoplatinum Compounds
• Oxaliplatin
• 1,2-cyclohexanediamine
• Glucose

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cyclohexylamines (chemistry)
• Glucose (analogs & derivatives, chemistry)
• Humans
• Ligands
• Models, Molecular
• Molecular Structure
• Organoplatinum Compounds (chemistry, pharmacology)
• Oxaliplatin
• Structure-Activity Relationship
• X-Ray Diffraction