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

Dufrasne, François; Gelbcke, Michel; Schnurr, Beate; Gust, Ronald

doi:10.1002/1521-4184(200205)335:5<229::aid-ardp229>3.0.co;2-q

Cited by 16 publications

(12 citation statements)

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“…[9] In an earlier study, we demonstrated the increase of in vitro cytotoxicity by the exchange of one 4-fluorophenyl residue with a methyl (4F-Ph/Me-PtCl 2 ), ethyl (4F-Ph/Et-PtCl 2 ) or propyl group (4F-Ph/ Prop-PtCl 2 ). [10][11][12] Interestingly, the C2-methyl substituent led to different cytotoxic effects of the threo isomers: S,S > R,R > S,R = R,S. [10] Elongation of the side chain in the erythro series with one or two methylene groups also produced this effect: &ok?…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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A series of leaving group derivatives of enantiomerically pure [1,2‐diamino‐1‐(4‐fluorophenyl)‐3‐methylbutane]platinum(II) complexes were synthesized and tested for cytotoxicity. The enantiomeric purity was determined by 1H NMR spectroscopy on the final diamines after derivation with (1R)‐myrtenal. For coordination to platinum, the diamines were reacted with K2PtI4. The treatment of diiodoplatinum(II) complexes (4F‐Ph/iProp‐PtI2) with Ag2SO4 resulted in the sulfatoplatinum(II) complexes (4F‐Ph/iProp‐PtSO4), which can be easily transformed to dichloroplatinum(II) complexes (4F‐Ph/iProp‐PtCl2) with 2 n HCl. The importance of the leaving groups and the configuration at the diamine ligand on the antiproliferative effects was evaluated on the hormone‐dependent MCF‐7 and the hormone‐independent MDA‐MB 231 breast cancer cell lines as well as the LNCaP/FGC prostate cancer cell line. (R,R)‐4F‐Ph/iProp‐PtCl2 was identified as the most active platinum(II) complex. The 3‐methyl group increased antiproliferative effects relative to the [1,2‐diamino‐1‐(4‐fluorophenyl)butane]platinum(II) complexes described in an earlier study.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…The investigations presented in this paper continue the structure activity relationship study on [1,2-diamino-1-(4-fluorophenyl)ethane]dichloroplatinum(II) complexes [16,17] The 4F-Ph-PtCl 2 complexes are cisplatin derivatives with high selectivity for mammary carcinoma cells [30].…”

Section: Discussionmentioning

confidence: 56%

“…Therefore, we tried to optimize the antiproliferative activity by exchanging a 4-fluorophenyl moiety for an alkyl chain. In a previously published SAR study [16,17], we demonstrated a marginal loss of cytotoxicity for the MCF- The antitumor activity was determined, besides the asymmetric C-atoms, by the kind of leaving group. It is expected that after the transport into the cytoplasm, the platinum complexes hydrolize into the aqua-and the diaquaplatinum(II) complexes, which then bind to nucleobases [35].…”

Section: Discussionmentioning

confidence: 79%

“…Therefore, we tried to optimize the antiproliferative activity by exchanging a 4-fluorophenyl moiety for an alkyl chain. In a previously published SAR study [16,17] It should be noted that the antitumor activity depended on the kind of cells used in the in vitro assays. The 4F-Ph/Et-PtCl 2 complexes showed the highest activity against LnCaP/FGC prostate cancer cells, superior to cisplatin.…”

Section: Discussionmentioning

confidence: 99%

“…To get more insight into the structural dependence of enantiomerically pure [1,2-diaminoethane]dichloroplatinum(II) complexes, we determined the antiproliferative effects of [1,2-diamino-1-phenylpropane]dichloroplatinum(II) (Ph/Me-PtCl 2 ) and [1,2-diamino-1-(4-fluorophenyl)propane]dichloroplatinum(II) (4F-Ph/MePtCl 2 ) isomers on the MCF-7 cell line [16,17].…”

Section: Introductionmentioning

confidence: 99%

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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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