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, Anja; Dufrasne, François; Gelbcke, Michel; Gust, Ronald

doi:10.1002/ardp.200400621

Cited by 19 publications

(19 citation statements)

References 43 publications

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“…The same enantioselectivity was observed for the erythro compounds: (R,S)-4F-Ph/Et-PtCl 2 was more active than (S,R)-4F-Ph/Et-PtCl 2 . [11] The lack of enhancement of the cytotoxicity by elongation of the ethyl chain prompted us to investigate the influence of a branched isopropyl group at C2 on the antiproliferative effects. This structural modification only marginally affected the activity of the threo-configured complexes on the MCF-7 cell line ( Figure 2) but was of great significance for their effects on the MDA-MB 231 cell line (Figure 4).…”

Section: Structural Characterizationmentioning

confidence: 99%

“…[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%

“…&R,R > S,S > R,S > S,R. [11,12] Our aim now is to optimize cytotoxic potency with the use of branched C2-alkyl chains. Herein, we report the synthesis of enantiomerically pure [1,2-diamino-1-(4-fluorophenyl)-3-methylbutane]platinum(II) complexes and their antiproliferative effects on the MCF-7 and MDA-MB 231 breast cancer cell lines as well as on the LNCaP/FGC prostate cancer cell line.…”

Section: Introductionmentioning

confidence: 99%

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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: Structural Characterizationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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 complexes (labeled 4-10 in Fig. 1) have been synthesized using the methods we detailed previously (16)(17)(18)(19). Briefly, the diamines have been obtained starting from diversely substituted benzaldehyde derivatives and through the hydrocyanation of their corresponding imines followed by the reduction of the nitrile (21).…”

Section: Methodsmentioning

confidence: 99%

“…Our group has already synthesized various Pt(II) complexes structurally related to 1-phenyl-alkane-1,2-diamines (Fig. 1); those substituted by a fluorine atom at position 4 of the aromatic ring display significant anticancer activity in vitro (16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Fourier Transform Infrared (FTIR) spectroscopy to monitor the cellular impact of newly synthesized platinum derivatives

Berger

Gasper²,

Lamoral-Theys³

et al. 2010

Int J Oncol

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Abstract. Platinum complexes remain widely used to combat various types of cancers. Three platinum complexes, cisplatin, carboplatin and oxaliplatin, are marketed for various oncological purposes. Additionally, nedaplatin, lobaplatin and heptaplatin have gained regionally limited approval for oncology purposes. Furthermore, various platinum derivatives are currently under clinical trials. More than 40 years after their discovery, however, the precise mechanism of action of platinum antitumor complexes remains elusive, partly because these compounds display numerous intracellular targets. Structure-activity-relationship analyses are therefore difficult to conduct to optimize the synthesis of novel platinum derivatives. The aim of the present study is to illustrate the potential of using Fourier Transform Infrared (FTIR) analyses to monitor the cellular modifications induced by the new platinum derivatives that we have synthesized. We show in the present study the advantages of combining an in vitro assay to determine the IC 50 growth inhibition concentrations of a series of compounds belonging to a given chemical series and FTIR analyses carried out at the IC 50 concentrations for each compound to identify potential hits within this series of compounds. The original pharmacological approach proposed here could, therefore, avoid large-scale pharmacological experiments to find hits within a given chemical series.

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Stereospecific Diaza‐Cope Rearrangement Driven by Steric Strain

et al. 2008

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Vögtle and Goldschmitt [1] were the first to use hydrogen bonds to drive diaza-Cope rearrangement reactions to completion over thirty years ago. Although many interesting publications on the topic have since appeared, [2] no other weak forces have been found to drive the rearrangement reaction to completion. The diaza-Cope rearrangement is useful for synthesizing a wide variety of chiral vicinal diamines (Scheme 1) [3] that may be valuable for the development of catalysts [4] and drugs. [2,5] [3,3] Sigmatropic reactions, including the Cope, Claisen, oxy-Cope, and aza-Cope reactions, have received much interest on both a theoretical [6] and a practical [7] level. The diaza-Cope rearrangement provides an ideal platform for studying the effects of weak forces in [3,3] sigmatropic reactions, as the systematic variation in the structure of the starting materials that is needed for these investigations can be achieved readily through simple synthesis. It is well known that strained molecules show remarkable reactivity. [8] Herein, we report the effect of steric strain on the rate and equilibrium constants of the diaza-Cope rearrangement reaction. Although ring strain has been used to drive [3,3] sigmatropic rearrangements, [1a, 9] this reaction is the first example of a [3,3] sigmatropic rearrangement driven by steric strain.We prepared (S,S)-1,2-bis(2,4,6-trimethylphenyl)-1,2-diaminoethane (TPEN) [10] through the diaza-Cope rearrangement of the diimine formed from (R,R)-1,2-bis(2-hydroxyphenyl)-1,2-diaminoethane (HPEN) and mesitaldehyde. [3] The addition of benzaldehydes (2.5 equiv) with electrondonating or electron-withdrawing substituents to (S,S)-1,2bis(2,4,6-trimethylphenyl)-1,2-diaminoethane in ethanol and subsequent stirring of the reaction mixture overnight at ambient temperature gave the corresponding rearranged diimines 1 b-3 b in good yields (80-85 %). The identity of products 1 b-3 b of the rearrangement reaction was confirmed by comparing their 1 H NMR spectra with those of the diimines prepared from the corresponding diamines and mesitaldehyde. Although the initial diimines 1 a-3 a were not isolated, their clean formation (d H = 5.6 ppm for 3 a, Figure 1) and conversion into the product diimines (d H = 4.8 ppm for 3 b) could be monitored readily by 1 H NMR spectroscopy. The equilibrium constants for the rearrangement reactions in Scheme 1 must be greater than 10 2 , as we did not observe any of the initial diimines by 1 H NMR spectroscopy after equilibration. We were pleasantly surprised that the steric effect was so dramatic and complete for the rearrangement reactions (Figure 1). Figure 2 a shows the crystal structure of 1 b formed through the rearrangement of 1 a. [11] This structure is "preorganized" [3c] for the reversible rearrangement reaction and resembles the computed transition-state (TS) structure for the rearrangement of 3 a (Figure 2 b). [12] We investigated the effect of steric strain on the rate and equilibrium constants for the rearrangement of 3 a to 3 b by DFT computation (...

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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

Cited by 19 publications

References 43 publications

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

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

Fourier Transform Infrared (FTIR) spectroscopy to monitor the cellular impact of newly synthesized platinum derivatives

Stereospecific Diaza‐Cope Rearrangement Driven by Steric Strain

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