Ring-substituted [1,2-bis(4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes: compounds with a selective effect on the hormone-dependent mammary carcinoma

Karl, Johann; Gust, Ronald; Spruß, Thilo; Mr, Schneider; Schönenberger, Helmut; Engel, Juergen; Kh, Wrobel; F, Lux; St, Haeberlin

doi:10.1021/jm00396a012

Cited by 97 publications

(69 citation statements)

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“…Wheres compound I, compound II, and cisplatin inhibited cell proliferation in a dose-dependent manner, compound III was ineffective at even an extremely high (10 gmol 1-1) dose following long-term drug exposure (231 h). This observation contrasts with the results of previous studies, in which this estrogenic platinum complex displayed selective and highly reproducible inhibition of estrogen-receptor-positive, ovarian-dependent rodent breast cancers [14,29]. Cisplatin and both of the diastereoisomeric diaqua[ 1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) sulfates (compounds I and II) were equiactive at the 5-gM concentration (Fig.…”

Section: Discussioncontrasting

confidence: 95%

“…1. [14,18,24,25]. Despite the ionic nature of the diaqua(1,2-diphenylethylenediamine)platinum(II) sulfates, their water solubility is quite low because of the contribution of the large, hydrophobic neutral ligand.…”

Section: Drugsmentioning

confidence: 99%

“…Quite recently, our group has described diastereoisomeric ring-substituted (1,2-diphenylethylenediamine)platinum (II) complexes that have been highly effective against several rodent tumor models in vivo. Meso-configurated [1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) complexes exhibit hormone-like properties and have been found to produce high response rates in the hormone-sensitive rodent tumor models MXT (M 3.2) mammary carcinoma of the B6D2F1 mouse, DMBA-induced mammary carcinoma of the Sprague-Dawley rat [ 14,29], and Dunning R 3327 and Noble prostatic carcinoma of the rat [27]. Diastereoisomeric diaqua[ 1,2-bis(4-fluorophenyl)ethylenediamine]-platinum(II) salts, which lack estrogenic activity, produce strong inhibition of the ovarian-dependent MXT (M 3.2) mammary carcinoma of the B6D2F1 mouse.…”

Section: Introductionmentioning

confidence: 99%

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Chemosensitivity of human MCF-7 breast cancer cells to diastereoisomeric diaqua(1,2-diphenylethylenediamine) platinum(II) sulfates and specific platinum accumulation

Reile

Bernhardt

Koch

et al. 1992

Cancer Chemother. Pharmacol.

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Summary. Cisplatin, raceme-diaqua[1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) sulfate (compound I), meso-diaqua[ 1,2-bis(4-fluorophenyl)ethylenediamine]-platinum(II) sulfate (compound II), and meso-diaqua[1,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]platinum(II) sulfate (compound III) were compared with regard to their effect on the MCF-7 breast cancer cell line in vitro. At equimolar concentrations (5 gM), cisplatin, compound I, and compound II were equiactive after 231 h drug exposure, whereas compound III was ineffective. Although compounds I and II showed markedly greater inactivation than did cisplatin after 6 h incubation with culture medium, compound I (but not compound II) exhibited antitumor activity equivalent to that of cisplatin when cells were exposed to the drugs for 6 h. Platinum measurements by neutron-activation analysis revealed that compound I was selectively and rapidly accumulated by MCF-7 cells, resuiting in a high degree of DNA platination within the first few hours of drug exposure. However, when the drug-exposure period was long enough, platinum enrichment was not reflected in an overall difference in the cytotoxicity of compound I vs cisplatin. Nevertheless, compound I should be superior to cisplatin in vivo, provided that effective plasma levels can be maintained for about 6 h.

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Section: Discussioncontrasting

confidence: 95%

Section: Drugsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemosensitivity of human MCF-7 breast cancer cells to diastereoisomeric diaqua(1,2-diphenylethylenediamine) platinum(II) sulfates and specific platinum accumulation

Reile

Bernhardt

Koch

et al. 1992

Cancer Chemother. Pharmacol.

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“…In contrast, the Pt-Cl bond is hydrolyzed in the cytoplasm in sufficient amounts to achieve high cytotoxicity. Interestingly, the aquasulfatoplatinum(II) complexes which are rapidly transformed into the diaquaplatinum(II) form [39] were more active than the dichloroplatinum(II) complexes. This correlates very well with the findings obtained with the parent compound 4F-Ph-PtSO 4 .…”

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

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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...

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“…ethylenedia- Fig. 1, complex A) was synthesized and characterized as described by Karl et al (1988). Experimentalprotocol.…”

Section: In Vivo Studiesmentioning

confidence: 99%

Antitumour activity of miltefosine alone and after combination with platinum complexes on MXT mouse mammary carcinoma models

Spruß

Bernhardt

Schönenberger

et al. 1993

J Cancer Res Clin Oncol

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Summary.Miltefosine, an alkylphosphocholine structurally related to alkyllysophospholipids showed highly selective antitumour activity against the hormone-sensitive variant of the s.c. transplantable MXT mouse mammary adenocarcinoma, the ovary-dependent MXT (M3.2), whereas it was inactive against the hormone-insensitive MXT (M3.2) OVEX variant. A dose of 32 mg/kg miltefosine p.o. daily for 5 weeks was well tolerated. Histopathological evaluation gave no signs of gastroenteral toxicity. After therapy the microarchitecture of the MXT (M3.2) tumours changed from that of a moderately differentiated adenocarcinoma to that of an anaplastic mammary carcinoma. A dose of 16 mg/kg miltefosine p.o. daily, though in effective per se, enhanced the antitumour activity of suboptimal i.p. doses of cisplatin and the hormone-like platinum analogue [meso-l,2-bis(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II). Furthermore, it was shown, that miltefosine exhibited no (anti)hormonaI properties. However, the mechanism of action of miltefosine remains unclear.

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Ring-substituted [1,2-bis(4-hydroxyphenyl)ethylenediamine]dichloroplatinum(II) complexes: compounds with a selective effect on the hormone-dependent mammary carcinoma

Cited by 97 publications

References 3 publications

Chemosensitivity of human MCF-7 breast cancer cells to diastereoisomeric diaqua(1,2-diphenylethylenediamine) platinum(II) sulfates and specific platinum accumulation

Chemosensitivity of human MCF-7 breast cancer cells to diastereoisomeric diaqua(1,2-diphenylethylenediamine) platinum(II) sulfates and specific platinum accumulation

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

Antitumour activity of miltefosine alone and after combination with platinum complexes on MXT mouse mammary carcinoma models

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