Comparison of chemical reactivity, cytotoxicity, interstrand cross-linking and DNA sequence specificity of bis(platinum) complexes containing monodentate or bidentate coordination spheres with their monomeric analogues.
The properties of a new bis(platinum) complex containing two monodentate coordination spheres, [(trans-PtCl(NH3)2)2H2N(CH2)4NH2]Cl2 (1,1/t,t), are reported. Comparison is made with respect to chemical reactivity, in vitro biological activity in murine and tumor cells, DNA conformational changes, cross-linking efficiency, and sequence specificity between this complex and the previously reported complex containing two bidentate platinum atoms, [(Pt(mal)(NH3))2H2N(CH2)4NH2] (2,2/c,c), as well as with their respective monomeric analogues, [PtCl(dien)]Cl and cis-[PtCl2(NH3)2](cis-DDP). While both bis(platinum) complexes are active against cis-DDP-resistant cells, the monodentate bis(platinum) complex (1,1/t,t) has a lower resistance factor than the complex with bidentate coordination spheres (2,2/c,c). More importantly, this property is repeated in a human ovarian carcinoma cell line. DNA-binding studies show that DNA interstrand cross-linking is more efficient for the 1,1/t,t complex. DNA sequencing studies employing the exonuclease activity of T4-polymerase demonstrate that there are a variety of binding sites; some are common to all complexes and some common to both bis(platinum) complexes, while the monodentate 1,1/t,t species also reacts at unique sites, not attacked by any of the other complexes studied. The circular dichroism of CT DNA modified by the 1,1/t,t complex is also unique and is not seen for any of the other agents.
Farrell
N
N
Department of Chemistry, University of Vermont, Burlington 05405.
Qu
Y
Y
Feng
L
L
Van Houten
B
B
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry*; D004706:Endodeoxyribonucleases / Q000378:metabolism; D029968:Escherichia coli Proteins; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010984:Platinum / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D029968:Escherichia coli Proteins; D010984:Platinum; D004247:DNA; D004706:Endodeoxyribonucleases; C036385:endodeoxyribonuclease uvrABC