The tumor-inhibiting effect of isomeric dichloro(diphenylethylenediamine)platinum(II) complexes

Wappes, B.; Jennerwein, Margaretha; Angerer, Erwin von; Engel, Jürgen; Schönenberger, Helmut; Brunner, Henri; Schmidt, Monika; Berger, Massimo; Schmäh, D.; Seeber, S.

doi:10.1007/bf00395485

Cited by 25 publications

(4 citation statements)

References 24 publications

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“…25,26 Particularly, it has been reported that optically pure (1,2-diarylethane-1,2-diamine)dichloroplatinum(II) complexes induce significant inhibitory effects on the growth of leukemic and tumor cells, and a distinctly better effect was generally observed with the R,R/S,S configurations compared with the R,S counterparts. [27][28][29][30] These results motivated us to apply the findings from platinum(II) complexes to iridium(III) complexes. In this manuscript, we report the synthesis of novel dichlorobis[enantiopure 1,2-diarylethane-1,2-diamine]iridium(III) chlorides (general formula see Graphic Abstract) and their antiproliferative effects on a panel of representative human solid tumor cell lines.…”

Section: Introductionmentioning

confidence: 89%

Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands

Yang

Chang

Song

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Section: Introductionmentioning

confidence: 89%

Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands

Yang

Chang

Song

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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“…The platinum(I1) complexes (as sulfates) diaqua(rneso-1,2-diphenylethylenediamine)platinum(II) [ [Pt(H20)2(rac-20H)]2+ were synthesized according to [4][5][6][12][13][14] and were gifts of Dr. Schonenberger (Regensburg, FRG). Cisplatin was a gift of Degussa (Frankfurt, FRG).…”

Section: Methodsmentioning

confidence: 99%

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

Bernges¹,

Holler²

1992

European Journal of Biochemistry

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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...

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“…This drastic reduction method was unsuccessful for the 1,2-diaryl-1,2-diazidoethanes substituted in ortho and para position. By means of catalytic hydrogenation threo-l-(2-methoxyphenyl)-2-phenyl-1,2-ethanediamine (9) was obtained free of byproducts and in high yields (Scheme 1, method A).…”

Section: (3)mentioning

confidence: 99%

Stereoisomeric Dichloro[1‐(hydroxyphenyl)‐2‐phenyl‐1,2‐ethanediamine]platinum(II) Complexes, Part I: Synthesis

et al. 1991

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Various erythro-and threo-configurated dichloro[l-(hydroxyphenyl)-2-phenyl-l,2-ethanediamine]platinum(II) complexes were synthesized with the hydroxy group located in either the 2-, 3-, or 4-position of the phenyl ring (38-40). The diastereoisomeric 1-(3-hydroxyphenyl)-2-phenyl-1,2-ethanediamines (31, 32) and threo-l-(2-hydroxyphenyl)-2-phenyl-1,2-ethanediamine (30) were obtained by reduction of the 1,2-diazidoethanes and subsequent ether cleavage. The configuration of the threo-1,2-diazido-l-(2-methoxyphenyl)-2-phenylethane (5) was elucidated by X-ray analysis. The reduction of the erythro-1,2-diaryl-l,2-diazidoethanes, substituted with a methoxy group in ortho or para position, results in elimination reactions with formation of side products. The desired 1,2-diaryl-l,2-ethanediamines were finally synthesized via either an aziridine derivative 21 or by reduction of the respective dioximes 27, 28. The diamine ligands were converted into the corresponding dichloroplatinum(II) complexes 38 -40.The antitumor activity') of cisplatin [cis-diamminedichloroplatinum(II)] is well established for the treatment of a variety of tumors such as cancers of the ovaries and testes as well as solid tumors of the head and neck2). In spite of the high response rate of 63% of the ovarian carcinoma the overall survival times remain short ' ). In many cases a relapse occurs within two years. The regrowing tumor usually responds poorly to another therapy with cisplatin4). A variety of mechanisms is discussed to explain the incidence of resistance. A P-glycoprotein which accelerates the drug efflux from the cell is responsible for the multidrug resistance against many lipophilic anticancer compounds 'I. Drugs forming adducts with the DNA like alkylating agents or platinum complexes are not affected by this multidrug resistance6). The current literature contains discussions of several characteristic properties of tumor cells resistant to cisplatin. For example, increased intracellular levels of peptides and proteins containing thiol or thioether groups can deactivate platinum compounds. Furthermore, an increased DNA-repair activity or a lowered uptake of the drug into the cell may be responsible for the resistance (for references see Canon et al.')). Much effort has been made in developing platinum compounds with a specific action in cisplatin-resistant tumor models. The results indicate that a chelating diamine ligand is essential for the antitumor action [e.g. 1,2-diaminocyclohexane, 1,1 -bis(aminomethyl)cyclohexane] *). In earlier publications we described the synthesis and testing of a series of (1,2-diaryl-l,2-ethanediamine)platinum(II) complexes in various cisplatin-resistant tumor modelsy-").( )-Dichloro( 1,2-diphenyl-1,2-ethanediamine)platinum(II) as well as compounds which were hydroxy-substituted in both phenyl rings showed antitumor action in these models. ( )-[ 1,2-Bis(2-hydroxyphenyl)-1,2-ethanediamine]dichloro-platinum(I1) produced marked inhibitory effects on the cisplatin-resistant Ehrlich ascites tumor (70% of the tumorbe...

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The tumor-inhibiting effect of isomeric dichloro(diphenylethylenediamine)platinum(II) complexes

Cited by 25 publications

References 24 publications

Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands

Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands

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

Stereoisomeric Dichloro[1‐(hydroxyphenyl)‐2‐phenyl‐1,2‐ethanediamine]platinum(II) Complexes, Part I: Synthesis

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