Platinum(II) compounds with chelating ligands based on pyridine and pyrimidine: DNA and protein binding studies.
Four Pt(II) compounds (C1-C4) have been studied in their DNA and protein binding. The compounds contain chelating diimine ligands bis(pyridine-2-yl)amine, abbreviated dpa, and bis(pyrimidine-2-yl)amine, abbreviated dipm. The anions for the compounds C1 and C3 are chloride (coordinated) and nitrate (non-coordinated) for C2 and C4. Calf-thymus DNA and an abundant plasma protein have been taken as models for the two major targets for metallodrug interactions investigated by CD spectroscopy. The modifications in the carrier ligands (chloride or ammine) or ancillary secondary amines have been considered to reveal the mode of interactions. The simultaneous effects of coordinative binding and partial intercalation to DNA are evident from several spectroscopic studies. To evaluate the permeability of the cytoplasmic and cellular membrane and the transportation inside the cells, partition coefficients of the four platinum compounds were determined. Two compounds (C3 and C4) induce two-step single-strand DNA cleavage, initiated by partial intercalation. The combined effect of several binding modes towards different bio-molecules is elucidated, providing a rationale for their in vitro activity profile.
Roy
Sudeshna
S
Leiden Institute of Chemistry, Leiden University, The Netherlands.
Westmaas
Joyce A
JA
Hagen
Katharine D
KD
van Wezel
Gilles P
GP
Reedijk
Jan
J
D002614:Chelating Agents / Q000378:metabolism* / Q000494:pharmacology; D002942:Circular Dichroism; D004247:DNA / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded / Q000187:drug effects; D004278:DNA, Superhelical / Q000378:metabolism; D015195:Drug Design; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D008024:Ligands; D009944:Organoplatinum Compounds / Q000378:metabolism* / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D012710:Serum Albumin, Bovine / Q000378:metabolism; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D017186:Titrimetry
D002614:Chelating Agents; D004278:DNA, Superhelical; D007202:Indicators and Reagents; D008024:Ligands; D009944:Organoplatinum Compounds; D012710:Serum Albumin, Bovine; D004247:DNA; C427203:calf thymus DNA