Anja Dullin

Freie Universit├Ąt Berlin, Berlin, Land Berlin, Germany

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Publications (4)14.57 Total impact

  • Timo Kapp, Anja Dullin, Ronald Gust
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    ABSTRACT: 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).
    Bioconjugate Chemistry 02/2010; 21(2):328-37. · 4.58 Impact Factor
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    ABSTRACT: 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.
    ChemMedChem 07/2006; 1(6):644-53. · 2.84 Impact Factor
  • Timo Kapp, Anja Dullin, Ronald Gust
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    ABSTRACT: A series of mononuclear and dinuclear alkylamine derivatives of [meso-1,2-bis(4-fluorophenyl)ethylenediamine]platinum(II) (m-4F-PtL-R1 and (m-4F-PtL)2-R2; R(1) = alkylamine, R(2) = alkyldiamine, L = DMSO or Cl) as well as the DAB(PA)(4) polyimine dendrimer complex ((m-4F-PtDMSO)4DAB(PA)4; DAB(PA)4 = N,N,N',N'-tetrakis(3-aminopropyl)butane-1,4-diamine) were synthesized and tested for cytotoxicity, intracellular distribution, and DNA and protein binding. All compounds strongly bound to human serum albumin by hydrophobic and electrostatic interactions. These inactivation reactions hindered the uptake into tumor cells and prevented strong cytotoxic effects. If serum-free medium was used, a high accumulation grade in MCF-7 breast cancer cells and a high DNA binding was observed. As most efficient compound (m-4F-PtDMSO)4DAB(PA)4 was identified. It showed a 20-fold higher cellular uptake and an approximately 700-fold higher DNA binding than cisplatin.
    Journal of Medicinal Chemistry 03/2006; 49(3):1182-90. · 5.61 Impact Factor
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    ABSTRACT: Enantiomerically pure 1, 2-diamino-1-(4-fluorophenyl)butanes were synthesized by stereoselective procedures. The enantiomeric purity was determined by (1)H NMR spectroscopy after derivatization with (1R)-myrtenal. For the coordination to platinum, the diamines were reacted with K(2)PtI(4). Reaction with Ag(2)SO(4) 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: MCF-7: (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).
    Archiv der Pharmazie 12/2004; 337(12):654-67. · 1.54 Impact Factor