Ring‐substituted diaqua(1,2‐diphenylethylenediamine)platinum(II) sulfate reacts with DNA through a dissociable complex

Abstract

Ring-substituted diaqua( 1,2-diphenylethylenediamine)platinurn(II) sulfate shows unusual kinetics in its reaction with salmon testis DNA. The mechanism for diaqua[meso-l,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) sulfate, [Pt(H,O>,]~ +SO:-, a representative of this series, has been investigated and compared with that for ~i s -[ P t ( N H~)~( H , 0 )~1~+ .Reactions were followed by atomic absorption, analytical HPLC of Pt-DNA digests, arrest of enzymatic DNA synthesis/degradation, ultraviolet and fluorescence spectrophotometry. Except for the formation of monofunctional DNA adducts, the kinetics of the platinum(I1) complexes are comparable. The pseudo-first-order rate constant for the attack of DNA by [Pt(H20),(meso-6)]'+ follows the concentration of DNA in a hyperbolic fashion, which is in contrast to the linear dependence for cis-[Pt(NH3)2(H20)2]2+. The hyperbolic dependence is typical for a dissociable DNA/drug complex preceding the coordination reaction. By studying the binding of free ligand to DNA, and by correlating ligand structures and electrostatic charges with effects on adduct formation, both the phenyl residues and the positive charge of the platinum(I1) complex are shown to be crucial for the stability of the dissociable complex. A non-intercalative mode of binding to the DNA backbone is suggested. At the high concentrations of DNA found in cell nuclei, the reaction of the dissociable complex can, principally, become rate-limiting in the attack of DNA and thus reduce the cytotoxic efficiency of a drug.Cis-diamminedichloroplatinum(I1) (cisplatin) displays anticancer activity against tumors of human testis, ovarian, bladder or head and neck [I]. However, side effects such as nephrotoxicity [2] and the frequent development of cisplatin resistance are major obstacles to curative therapy (for a recent review see [3]). The drug diaqua[meso-I ,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) sulfate, [Pt(H2-O),(mes0-6)]~ 'SO:-, was designed to overcome this disadvantage. It belongs to a family of compounds derived from dichloroethylenediamineplatinum(II), [PtClz(en)], the ringsubstituted [ 1,2-diphenylethylenediamine]platinum(II) complexes, and was designed to bind to estrogen receptor. This binding activity is supposed to direct the platinum complex to estrogen-positive tumor cells [4 -61.The main cellular target of cisplatin is assumed to be DNA. The formation of DNA adducts is supposed to cause inhibition of cell growth and finally cell death. After prolonged Abbreviations. Cisplatin, cis-diamminedichloroplatinum(I1); en, ethylenediamine; meso-6, meso-1,2-bis(2,6-dichloro-5-hydroxypheny1)ethylenediamine ; meso-4F, meso-l,2-bis(4-fluorophenyl)ethylenediamine; rac-4F, rac-I ,2-bis(4-fluorophenyl)ethylenediamine; meso-H, meso-l,2-diphenylethylenediamine; meso-20H, meso-I ,2-bis(2-hydroxypheny1)ethylenediamine; rac-20H, rac-1,2-bis(2-hydroxypheny1)ethylenediamine.Enzymes. Alkaline phosphatase (EC 3.1.3.1); BenzonaseTM deoxyribonuclease I (EC 3.1.21.1); DNA polymerase (EC...

Synthesis and Antitumor Activity of Enantiomerically Pure [1, 2-Diamino-1-(4-fluorophenyl) propane]dichloroplatinum(II) Complexes

“…In a first series of platinum(II) complexes with ligands such as 1,2-diamino-1,2-diphenylethanes [11,12,[23][24][25][26], 1,2-diamino-1-phenylpropane [8], 1,2-diamino-3-phenylpropanes [27], 2-picoline [28] or 1-(2-aminophenyl)isoquinolines [29], it was postulated that this kind of compounds should be more strongly bound to DNA, possibly by intercalating the aromatic rings between the DNA bases.This theory was later reconsidered [30] when it was proved that aromatic groups cause a steric hindrance during the attachment to the DNA bases. Although the precise mechanism of action of platinum(II) complexes still remains imperfectly known, two facts seem well established: (i) Platinum(II) complexes bind to DNA without dissociation of their neutral ligand [6], and (ii) fixation of the complexes induces changes in the conformation of DNA [31] and inhibits DNA polymerase which in turn inhibits DNA duplication and transcription, and finally cell replication [32,33].…”

Synthesis and Cytotoxicity of Enantiomerically Pure [1,2‐Diamino‐1‐(4‐fluorophenyl)‐3‐methylbutane]platinum(II) Complexes

“…[9] This negative result was not predictable because asymmetric DNA was identified as a target of (R,R/S,S)-4F-Ph/4-Ph-PtCl 2 . [17] The mode of&ok?& DNA attack should be identical for the enantiomers, resulting in diastereomeric adducts with the chiral DNA that should form intrastrand cross links with different kinetics. However, this last step in the reaction with the target seems to be identical for the enantiomers.…”

Platinum Complexes as Anticancer Agents

“…Schonenberger et al presented antitumor active (1,2-diphenylethylenediamine)-platinum (II) complex compounds [113]. Ring-substituted diaqua(1,2-diphenylethylenediamine)platinum(II) sulfate was prepared [114] and mode of binding to the DNA was studied. [1,2-bis(4-hydroxyphenyl)ethylenediamine] dichloroplatinum (II) complexes with one substituent in the 2-position (CH 3 , CF 3 , F, Cl, Br, I: meso-and d,l-1-PtCl 2 , meso-(3-5)-PtCl 2 , meso-(7 and 8)-PtCl 2 ) or two substituents in the 2,6-positions (CH 3 , Cl: meso-2-PtCl 2 , meso-and d,l-6-PtCl 2 ) in both benzene rings were synthesized and tested for estrogenic and cytotoxic activities [115].…”