Water-soluble platinum(II) complexes of diamine chelating ligands bearing amino-acid type substituents: the effect of the linked amino acid and the diamine chelate ring size on antitumor activity, and interactions with 5'-GMP and DNA.
Six new Pt(II) complexes are described having the general formula PtCl(2)(LL), in which LL is a chelating diamine ligand bearing an amino acid as substituent. The amino acids chosen are l-alanine and its methyl ester, and l-phenylalanine. The compounds have been characterized using analytical and spectroscopic methods. The influence on the biological properties of the size of the chelate ring and the structure of the amino acid substituent has been studied. The effect of the presence of a carboxylic or carboxylate group on the amino acid C-terminus has also been determined. It is demonstrated by circular dichroism (CD) that the effect on the secondary structure of DNA induced by the six complexes differ from each other. In all cases, the interaction takes place at the N7 position of the purine bases, as shown by NMR monitoring. The general behavior of these platinum complexes, with one exception, is to uncoil the DNA from the B form to the C form. The interactions with 5'-GMP and DNA have been compared with their expected antitumour activity. The complexes with l-alanine and l-phenylalanine exhibit cytotoxic activity in HeLa and HL-60 cell lines, in a dose- and time-dependent manner. No cytotoxic activity of the methyl ester derivatives have been determined because of their low solubility in aqueous solution.
Moradell
Silvia
S
Departament de Química, Area de Química Inorgànica, Facultat de Ciències, Universitat de Girona, Av. Montilivi s/n, 17071 Girona, Spain.
Lorenzo
Julia
J
Rovira
Ana
A
van Zutphen
Steven
S
Avilés
Francesc X
FX
Moreno
Virtudes
V
de Llorens
Rafael
R
Martinez
M Angeles
MA
Reedijk
Jan
J
Llobet
Antoni
A
D000596:Amino Acids; D004247:DNA / Q000737:chemistry*; D003959:Diamines; D006157:Guanosine Monophosphate / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
D000596:Amino Acids; D003959:Diamines; D009944:Organoplatinum Compounds; D014867:Water; D006157:Guanosine Monophosphate; D004247:DNA