A set of polyamidoamine dendrimers were modified in such a way that they are able to act as carrier and drug delivery systems for cytostatics. The terminal binding of the non-proteinogenic D,L-2,3-diaminopropionic acid allowed the attachment of the cytotoxic PtX(2) moiety (X = Cl, I: A(PtI(2))(2), A(PtCl(2))(2), B(PtI(2))(2), B(PtCl(2))(2)), while the 2-carboxypentanedioic acid acted as leaving group for [meso-1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) ((m-4F-Pt)(3)C, (m-4F-Pt)(3)D). Poly(ethylene glycol) chains at C(PtI(2))(3) and C(PtCl(2))(3) as well as (m-4F-Pt)(3)C and (m-4F-Pt)(3)D mediated sufficient water solubility. Additional dansyl residues (B(PtI(2))(2) and (m-4F-Pt)(3)D) made a simultaneous determination of platinum (graphite furnace atomic absorption spectroscopy (GF-AAS)) and dendrimer (fluorimetry) possible. The ethylenediamine-terminated dendrimers were typically accumulated into MCF-7 cells in clathrin-dependent pathways and targeted the platinum moieties to the nuclear compartment. The highest intracellular platinum concentration and DNA binding caused the dendrimers A(PtX(2))(2) and B(PtX(2))(2). A coordinative DNA binding, however, is very unlikely because of low cytotoxic effects. (m-4F-Pt)(3)C and (m-4F-Pt)(3)D are labile conjugates and liberated the m-4F-Pt moiety in biological systems. The effects of these dendrimers were similar to that of the reference compounds m-4F-PtCl(2) and m-4F-Pt(H(2)O)(2).
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...
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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