Influence of ring substituents on the antitumor effect of dichloro(1,2-diphenylethylenediamine)platinum(II) complexes

Jennerwein, Margaretha; Wappes, B.; Gust, Ronald; Schönenberger, Helmut; Engel, Jürgen; Seeber, S.; Osieka, R.

doi:10.1007/bf02128177

Cited by 40 publications

(29 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It could be shown, that the activity against cisplatin-resistance tumors depends on the nature and position of ring substituents and also on the ligand configuration [25]. Resuming this work, we developed 1,2-diamino-1-arylalkanes as neutral ligands for platinum(II) complexes [8].…”

Section: Discussionmentioning

confidence: 99%

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

Dufrasne

Gelbcke

Schnurr

et al. 2002

Arch. Pharm. Pharm. Med. Chem.

Self Cite

View full text Add to dashboard Cite

Enantiomerically pure 1, 2‐diamino‐1‐(4‐fluorophenyl)propanes were synthesized by stereospecific and stereoselective procedures by use of the (1R, 2S)‐ and (1S, 2R)‐2‐amino‐1‐(4‐fluorophenyl)propanols (12a) as intermediates. The enantiomeric purity was determined by 1H NMR spectroscopy after conversion of the propanolamines and the diamines with (1R)‐myrtenal into mono‐ and diimines. For the coordination to platinum the diamines were reacted with K2PtCl4. The resulting dichloroplatinum(II) complexes 4F‐Ph/Me‐PtCl2 were tested for antiproliferative activity on the MCF‐7 breast cancer cell line. (SS)‐ and (RR)‐4F‐Ph/Me‐PtCl2 produced the strongest inhibitory effect. Both complexes showed cytocidal effects, (SS)‐4F‐Ph/Me‐PtCl2 even in a concentration of 1 μM. The (1S, 2R)‐ and (1R, 2S)‐configurated complexes were far less active (SS > RR > RS = SR) and comparable in this respect with the standard cisplatin.

show abstract

Section: Discussionmentioning

confidence: 99%

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

Dufrasne

Gelbcke

Schnurr

et al. 2002

Arch. Pharm. Pharm. Med. Chem.

Self Cite

View full text Add to dashboard Cite

show abstract

“…It was demonstrated in various pharmacological studies that the complexes possessed high antiproliferative effects against MCF-7 and MDA-MB 231 breast cancer cells and were also active on the LnCaP/FGC prostate cancer cell line [30,31]. The R,R/S,S-configurated compound was by far more active than its diastereomer.…”

Section: Discussionmentioning

confidence: 99%

Enantiomerically Pure [1, 2‐Diamino‐1‐(4‐fluorophenyl)butane]platinum(II) Complexes: Synthesis and Antitumor Activity against MCF‐7 and MDA‐MB 231 Breast Cancer and LnCaP/FGC Prostate Cancer Cell Lines

Dullin

Dufrasne

Gelbcke

et al. 2004

Archiv der Pharmazie

Self Cite

View full text Add to dashboard Cite

Germany b Laboratoire de ChimieEnantiomerically pure 1,2-diamino-1-(4-fluorophenyl)butanes were synthesized Pharmaceutique Organique, by stereoselective procedures. The enantiomeric purity was determined by 1 H Institut de Pharmacie, NMR spectroscopy after derivatization with (1R)-myrtenal. For the coordination Université Libre de Bruxelles, to platinum, the diamines were reacted with K 2 PtI 4 . Reaction with Ag 2 SO 4 Bruxelles, Belgium yielded the respective sulfatoplatinum(II) complexes, which were converted into the dichloroplatinum(II) complexes by treatment with 2 N HCl. The influence of the configuration and the kind of leaving group on the antitumor activity was studied on the MCF-7 and MDA-MB 231 breast cancer cell lines, as well as on the LnCaP/FGC prostate cancer cell line. It was demonstrated that the dichloroplatinum(II) complexes were more active than the respective diiodoplatinum(II) derivatives. Conversion into the sulfatoplatinum(II) complexes further enhanced the antiproliferative effects. The configuration determined the antitumor effects, dependent on the cell line used: : (R,R) > (S,S) > (R,S) > (S,R); MDA-MB 231: (S,S) > (R,R) > (R,S) = (S,R); LnCaP/FGC: (S,S) > (R,R) > (R,S) > (S,R). Keywords IntroductionSince the discovery of the cytotoxicity of platinum complexes by Rosenberg et al. [1], numerous diaminedichloroplatinum(II) complexes have been synthesized and tested for antitumor activity.Cisplatin exhibits high antitumor activity, but its clinical use is mostly limited by toxic side effects [2]. Exchange of both chlorides by cyclobutane-1,1-dicarboxylate led to carboplatin, which showed higher water solubility and reduced toxic side effects; however, myelosuppression and the development of resistance are intolerable disadvantages [3].In order to overcome these drawbacks and to enhance the tumor selectivity, many carrier ligands were developed and coordinated to platinum. The most successful ligand, the 1,2-diaminocyclohexane (DACH), made oxaliplatin to the first platinum-based drug licensed for the therapy of colorectal cancer [4]. It has also shown The cytotoxic potency of Ph/Me-PtCl 2 decreased in the series (R,R) > (S,S) > (S,R) = (R,S), while in the case of 4F-Ph/Me-PtCl 2 , the S,S-enantiomer is more active than its isomers.Because of these studies, we focussed our attention on the 4-F derivatives and determined the influence of the elongation of the C2-alkyl chain (methyl Ǟ ethyl), as well as the significance of the leaving groups, on Scheme 2. Synthesis of 1R,2R-configurated 1,2-diamino-1-(4-fluorophenyl)butanes. Reagents and conditions: a: BOC anhydride (1.1 eq.), TEA (1.1 eq.), CH 2 Cl 2 , O°C to room temperature; b: DMSO (2 eq.), oxalyl chloride (1 eq.), TEA (5 eq.), CH 2 Cl 2 , Ϫ60°C; c: benzylhydroxylamine (1 eq.), MgSO 4 (1 eq.), CH 2 Cl 2 , room temperature; d: 4F-phenylmagnesium bromide (3 eq.), THF, Ϫ50°C; e: column chromatography, petroleum ether ( Results SynthesisThe 1S Using the (2S)-2-aminobutanol (2S)-1, diamine (1S,2S)-13 was available.The optical purity of th...

show abstract

“…An alternative route to obtain the 12-ethanediamines from the 1,2-diazidoethanes is shown in Scheme 4; mesol 19 An alternative way to unsymmetrically phenyl-substituted 1,2-diaryl-1,2-ethanediamines is shown in Scheme 5. The reduction of 1-(4-methoxypheny1)-2-phenylethanone oxime (20) with LiAlH4 in absol.…”

Section: (3)mentioning

confidence: 99%

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

et al. 1991

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Influence of ring substituents on the antitumor effect of dichloro(1,2-diphenylethylenediamine)platinum(II) complexes

Cited by 40 publications

References 13 publications

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

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

Enantiomerically Pure [1, 2‐Diamino‐1‐(4‐fluorophenyl)butane]platinum(II) Complexes: Synthesis and Antitumor Activity against MCF‐7 and MDA‐MB 231 Breast Cancer and LnCaP/FGC Prostate Cancer Cell Lines

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

Contact Info

Product

Resources

About