Three new asymmetric trans-amine(azole)dichloridoplatinum complexes that overcome cisplatin resistance and their reactions with 5'-GMP.
Three new asymmetric platinum(II) complexes comprising an isopropylamine ligand trans to an azole ligand were synthesized and fully characterized by (1)H NMR, (195)Pt NMR, IR and elemental analysis. In addition the X-ray crystal structure of all three complexes was determined. The reaction kinetics of the complexes with DNA model base guanosine-5'-monophosphate (GMP) was studied, revealing reaction kinetics comparable to cisplatin. To gain insight in the complexes as potential antitumor agents, cytotoxicity assays were performed on a variety of human tumor cell lines. These assays showed the complexes all to possess cytotoxicity profiles comparable to cisplatin. Furthermore, the complexes largely retain their activity in a human ovarian carcinoma cell line resistant to cisplatin, A2780R, compared to the cisplatin sensitive parent cell line A2780. These results are of fundamental importance, illustrating how platinum complexes of trans geometry can show improved activity compared to cisplatin in both cisplatin sensitive and cisplatin resistant cell lines.
Pantoja
Elena
E
Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
Gallipoli
Agata
A
van Zutphen
Steven
S
Komeda
Seiji
S
Reddy
Desigan
D
Jaganyi
Deogratius
D
Lutz
Martin
M
Tooke
Duncan M
DM
Spek
Anthony L
AL
Navarro-Ranninger
Carmen
C
Reedijk
Jan
J
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006157:Guanosine Monophosphate / Q000737:chemistry*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D013055:Spectrophotometry, Infrared
D000970:Antineoplastic Agents; D017671:Platinum Compounds; D006157:Guanosine Monophosphate; D002945:Cisplatin